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Meral R, Celik Guler M, Kaba D, Prativadi J, Frontera ED, Foss-Freitas MC, Nachawi N, Broome DT, Lightbourne M, Brown RJ, Taylor SI, Oral EA. Metabolic Improvements With Tirzepatide in Lipodystrophy: A Novel Option? Diabetes Care 2025; 48:756-762. [PMID: 40063619 PMCID: PMC12034899 DOI: 10.2337/dc24-2408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Accepted: 02/04/2025] [Indexed: 03/19/2025]
Abstract
OBJECTIVE Lipodystrophy encompasses a group of rare disorders associated with severe metabolic disease. These disorders are defined by abnormal fat distribution, with near-total (generalized lipodystrophy [GL]) or partial (partial lipodystrophy [PL]; e.g., familial partial lipodystrophy [FPLD]) absence of adipocyte mass, leading to a decreased ability to store lipids safely. Excess lipids are more likely to be stored in nonadipose tissues, which leads to the metabolic manifestations. We have recently shown that glucagon-like peptide-1 agonists are associated with metabolic improvements in FPLD. Here, we hypothesize that tirzepatide, a dual incretin, may also lead to metabolic improvement in patients with lipodystrophy. RESEARCH DESIGN AND METHODS An observational cohort of patients with lipodystrophy who received tirzepatide clinically were tracked in the context of ongoing natural history studies. RESULTS Seventeen patients received tirzepatide, 14 who had FPLD (aged 30-74 years; n = 12 female and 2 male). After a median 8.7 months of follow-up, the following were significantly reduced: BMI (median difference, -1.7; range, -5.9 to 0.9 kg/m2; P = 0.008), HbA1c (median difference, -1.1%; range, -6.3% to -0.1%; P < 0.001), triglycerides (median difference, -65 mg/dL [-0.73 mmol/L]; range, -3,820 to 43 mg/dL [-43.2 to 0.49 mmol/L]; P = 0.003), and total daily insulin requirements (median difference, -109; range, -315 to 0 units/day; P = 0.002). Three additional patients with rarer forms of lipodystrophy, also with robust response to tirzepatide, are also discussed (atypical PL, n = 1; acquired GL, n = 2; aged 35-64 years; all female). Side effects were limited to benign gastrointestinal symptoms. CONCLUSIONS Tirzepatide may be an effective treatment for patients with lipodystrophy.
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Affiliation(s)
- Rasimcan Meral
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI
- Institute of Graduate Studies in Health Sciences, Department of Medical Biology, Istanbul University, Istanbul, Türkiye
| | - Merve Celik Guler
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI
- Division of Internal Medicine, Dokuz Eylul University, İzmir, Türkiye
| | - Diarratou Kaba
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI
| | - Jeevitha Prativadi
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI
| | - Eric D. Frontera
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI
| | - Maria Cristina Foss-Freitas
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI
| | - Noura Nachawi
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI
| | - David T. Broome
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI
| | - Marissa Lightbourne
- Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, MD
| | - Rebecca J. Brown
- Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, MD
| | - Simeon I. Taylor
- Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland, Baltimore, MD
| | - Elif A. Oral
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI
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Hong L, Sun Y, Lu X, Xu X. Non‑high‑density lipoprotein cholesterol to high‑density lipoprotein cholesterol ratio as a biomarker for liver health: Insights from National Health and Nutrition Examination Survey data. Biomed Rep 2025; 22:61. [PMID: 39990999 PMCID: PMC11843208 DOI: 10.3892/br.2025.1939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 11/28/2024] [Indexed: 02/25/2025] Open
Abstract
The non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR), a lipid-related biomarker, remains underexplored in relation to the risk of advanced fibrosis and hepatic steatosis. The present study aimed to investigate the potential association between the NHHR and these hepatic conditions. A total of 6,907 individuals aged 20 years and older from the National Health and Nutrition Examination Survey 2017-2020 were included in the present study. Advanced fibrosis and hepatic steatosis were assessed using hepatic vibration-controlled transient elastography. Multivariate regression analysis and subgroup analysis were performed to explore the independent association between the NHHR and the presence of advanced fibrosis and hepatic steatosis. Among the 6,907 adults included in the present study (mean age, 50.56±17.21 years; 3,398 male patients and 3,509 female patients), 409 (5.92%) were diagnosed with advanced fibrosis and 3,034 (43.93%) were diagnosed with hepatic steatosis. Following multivariable adjustment (age, sex, ethnicity, education level, family income-to-poverty ratio, smoking status, alcohol use and vigorous physical activity), logistic regression analysis demonstrated that an elevated NHHR was positively associated with increased possibility for advanced fibrosis [odds ratio (OR), 1.10; 95% confidence interval (CI), 1.03-1.17; P=0.005]. The restricted cubic spline model indicated a linear dose-response association between the NHHR and advanced fibrosis. The NHHR also exhibited a significant association with a higher risk of hepatic steatosis after full adjustment for covariates (OR, 1.61; 95% CI, 1.53-1.68; P<0.001). Using a two-segment linear regression model, an S-shaped relationship was identified between the NHHR and hepatic steatosis, with an inflection point at 3.83. In conclusion, the present study established a robust association of the NHHR with advanced fibrosis and hepatic steatosis. The NHHR may serve as a straightforward anthropometric index for predicting these conditions.
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Affiliation(s)
- Liekai Hong
- Department of Cardiology, First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515000, P.R. China
| | - Yifan Sun
- Department of Cardiology, First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515000, P.R. China
| | - Xiaojia Lu
- Department of Cardiology, First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515000, P.R. China
| | - Xinwu Xu
- Department of Cardiology, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515000, P.R. China
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Ancona G. Clinical features of acquired lipodystrophy after total body irradiation: a case report and mini review. Curr Med Res Opin 2025; 41:627-637. [PMID: 40340619 DOI: 10.1080/03007995.2025.2475090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 02/21/2025] [Accepted: 02/28/2025] [Indexed: 05/10/2025]
Abstract
BACKGROUND Acquired partial lipodystrophy is a late complication of total body irradiation (TBI) performed during hematopoietic stem cell transplantation. Diagnosing this condition remains challenging due to its rarity and limited clinical awareness. Long-term patient observation is essential since this type of lipodystrophy develops more than a decade post-TBI. CASE REPORT We present a unique case of a patient with acquired lipodystrophy who underwent TBI for leukemia treatment in 2003 and was diagnosed with diabetes in 2013, but standard diabetes therapies proved ineffective. By 2018, the patient exhibited distinctive features, i.e. hirsutism, reduced lean mass, cutaneous alterations (including an umbilical psoriatic plaque), barrel chest, hepatomegaly, lipoatrophy of upper and lower limbs, acanthosis nigricans in the axillae and Cushingoid facies. In 2020, she was diagnosed with breast cancer, followed by liver, ovarian and pancreatic metastases in 2021. RESULTS In addition to this case report, we reviewed the literature on acquired lipodystrophy cases following TBI to compare their clinical features and phenotypes with those of our patient. This comparison aims to aid clinical practice by facilitating earlier diagnosis and treatment of lipodystrophy. CONCLUSION TBI can lead to acquired lipodystrophy, which is associated with severe comorbidities. Due to its diagnostic complexity, expert clinicians and a multidisciplinary approach are essential for early identification and appropriate treatment according to etiologic aspects. We hypothesize that this condition may serve as a model for studying metabolic dysfunction in fat-related diseases.
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Affiliation(s)
- Giuseppe Ancona
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
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Vakili S, Cao K. Angiopoietin-2: A Therapeutic Target for Vascular Protection in Hutchinson-Gilford Progeria Syndrome. Int J Mol Sci 2024; 25:13537. [PMID: 39769300 PMCID: PMC11676795 DOI: 10.3390/ijms252413537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 12/12/2024] [Accepted: 12/13/2024] [Indexed: 01/11/2025] Open
Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is a pediatric condition characterized by clinical features that resemble accelerated aging. The abnormal accumulation of a toxic form of the lamin A protein known as progerin disrupts cellular functions, leading to various complications, including growth retardation, loss of subcutaneous fat, abnormal skin, alopecia, osteoporosis, and progressive joint contractures. Death primarily occurs as the result of complications from progressive atherosclerosis, especially from cardiac disease, such as myocardial infarction or heart failure, or cerebrovascular disease like stroke. Despite the availability of lonafarnib, the only US Food and Drug Administration-approved treatment for HGPS, cardiovascular complications remain the leading cause of morbidity and mortality in affected patients. Defective angiogenesis-the process of forming new blood vessels from existing ones-plays a crucial role in the development of cardiovascular disease. A recent study suggests that Angiopoietin-2 (Ang2), a pro-angiogenic growth factor that regulates angiogenesis and vascular stability, may offer therapeutic potential for the treatment of HGPS. In this review, we describe the clinical features and key cellular processes impacted by progerin and discuss the therapeutic potential of Ang2 in addressing these challenges.
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Affiliation(s)
| | - Kan Cao
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA;
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Janssen JAMJL. The Causal Role of Ectopic Fat Deposition in the Pathogenesis of Metabolic Syndrome. Int J Mol Sci 2024; 25:13238. [PMID: 39769002 PMCID: PMC11675790 DOI: 10.3390/ijms252413238] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/03/2024] [Accepted: 12/08/2024] [Indexed: 01/11/2025] Open
Abstract
Consuming a "modern" Western diet and overnutrition may increase insulin secretion. Additionally, nutrition-mediated hyperinsulinemia is a major driver of ectopic fat deposition. The global prevalence of metabolic syndrome is high and growing. Within this context, people with congenital lipodystrophy often experience a severe form of metabolic syndrome. Evidence is increasingly supporting that subtle partial lipodystrophy plays an important role in the development of metabolic syndrome in the general population. In individuals in the general population with subtle partial lipodystrophy, as well as in those with congenital lipodystrophy, the subcutaneous adipose tissues are unable to accommodate surplus energy intake. In both conditions, (excess) fat is directed toward the liver, pancreas, and muscles, where it is deposited as ectopic fat, as this fat can no longer be stored in the "safe" subcutaneous fat depots. Ectopic fat depositions cause insulin resistance in the liver and muscles, as well as β-cell dysfunction in the pancreas. Support of a direct pathological role of ectopic fat deposition in this condition is further provided by the rapid normalization of hepatic insulin sensitivity and improvement in pancreatic β-cell function after marked reductions in ectopic fat depositions. Thus, ectopic fat deposition in the liver, pancreas, and muscles may play a causal role in the pathogenesis of metabolic syndrome even in the general population. As such, the prevention of ectopic fat deposition may reduce the risk of metabolic syndrome and mitigate its effects.
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Affiliation(s)
- Joseph A M J L Janssen
- Department of Internal Medicine, Erasmus Medical Center (Erasmus MC), Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands
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Fourman LT, Lima JG, Simha V, Cappa M, Alyaarubi S, Montenegro R, Akinci B, Santini F. A rapid action plan to improve diagnosis and management of lipodystrophy syndromes. Front Endocrinol (Lausanne) 2024; 15:1383318. [PMID: 38952397 PMCID: PMC11215967 DOI: 10.3389/fendo.2024.1383318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 05/13/2024] [Indexed: 07/03/2024] Open
Abstract
Introduction Lipodystrophy syndromes are rare diseases that can present with a broad range of symptoms. Delays in diagnosis are common, which in turn, may predispose to the development of severe metabolic complications and end-organ damage. Many patients with lipodystrophy syndromes are only diagnosed after significant metabolic abnormalities arise. Prompt action by clinical teams may improve disease outcomes in lipodystrophy syndromes. The aim of the Rapid Action Plan is to serve as a set of recommendations from experts that can support clinicians with limited experience in lipodystrophy syndromes. Methods The Rapid Action Plan was developed using insights gathered through a series of advisory meetings with clinical experts in lipodystrophy syndromes. A skeleton template was used to facilitate interviews. A consensus document was developed, reviewed, and approved by all experts. Results Lipodystrophy is a clinical diagnosis. The Rapid Action Plan discusses tools that can help diagnose lipodystrophy syndromes. The roles of clinical and family history, physical exam, patient and family member photos, routine blood tests, leptin levels, skinfold measurements, imaging studies, and genetic testing are explored. Additional topics such as communicating the diagnosis to the patients/families and patient referrals are covered. A set of recommendations regarding screening and monitoring for metabolic diseases and end-organ abnormalities is presented. Finally, the treatment of lipodystrophy syndromes is reviewed. Discussion The Rapid Action Plan may assist clinical teams with the prompt diagnosis and holistic work-up and management of patients with lipodystrophy syndromes, which may improve outcomes for patients with this rare disease.
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Affiliation(s)
- Lindsay T. Fourman
- Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Josivan Gomes Lima
- Hospital Universitário Onofre Lopes, Departamento de Clinica Medica, Universidade Federal do Rio Grande do Norte, Natal, Brazil
| | - Vinaya Simha
- Division of Endocrinology, Mayo Clinic, Rochester, MN, United States
| | - Marco Cappa
- Research Area for Innovative Therapies in Endocrinopathies Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Saif Alyaarubi
- Pediatric Endocrinology, Oman Medical Specialty Board, Muscat, Oman
| | - Renan Montenegro
- Brazilian Group for the Study of Inherited and Acquired Lipodystrophies (BRAZLIPO), Clinical Research Unit, Walter Cantidio University Hospital, Federal University of Ceará/Ebserh, Fortaleza, Brazil
| | - Baris Akinci
- Dokuz Eylul University Health Campus Technopark (DEPARK), Dokuz Eylul University, Izmir, Türkiye
- Department of Research Programs, Technological Research, Izmir Biomedicine and Genome Center (IBG), Izmir, Türkiye
| | - Ferruccio Santini
- Obesity and Lipodystrophy Center, Endocrinology Unit, University Hospital of Pisa, Pisa, Italy
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Zhao Y, Yue R. Aging adipose tissue, insulin resistance, and type 2 diabetes. Biogerontology 2024; 25:53-69. [PMID: 37725294 DOI: 10.1007/s10522-023-10067-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Accepted: 08/28/2023] [Indexed: 09/21/2023]
Abstract
With the increase of population aging, the prevalence of type 2 diabetes (T2D) is also rising. Aging affects the tissues and organs of the whole body, which is the result of various physiological and pathological processes. Adipose tissue has a high degree of plasticity and changes with aging. Aging changes the distribution of adipose tissue, affects adipogenesis, browning characteristics, inflammatory status and adipokine secretion, and increases lipotoxicity. These age-dependent changes in adipose tissue are an important cause of insulin resistance and T2D. Understanding adipose tissue changes can help promote healthy aging process. This review summarizes changes in adipose tissue ascribable to aging, with a focus on the role of aging adipose tissue in insulin resistance and T2D.
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Affiliation(s)
- Yixuan Zhao
- Hospital of Chengdu University of Traditional Chinese Medicine, NO. 39 Shi-Er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
| | - Rensong Yue
- Hospital of Chengdu University of Traditional Chinese Medicine, NO. 39 Shi-Er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China.
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Aliyev A, Samadov E, Ibrahimli A, Hajiyev A, Allahverdiyeva G, Ahmadov E. Liver transplantation in patient with Berardinelli-Seip syndrome: A literature review and case report. Pediatr Transplant 2024; 28:e14680. [PMID: 38149359 DOI: 10.1111/petr.14680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 10/26/2023] [Accepted: 12/07/2023] [Indexed: 12/28/2023]
Abstract
BACKGROUND Berardinelli-Seip syndrome is an infrequently seen and potentially fatal genetic disorder characterized by the absence of adipose tissue. Herein, we report a first-in-literature liver transplant done on a 7-year-old girl because of liver cirrhosis caused by the Berardinelli-Seip syndrome. CASE REPORT Physical examination showed prominent subdermal fat tissue loss and mild muscle hypertrophy, giving her a slim appearance, hirsutism, thick hair, a large head in contrast to the body, low anterior hairline, icterus, prominent facial contours, prominent mandibula, loss of buccal fat, low set ears, and large limbs. After the diagnosis, she admitted to our clinic because of variceal esophageal bleeding and increasing liver enzymes. Transplantation decision was made and orthothopic liver transplantation done by the surgery team. DISCUSSION Common causes of death in Berardinelli-Seip syndrome patients are infections and liver cirrhosis. The mean age of the patients was 27.1 at the time of death. There is no any established cure for congenital lipodystrophies so far. However, some symptomatic treatment methods are found to be helpful. The main point of the case report to be discussed is the liver transplantation done by our surgical team. There are no examples of any transplantation in Berardinelli-Seip syndrome patients, but several reports can be found of patients with kidney or liver failure. CONCLUSION Berardinelli-Seip syndrome is a rare disorder with no cure but a chance of improving lifestyle and life expectancy. The transplantation option should be considered in young patients after a multidisciplinary review.
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Li X, Ren H, Xu H, Han X, Lu J, Yang Z. Behind BMI: The Potential Indicative Role of Abdominal Ectopic Fat on Glucose Metabolism. Obes Facts 2024; 17:158-168. [PMID: 38246158 PMCID: PMC10987183 DOI: 10.1159/000536160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 01/04/2024] [Indexed: 01/23/2024] Open
Abstract
INTRODUCTION The purpose of this study was to compare the difference in abdominal fat distribution between different metabolic groups and find the ectopic fat with the most risk significance. METHODS A total of 98 subjects were enrolled; there were 53 cases in the normal glucose metabolism group and 45 cases in the abnormal glucose metabolism group. Chemical shift-encoded magnetic resonance imaging was applied for quantification of pancreatic fat fraction (PFF) and hepatic fat fraction (HFF), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT). The correlation and the difference of fat distribution between different metabolism groups were analyzed. The receiver operating characteristic (ROC) curve was used to analyze the suggestive effect of different body fat fraction. RESULTS Correlation analysis showed that body mass index (BMI) had the strongest correlation with fasting insulin (r = 0.473, p < 0.001), HOMA-IR (r = 0.363, p < 0.001), and C-reactive protein (r = 0.245, p < 0.05). Pancreatic fat has a good correlation with fasting blood glucose (r = 0.247, p < 0.05) and HbA1c (r = 0.363, p < 0.001). With the increase of BMI, PFF, VAT, and SAT showed a clear upward trend, but liver fat was distributed relatively more randomly. The pancreatic fat content in the abnormal glucose metabolism group is significantly higher than that in the normal group, and pancreatic fat is also a reliable indicator of abnormal glucose metabolism, especially in the normal and overweight groups (the area under the curve was 0.859 and 0.864, respectively). CONCLUSION MR-based fat quantification techniques can provide additional information on fat distribution. There are differences in fat distribution among people with different metabolic status. People with more severe pancreatic fat deposition have a higher risk of glucose metabolism disorders.
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Affiliation(s)
- Xiaoyang Li
- Beijing Friendship Hospital, Capital Medical University, Beijing, China,
| | - Hao Ren
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Hui Xu
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xinjun Han
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Jun Lu
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhenghan Yang
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
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Tiwari M, Mcilroy GD. From scarcity to solutions: Therapeutic strategies to restore adipose tissue functionality in rare disorders of lipodystrophy. Diabet Med 2023; 40:e15214. [PMID: 37638531 DOI: 10.1111/dme.15214] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 08/19/2023] [Accepted: 08/22/2023] [Indexed: 08/29/2023]
Abstract
AIMS Lipodystrophy is a rare disorder characterised by abnormal or deficient adipose tissue formation and distribution. It poses significant challenges to affected individuals, including the development of severe metabolic complications like diabetes and fatty liver disease. These conditions are often chronic, debilitating and life-threatening, with limited treatment options and a lack of specialised expertise. This review aims to raise awareness of lipodystrophy disorders and highlights therapeutic strategies to restore adipose tissue functionality. METHODS Extensive research has been conducted, including both historical and recent advances. We have examined and summarised the literature to provide an overview of potential strategies to restore adipose tissue functionality and treat/reverse metabolic complications in lipodystrophy disorders. RESULTS A wealth of basic and clinical research has investigated various therapeutic approaches for lipodystrophy. These include ground-breaking methods such as adipose tissue transplantation, innovative leptin replacement therapy, targeted inhibition of lipolysis and cutting-edge gene and cell therapies. Each approach shows great potential in addressing the complex challenges posed by lipodystrophy. CONCLUSIONS Lipodystrophy disorders require urgent attention and innovative treatments. Through rigorous basic and clinical research, several promising therapeutic strategies have emerged that could restore adipose tissue functionality and reverse the severe metabolic complications associated with this condition. However, further research and collaboration between academics, clinicians, patient advocacy groups and pharmaceutical companies will be crucial in transforming these scientific breakthroughs into effective and viable treatment options for individuals and families affected by lipodystrophy. Fostering such interdisciplinary partnerships could pave the way for a brighter future for those battling this debilitating disorder.
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Affiliation(s)
- Mansi Tiwari
- The Rowett Institute, University of Aberdeen, Aberdeen, UK
- Aberdeen Cardiovascular and Diabetes Centre, University of Aberdeen, Aberdeen, UK
| | - George D Mcilroy
- The Rowett Institute, University of Aberdeen, Aberdeen, UK
- Aberdeen Cardiovascular and Diabetes Centre, University of Aberdeen, Aberdeen, UK
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Cook JR, Hawkins MA, Pajvani UB. Liver insulinization as a driver of triglyceride dysmetabolism. Nat Metab 2023; 5:1101-1110. [PMID: 37460842 DOI: 10.1038/s42255-023-00843-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 06/13/2023] [Indexed: 07/26/2023]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is an increasingly prevalent fellow traveller with the insulin resistance that underlies type 2 diabetes mellitus. However, the mechanistic connection between MAFLD and impaired insulin action remains unclear. In this Perspective, we review data from humans to elucidate insulin's aetiological role in MAFLD. We focus particularly on the relative preservation of insulin's stimulation of triglyceride (TG) biosynthesis despite its waning ability to curb hepatic glucose production (HGP). To explain this apparent 'selective insulin resistance', we propose that hepatocellular processes that lead to TG accumulation require less insulin signal transduction, or 'insulinization,' than do those that regulate HGP. As such, mounting hyperinsulinaemia that barely compensates for aberrant HGP in insulin-resistant states more than suffices to maintain hepatic TG biosynthesis. Thus, even modestly elevated or context-inappropriate insulin levels, when sustained day and night within a heavily pro-lipogenic metabolic milieu, may translate into substantial cumulative TG biosynthesis in the insulin-resistant state.
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Affiliation(s)
- Joshua R Cook
- Naomi Berrie Diabetes Center, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Columbia University College of Physicians & Surgeons, New York City, NY, USA.
| | - Meredith A Hawkins
- Diabetes Research and Training Center, Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, New York City, NY, USA
| | - Utpal B Pajvani
- Naomi Berrie Diabetes Center, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Columbia University College of Physicians & Surgeons, New York City, NY, USA
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Bonnefond A, Semple RK. Achievements, prospects and challenges in precision care for monogenic insulin-deficient and insulin-resistant diabetes. Diabetologia 2022; 65:1782-1795. [PMID: 35618782 PMCID: PMC9522735 DOI: 10.1007/s00125-022-05720-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 02/01/2022] [Indexed: 01/19/2023]
Abstract
Integration of genomic and other data has begun to stratify type 2 diabetes in prognostically meaningful ways, but this has yet to impact on mainstream diabetes practice. The subgroup of diabetes caused by single gene defects thus provides the best example to date of the vision of 'precision diabetes'. Monogenic diabetes may be divided into primary pancreatic beta cell failure, and primary insulin resistance. In both groups, clear examples of genotype-selective responses to therapy have been advanced. The benign trajectory of diabetes due to pathogenic GCK mutations, and the sulfonylurea-hyperresponsiveness conferred by activating KCNJ11 or ABCC8 mutations, or loss-of-function HNF1A or HNF4A mutations, often decisively guide clinical management. In monogenic insulin-resistant diabetes, subcutaneous leptin therapy is beneficial in some severe lipodystrophy. Increasing evidence also supports use of 'obesity therapies' in lipodystrophic people even without obesity. In beta cell diabetes the main challenge is now implementation of the precision diabetes vision at scale. In monogenic insulin-resistant diabetes genotype-specific benefits are proven in far fewer patients to date, although further genotype-targeted therapies are being evaluated. The conceptual paradigm established by the insulin-resistant subgroup with 'adipose failure' may have a wider influence on precision therapy for common type 2 diabetes, however. For all forms of monogenic diabetes, population-wide genome sequencing is currently forcing reappraisal of the importance assigned to pathogenic mutations when gene sequencing is uncoupled from prior suspicion of monogenic diabetes.
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Affiliation(s)
- Amélie Bonnefond
- Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France.
- Université de Lille, Lille, France.
- Department of Metabolism, Imperial College London, London, UK.
| | - Robert K Semple
- Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
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Liu X, Huang L, Wu Q, Chen Y, Chen X, Chen H, Gao J, Xiao Q. Sleep characteristic profiles and the correlation with spectrum of metabolic syndrome among older adult: a cross-sectional study. BMC Geriatr 2022; 22:414. [PMID: 35546663 PMCID: PMC9097235 DOI: 10.1186/s12877-022-03074-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 04/20/2022] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Metabolic Syndrome (MetS) is a common health problem among older adults. Previous studies have revealed the relationship between sleep duration as well as global sleep status and MetS. OBJECTIVES This study aims to examine the association between the specific sleep characteristic and MetS as well as MetS components among community-dwelling old adults. METHODS This cross-sectional study included 1499 community residents aged ≥ 60 years. Sleep characteristics were assessed using the Pittsburgh Sleep Quality Index (PSQI) and bed/rise time of the residents. Logistic regression analysis and multiple linear regression analysis were used to examine the associations between sleep characteristics and MetS as well as MetS components. A generalized additive model was built to assess the smooth relationship between triglyceride (TG) levels and sleep duration. RESULTS Of the 1499 participants, 449 (30.0%) had MetS, and 443 (29.6%) had poor sleep quality. The rise time was found to be associated with MetS (> 6:00 vs. 5:00 ~ 6:00: adjusted OR (95%) = 1.77 (1.17-2.69), P = 0.007). For the MetS components, a U-shaped relationship was first revealed for sleep duration and TG levels (EDF = 1.85, P < 0.001). Furthermore, significant associations also included the associations of subjective sleep quality and daytime dysfunction with hypertension, the associations of sleep efficiency and rise time with hyperglycemia, the associations of rise time with TG levels, and the association of bedtime with waist circumference. CONCLUSIONS The different sleep characteristics were associated with different MetS components.
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Affiliation(s)
- Xin Liu
- Department of Preventive Medicine and Health Education, School of Public Health, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China
| | - Limei Huang
- Songjiang Center of Disease Prevention and Control, Shanghai, 201620, China
| | - Qiang Wu
- Songjiang District Xinqiao Town Community Health Service Center, Shanghai, 201600, China
| | - Yingwei Chen
- Department of Preventive Medicine and Health Education, School of Public Health, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China
| | - Xiuqin Chen
- Songjiang Center of Disease Prevention and Control, Shanghai, 201620, China
| | - Hao Chen
- Department of Preventive Medicine and Health Education, School of Public Health, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China
| | - Junling Gao
- Department of Preventive Medicine and Health Education, School of Public Health, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China.
| | - Qianyi Xiao
- Department of Preventive Medicine and Health Education, School of Public Health, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China.
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14
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Leuthardt AS, Bayer J, Monné Rodríguez JM, Boyle CN. Influence of High Energy Diet and Polygenic Predisposition for Obesity on Postpartum Health in Rat Dams. Front Physiol 2022; 12:772707. [PMID: 35222059 PMCID: PMC8867007 DOI: 10.3389/fphys.2021.772707] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 12/16/2021] [Indexed: 02/06/2023] Open
Abstract
It is estimated that 30% of pregnant women worldwide are overweight or obese, leading to adverse health effects for both mother and child. Women with obesity during pregnancy are at higher risk for developing both metabolic and mental disorders, such as diabetes and depression. Numerous studies have used rodent models of maternal obesity to understand its consequences on the offspring, yet characterization of changes in the dams is rare, and most rodent models rely solely on a high fat diet to induce maternal obesity, without regarding genetic propensity for obesity. Here we present the influence of both peripartum high energy diet (HE) and obesity-proneness on maternal health using selectively bred diet-resistant (DR) and diet-induced obese (DIO) rat dams. Outbred Sprague-Dawley rats were challenged with HE diet prior to mating and bred according to their propensity to gain weight. The original outbred breeding dams (F0) were maintained on low-fat chow during pregnancy and lactation. By comparison, the F1 dams consuming HE diet during pregnancy and lactation displayed higher gestational body weight gain (P < 0.01), and HE diet caused increased meal size and reduced meal frequency (P < 0.001). Sensitivity to the hormone amylin was preserved during pregnancy, regardless of diet. After several rounds of selective breeding, DIO and DR dams from generation F3 were provided chow or HE during pregnancy and lactation and assessed for their postpartum physiology and behaviors. We observed strong diet and phenotype effects on gestational weight gain, with DIO-HE dams gaining 119% more weight than DR-chow (P < 0.001). A high-resolution analysis of maternal behaviors did not detect main effects of diet or phenotype, but a subset of DIO dams showed delayed nursing behavior (P < 0.05). In generation F6/F7 dams, effects on gestational weight gain persisted (P < 0.01), and we observed a main effect of phenotype during a sucrose preference test (P < 0.05), with DIO-chow dams showing lower sucrose preference than DR controls (P < 0.05). Both DIO and DR dams consuming HE diet had hepatic steatosis (P < 0.001) and exhibited reduced leptin sensitivity in the arcuate nucleus (P < 0.001). These data demonstrate that both diet and genetic obesity-proneness have consequences on maternal health.
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Affiliation(s)
- Andrea S. Leuthardt
- Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
| | - Julia Bayer
- Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
| | - Josep M. Monné Rodríguez
- Laboratory for Animal Model Pathology (LAMP), Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
| | - Christina N. Boyle
- Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
- *Correspondence: Christina N. Boyle,
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15
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Vitamin D Deficiency Is Inversely Associated with Homeostatic Model Assessment of Insulin Resistance. Nutrients 2021; 13:nu13124358. [PMID: 34959910 PMCID: PMC8705502 DOI: 10.3390/nu13124358] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 11/24/2021] [Accepted: 11/25/2021] [Indexed: 01/08/2023] Open
Abstract
The study was conducted to comprehensively assess the association of the concentration of vitamin D in the blood and insulin resistance in non-diabetic subjects. The objective was to pool the results from all observational studies from the beginning of 1980 to August 2021. PubMed, Medline and Embase were systematically searched for the observational studies. Filters were used for more focused results. A total of 2248 articles were found after raw search which were narrowed down to 32 articles by the systematic selection of related articles. Homeostatic Model Assessment of Insulin Resistance (HOMAIR) was used as the measure of insulin resistance and correlation coefficient was used as a measure of the relationship between vitamin D levels and the insulin resistance. Risk of bias tables and summary plots were built using Revman software version 5.3 while Comprehensive meta-analysis version 3 was used for the construction of forest plot. The results showed an inverse association between the status of vitamin D and insulin resistance (r = -0.217; 95% CI = -0.161 to -0.272; p = 0.000). A supplement of vitamin D can help reduce the risk of insulin resistance; however further studies, like randomized controlled trials are needed to confirm the results.
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16
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Dong Y, Bai L, Cai R, Zhou J, Ding W. Children's Lipid Accumulation Product Combining Visceral Adiposity Index is a Novel Indicator for Predicting Unhealthy Metabolic Phenotype Among Chinese Children and Adolescents. Diabetes Metab Syndr Obes 2021; 14:4579-4587. [PMID: 34848982 PMCID: PMC8627249 DOI: 10.2147/dmso.s337412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 10/29/2021] [Indexed: 11/30/2022] Open
Abstract
PURPOSE The predictive capacity between children's lipid accumulation product (CLAP) combining visceral adiposity index (VAI), CLAP, and VAI with metabolically unhealthy phenotype remained unclear. This study aimed to compare the ability of CLAP combining VAI, CLAP, VAI and traditional adiposity indicators (body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR) and waist-to-hip ratio (WHR)) to predict metabolically unhealthy phenotype among Chinese children and adolescents. PATIENTS AND METHODS In the cross-sectional study, 1714 children and adolescents aged 12 to 18 were selected by random cluster sampling, underwent a questionnaire survey, physical examination, biochemical tests and body composition was measured by bioelectrical impedance analysis (BIA). Participants were divided into four phenotypes according to BMI and metabolic syndrome components. The logarithmic CLAP (LnCLAP), VAI, BMI, WC, WHtR and WHR were standardized for sex and age using the z-score method (standardized variables: LnCLAP-z, VAI-z, BMI-z, WC-z, WHtR-z and WHR-z). RESULTS LnCLAP-z ≥ 1, VAI-z ≥ 1, WC-z ≥ 1, and WHR-z ≥ 1 increased the risk of metabolically unhealthy normal-weight phenotype (the OR and 95% CI were 4.18 (1.75-10.02), 24.05 (12.79-45.21), 6.17 (1.14-33.51), 2.69 (1.07-6.72), respectively), LnCLAP-z ≥ 1, VAI-z ≥ 1 and WC-z ≥ 1 increased the risk of metabolically unhealthy overweight or obese phenotype (the OR and 95% CI were 2.67 (1.40-5.09), 10.30 (3.03-35.03), 2.19 (1.18-4.09), respectively). The area under the ROC curve (AUC) for CLAP combining VAI in the prediction of the metabolically unhealthy phenotype were 0.837 (0.776-0.899) and 0.876 (0.834-0.918) for boys and girls with normal-weight, 0.853 (0.803-0.903) and 0.794 (0.711-0.878) for boys and girls with overweight and obese (all P < 0.001), which were higher than CLAP, VAI, BMI, WC, WHtR and WHR. CONCLUSION Among Chinese children and adolescents, CLAP combining VAI was a more effective indicator than CLAP, VAI and traditional adiposity indicators in predicting unhealthy metabolic phenotype.
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Affiliation(s)
- Yangyang Dong
- School of Public Health and Management, Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China
- Key Laboratory of Environmental Factors and Chronic Disease Control, Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China
| | - Ling Bai
- School of Public Health and Management, Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China
- Key Laboratory of Environmental Factors and Chronic Disease Control, Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China
| | - Rongrong Cai
- School of Public Health and Management, Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China
- Key Laboratory of Environmental Factors and Chronic Disease Control, Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China
| | - Jinyu Zhou
- School of Public Health and Management, Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China
- Key Laboratory of Environmental Factors and Chronic Disease Control, Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China
| | - Wenqing Ding
- School of Public Health and Management, Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China
- Key Laboratory of Environmental Factors and Chronic Disease Control, Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China
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17
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Chung E, Gonzalez K, Ullevig SL, Zhang J, Umeda M. Obesity, not a high fat, high sucrose diet alone, induced glucose intolerance and cardiac dysfunction during pregnancy and postpartum. Sci Rep 2021; 11:18057. [PMID: 34508150 PMCID: PMC8433413 DOI: 10.1038/s41598-021-97336-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 08/17/2021] [Indexed: 12/25/2022] Open
Abstract
Cardiovascular disease is the leading cause of death in women during pregnancy and the postpartum period. Obesity is an independent risk factor for cardiovascular diseases. Nearly 60% of women of reproductive age are considered overweight or obese, cardiovascular disease morbidity and mortality continue to be pervasive. The objective of this study was to determine the effects of an obesogenic diet on the cardiometabolic health of dams during pregnancy and postpartum. Female mice were fed either a high-fat, high-sucrose diet (HFHS) or a refined control diet (CON) for 8 weeks before initiation of pregnancy and throughout the study period. Mice in the HFHS showed two distinct phenotypes, obesity-prone (HFHS/OP) and obesity resistance (HFHS/OR). Pre-pregnancy obesity (HFHS/OP) induced glucose intolerance before pregnancy and during postpartum. Systolic function indicated by the percent fractional shortening (%FS) was significantly decreased in the HFHS/OP at late pregnancy (vs. HFHS/OR) and weaning (vs. CON), but no differences were found at 6 weeks of postpartum among groups. No induction of pathological cardiac hypertrophy markers was found during postpartum. Plasma adiponectin was decreased while total cholesterol was increased in the HFHS/OP. Our results suggested that obesity, not the diet alone, negatively affected cardiac adaptation during pregnancy and postpartum.
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Affiliation(s)
- Eunhee Chung
- Department of Kinesiology, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX, 78249, USA.
| | - Kassandra Gonzalez
- Department of Kinesiology, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX, 78249, USA
| | - Sarah L Ullevig
- College for Health, Community and Policy, University of Texas at San Antonio, San Antonio, TX, USA
| | - John Zhang
- Department of Kinesiology, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX, 78249, USA
| | - Masataka Umeda
- Department of Kinesiology, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX, 78249, USA
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18
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Scherer T, Sakamoto K, Buettner C. Brain insulin signalling in metabolic homeostasis and disease. Nat Rev Endocrinol 2021; 17:468-483. [PMID: 34108679 DOI: 10.1038/s41574-021-00498-x] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/22/2021] [Indexed: 02/06/2023]
Abstract
Insulin signalling in the central nervous system regulates energy homeostasis by controlling metabolism in several organs and by coordinating organ crosstalk. Studies performed in rodents, non-human primates and humans over more than five decades using intracerebroventricular, direct hypothalamic or intranasal application of insulin provide evidence that brain insulin action might reduce food intake and, more importantly, regulates energy homeostasis by orchestrating nutrient partitioning. This Review discusses the metabolic pathways that are under the control of brain insulin action and explains how brain insulin resistance contributes to metabolic disease in obesity, the metabolic syndrome and type 2 diabetes mellitus.
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Affiliation(s)
- Thomas Scherer
- Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
| | - Kenichi Sakamoto
- Division of Endocrinology, Metabolism & Nutrition, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Christoph Buettner
- Division of Endocrinology, Metabolism & Nutrition, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
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19
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Najdi F, Krüger P, Djabali K. Impact of Progerin Expression on Adipogenesis in Hutchinson-Gilford Progeria Skin-Derived Precursor Cells. Cells 2021; 10:cells10071598. [PMID: 34202258 PMCID: PMC8306773 DOI: 10.3390/cells10071598] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 06/19/2021] [Accepted: 06/23/2021] [Indexed: 01/10/2023] Open
Abstract
Hutchinson–Gilford progeria syndrome (HGPS) is a segmental premature aging disease caused by a mutation in LMNA. The mutation generates a truncated and farnesylated form of prelamin A, called progerin. Affected individuals develop several features of normal aging, including lipodystrophy caused by the loss of general subcutaneous fat. To determine whether premature cellular senescence is responsible for the altered adipogenesis in patients with HGPS, we evaluated the differentiation of HGPS skin-derived precursor stem cells (SKPs) into adipocytes. The SKPs were isolated from primary human HGPS and normal fibroblast cultures, with senescence of 5 and 30%. We observed that the presence of high numbers of senescent cells reduced SKPs’ adipogenic differentiation potential. Treatment with baricitinib, a JAK–STAT inhibitor, ameliorated the ability of HGPS SKPs to differentiate into adipocytes. Our findings suggest that the development of lipodystrophy in patients with HGPS may be associated with an increased rate of cellular senescence and chronic inflammation.
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20
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Myers MG, Affinati AH, Richardson N, Schwartz MW. Central nervous system regulation of organismal energy and glucose homeostasis. Nat Metab 2021; 3:737-750. [PMID: 34158655 DOI: 10.1038/s42255-021-00408-5] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 05/12/2021] [Indexed: 02/05/2023]
Abstract
Growing evidence implicates the brain in the regulation of both immediate fuel availability (for example, circulating glucose) and long-term energy stores (that is, adipose tissue mass). Rather than viewing the adipose tissue and glucose control systems separately, we suggest that the brain systems that control them are components of a larger, highly integrated, 'fuel homeostasis' control system. This conceptual framework, along with new insights into the organization and function of distinct neuronal systems, provides a context within which to understand how metabolic homeostasis is achieved in both basal and postprandial states. We also review evidence that dysfunction of the central fuel homeostasis system contributes to the close association between obesity and type 2 diabetes, with the goal of identifying more effective treatment options for these common metabolic disorders.
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Affiliation(s)
- Martin G Myers
- Departments of Medicine and Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Alison H Affinati
- Departments of Medicine and Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Nicole Richardson
- UW Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Michael W Schwartz
- UW Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, WA, USA.
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21
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Rafiq S, Jeppesen PB. Insulin Resistance Is Inversely Associated with the Status of Vitamin D in Both Diabetic and Non-Diabetic Populations. Nutrients 2021; 13:1742. [PMID: 34063822 PMCID: PMC8224049 DOI: 10.3390/nu13061742] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/11/2021] [Accepted: 05/17/2021] [Indexed: 02/06/2023] Open
Abstract
Vitamin D has been implicated in the regulation of glucose metabolism and insulin resistance. We designed this study to provide evidence that insulin resistance is dependent on the concentration of vitamin D in the body. Forty observational studies of both type 2 diabetes mellitus patients and healthy subjects were included in this meta-analysis. Related articles were searched from Embase, PubMed, and Medline through January 2021. Filters for search were used to obtain more focused results. We used Comprehensive Meta-Analysis Version 3 for the construction of forest plots. RevMan software version 5.3 was used to build the risk of bias tables and summary plots. The observational studies included in this systematic review and meta-analysis showed an inverse relationship of insulin resistance with the status of vitamin D both in non-diabetic (r = -0.188; 95% CI = -0.141 to -0.234; p = 0.000) and diabetic (r = -0.255; 95% CI = -0.392 to -0.107, p = 0.001) populations. From the meta-analysis we concluded that hypovitaminosis D is related to increased levels of insulin resistance in both type 2 diabetes patients and the healthy population all over the world.
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Affiliation(s)
- Shamaila Rafiq
- Department of Clinical Medicine, Aarhus University, Aarhus N, 8200 Aarhus, Denmark;
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22
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Huesing C, Qualls‐Creekmore E, Lee N, François M, Torres H, Zhang R, Burk DH, Yu S, Morrison CD, Berthoud H, Neuhuber W, Münzberg H. Sympathetic innervation of inguinal white adipose tissue in the mouse. J Comp Neurol 2021; 529:1465-1485. [PMID: 32935348 PMCID: PMC7960575 DOI: 10.1002/cne.25031] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 09/08/2020] [Accepted: 09/09/2020] [Indexed: 12/24/2022]
Abstract
Adipose tissue plays an important role in metabolic homeostasis and its prominent role as endocrine organ is now well recognized. Adipose tissue is controlled via the sympathetic nervous system (SNS). New viral, molecular-genetic tools will soon allow a more detailed study of adipose tissue innervation in metabolic function, yet, the precise anatomical extent of preganglionic and postganglionic inputs to the inguinal white adipose tissue (iWAT) is limited. Furthermore, several viral, molecular-genetic tools will require the use of cre/loxP mouse models, while the available studies on sympathetic iWAT innervation were established in larger species. In this study, we generated a detailed map for the sympathetic innervation of iWAT in male and female mice. We adapted iDISCO tissue clearing to process large, whole-body specimens for an unprecedented view of the natural abdominal SNS. Combined with pseudorabies virus retrograde tracing from the iWAT, we defined the preganglionic and postganglionic sympathetic input to iWAT. We used fluorescence-guided anatomical dissections of sympathetic nerves in reporter mice to further clarify that postganglionic axons connect to iWAT via lateral cutaneous rami (dorsolumbar iWAT portion) and the lumbar plexus (inguinal iWAT portion). Importantly, these rami carry axons that branch to iWAT, as well as axons that travel further to innervate the skin and vasculature, and their functional impact will require consideration in denervation studies. Our study may serve as a comprehensive map for future experiments that employ virally driven neuromodulation techniques to predict anatomy-based viral labeling.
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Affiliation(s)
- Clara Huesing
- Neurobiology of Nutrition and Metabolism DepartmentPennington Biomedical Research Center, Louisiana State University SystemBaton RougeLouisianaUSA
| | - Emily Qualls‐Creekmore
- Neurobiology of Nutrition and Metabolism DepartmentPennington Biomedical Research Center, Louisiana State University SystemBaton RougeLouisianaUSA
| | - Nathan Lee
- Neurobiology of Nutrition and Metabolism DepartmentPennington Biomedical Research Center, Louisiana State University SystemBaton RougeLouisianaUSA
| | - Marie François
- Neurobiology of Nutrition and Metabolism DepartmentPennington Biomedical Research Center, Louisiana State University SystemBaton RougeLouisianaUSA
| | - Hayden Torres
- Neurobiology of Nutrition and Metabolism DepartmentPennington Biomedical Research Center, Louisiana State University SystemBaton RougeLouisianaUSA
| | - Rui Zhang
- Neurobiology of Nutrition and Metabolism DepartmentPennington Biomedical Research Center, Louisiana State University SystemBaton RougeLouisianaUSA
| | - David H. Burk
- Neurobiology of Nutrition and Metabolism DepartmentPennington Biomedical Research Center, Louisiana State University SystemBaton RougeLouisianaUSA
| | - Sangho Yu
- Neurobiology of Nutrition and Metabolism DepartmentPennington Biomedical Research Center, Louisiana State University SystemBaton RougeLouisianaUSA
| | - Christopher D. Morrison
- Neurobiology of Nutrition and Metabolism DepartmentPennington Biomedical Research Center, Louisiana State University SystemBaton RougeLouisianaUSA
| | - Hans‐Rudolf Berthoud
- Neurobiology of Nutrition and Metabolism DepartmentPennington Biomedical Research Center, Louisiana State University SystemBaton RougeLouisianaUSA
| | - Winfried Neuhuber
- Institute for Anatomy and Cell Biology, Friedrich‐Alexander UniversityErlangenGermany
| | - Heike Münzberg
- Neurobiology of Nutrition and Metabolism DepartmentPennington Biomedical Research Center, Louisiana State University SystemBaton RougeLouisianaUSA
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Abstract
Leptin is a pluripotent peptide hormone produced mainly by adipocytes, as well as by other tissues such as the stomach. Leptin primarily acts on the central nervous system, particularly the hypothalamus, where this hormone regulates energy homeostasis and neuroendocrine function. Owing to this, disruption of leptin signaling has been linked with numerous pathological conditions. Recent studies have also highlighted the diverse roles of leptin in the digestive system including immune regulation, cell proliferation, tissue healing, and glucose metabolism. Of note, leptin acts differently under physiological and pathological conditions. Here, we review the current knowledge on the functions of leptin and its downstream signaling in the gastrointestinal tract and accessory digestive organs, with an emphasis on its physiological and pathological implications. We also discuss the current therapeutic uses of recombinant leptin, as well as its limitations.
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Affiliation(s)
- Min-Hyun Kim
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Hyeyoung Kim
- Department of Food and Nutrition, College of Human Ecology, Yonsei University, Seoul, Korea
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24
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Shrestha N, Vidimce J, Holland OJ, Cuffe JSM, Beck BR, Perkins AV, McAinch AJ, Hryciw DH. Maternal and Postnatal High Linoleic Acid Diet Impacts Lipid Metabolism in Adult Rat Offspring in a Sex-Specific Manner. Int J Mol Sci 2021; 22:ijms22062946. [PMID: 33799409 PMCID: PMC7999727 DOI: 10.3390/ijms22062946] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 03/08/2021] [Accepted: 03/12/2021] [Indexed: 02/07/2023] Open
Abstract
Linoleic acid (LA), an n-6 polyunsaturated fatty acid (PUFA), is essential for fetal growth and development. We aimed to investigate the effect of maternal and postnatal high LA (HLA) diet on plasma FA composition, plasma and hepatic lipids and genes involved in lipid metabolism in the liver of adult offspring. Female rats were fed with low LA (LLA; 1.44% LA) or HLA (6.21% LA) diets for 10 weeks before pregnancy, and during gestation/lactation. Offspring were weaned at postnatal day 25 (PN25), fed either LLA or HLA diets and sacrificed at PN180. Postnatal HLA diet decreased circulating total n-3 PUFA and alpha-linolenic acid (ALA), while increased total n-6 PUFA, LA and arachidonic acid (AA) in both male and female offspring. Maternal HLA diet increased circulating leptin in female offspring, but not in males. Maternal HLA diet decreased circulating adiponectin in males. Postnatal HLA diet significantly decreased aspartate transaminase (AST) in females and downregulated total cholesterol, HDL-cholesterol and triglycerides in the plasma of males. Maternal HLA diet downregulated the hepatic mRNA expression of Hmgcr in both male and female offspring and decreased the hepatic mRNA expression of Cpt1a and Acox1 in females. Both maternal and postnatal HLA diet decreased hepatic mRNA expression of Cyp27a1 in females. Postnatal diet significantly altered circulating fatty acid concentrations, with sex-specific differences in genes that control lipid metabolism in the adult offspring following exposure to high LA diet in utero.
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Affiliation(s)
- Nirajan Shrestha
- School of Medical Science, Griffith University, Gold Coast, QLD 4222, Australia; (N.S.); (J.V.); (O.J.H.); (A.V.P.)
| | - Josif Vidimce
- School of Medical Science, Griffith University, Gold Coast, QLD 4222, Australia; (N.S.); (J.V.); (O.J.H.); (A.V.P.)
| | - Olivia J. Holland
- School of Medical Science, Griffith University, Gold Coast, QLD 4222, Australia; (N.S.); (J.V.); (O.J.H.); (A.V.P.)
- Institute of Health and Biomedical Innovation, Queensland University of Technology, South Brisbane, QLD 4001, Australia
| | - James S. M. Cuffe
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia;
| | - Belinda R. Beck
- Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD 4222, Australia;
- School of Allied Health Sciences, Griffith University, Gold Coast, QLD 4222, Australia
| | - Anthony V. Perkins
- School of Medical Science, Griffith University, Gold Coast, QLD 4222, Australia; (N.S.); (J.V.); (O.J.H.); (A.V.P.)
| | - Andrew J. McAinch
- Institute for Health and Sport, Victoria University, Melbourne, VIC 8001, Australia;
- Australian Institute for Musculoskeletal Science (AIMSS), Victoria University, St. Albans, VIC 3021, Australia
| | - Deanne H. Hryciw
- Institute for Health and Sport, Victoria University, Melbourne, VIC 8001, Australia;
- School of Environment and Science, Griffith University, Nathan, QLD 4111, Australia
- Environmental Futures Research Institute, Griffith University, Nathan, QLD 4111, Australia
- Correspondence:
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Abstract
Severe insulin resistance syndromes are a heterogeneous group of rare disorders characterized by profound insulin resistance, substantial metabolic abnormalities, and a variety of clinical manifestations and complications. The etiology of these syndromes may be hereditary or acquired, due to defects in insulin potency and action, cellular responsiveness to insulin, and/or aberrations in adipose tissue function or development. Over the past decades, advances in medical technology, particularly in genomic technologies and genetic analyses, have provided insights into the underlying pathophysiological pathways and facilitated the more precise identification of several of these conditions. However, the exact cellular and molecular mechanisms of insulin resistance have not yet been fully elucidated for all syndromes. Moreover, in clinical practice, many of the syndromes are often misdiagnosed or underdiagnosed. The majority of these disorders associate with an increased risk of severe complications and mortality; thus, early identification and personalized clinical management are of the essence. This Review aims to categorize severe insulin resistance syndromes by disease process, including insulin receptor defects, signaling defects, and lipodystrophies. We also highlight several complex syndromes and emphasize the need to identify patients, investigate underlying disease mechanisms, and develop specific treatment regimens.
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Affiliation(s)
- Angeliki M. Angelidi
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Andreas Filippaios
- Department of Medicine, Lowell General Hospital, Lowell, Massachusetts, USA
| | - Christos S. Mantzoros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
- Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts, USA
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Sekizkardes H, Chung ST, Chacko S, Haymond MW, Startzell M, Walter M, Walter PJ, Lightbourne M, Brown RJ. Free fatty acid processing diverges in human pathologic insulin resistance conditions. J Clin Invest 2021; 130:3592-3602. [PMID: 32191645 DOI: 10.1172/jci135431] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 03/17/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUNDPostreceptor insulin resistance (IR) is associated with hyperglycemia and hepatic steatosis. However, receptor-level IR (e.g., insulin receptor pathogenic variants, INSR) causes hyperglycemia without steatosis. We examined 4 pathologic conditions of IR in humans to examine pathways controlling lipid metabolism and gluconeogenesis.METHODSCross-sectional study of severe receptor IR (INSR, n = 7) versus postreceptor IR that was severe (lipodystrophy, n = 14), moderate (type 2 diabetes, n = 9), or mild (obesity, n = 8). Lipolysis (glycerol turnover), hepatic glucose production (HGP), gluconeogenesis (deuterium incorporation from body water into glucose), hepatic triglyceride (magnetic resonance spectroscopy), and hepatic fat oxidation (plasma β-hydroxybutyrate) were measured.RESULTSLipolysis was 2- to 3-fold higher in INSR versus all other groups, and HGP was 2-fold higher in INSR and lipodystrophy versus type 2 diabetes and obesity (P < 0.001), suggesting severe adipose and hepatic IR. INSR subjects had a higher contribution of gluconeogenesis to HGP, approximately 77%, versus 52% to 59% in other groups (P = 0.0001). Despite high lipolysis, INSR subjects had low hepatic triglycerides (0.5% [interquartile range 0.1%-0.5%]), in contrast to lipodystrophy (10.6% [interquartile range 2.8%-17.1%], P < 0.0001). β-hydroxybutyrate was 2- to 7-fold higher in INSR versus all other groups (P < 0.0001), consistent with higher hepatic fat oxidation.CONCLUSIONThese data support a key pathogenic role of adipose tissue IR to increase glycerol and FFA availability to the liver in both receptor and postreceptor IR. However, the fate of FFA diverges in these populations. In receptor-level IR, FFA oxidation drives gluconeogenesis rather than being reesterified to triglyceride. In contrast, in postreceptor IR, FFA contributes to both gluconeogenesis and hepatic steatosis.TRIAL REGISTRATIONClinicalTrials.gov NCT01778556, NCT00001987, and NCT02457897.FUNDINGNational Institute of Diabetes and Digestive and Kidney Diseases, US Department of Agriculture/Agricultural Research Service 58-3092-5-001.
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Affiliation(s)
| | - Stephanie Therese Chung
- National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Shaji Chacko
- Children's Nutrition Research Center, Department of Pediatrics, US Department of Agriculture/Agricultural Research Service, Baylor College of Medicine, Houston, Texas, USA
| | - Morey W Haymond
- Children's Nutrition Research Center, Department of Pediatrics, US Department of Agriculture/Agricultural Research Service, Baylor College of Medicine, Houston, Texas, USA
| | - Megan Startzell
- National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Mary Walter
- National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Peter J Walter
- National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | | | - Rebecca J Brown
- National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
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Lee J, Kim B, Kim W, Ahn C, Choi HY, Kim JG, Kim J, Shin H, Kang JG, Moon S. Lipid indices as simple and clinically useful surrogate markers for insulin resistance in the U.S. population. Sci Rep 2021; 11:2366. [PMID: 33504930 PMCID: PMC7840900 DOI: 10.1038/s41598-021-82053-2] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 12/08/2020] [Indexed: 01/30/2023] Open
Abstract
This study aimed to compare the accuracy of novel lipid indices, including the visceral adiposity index (VAI), lipid accumulation product (LAP), triglycerides and glucose (TyG) index, TyG-body mass index (TyG-BMI), and TyG-waist circumference (TyG-WC), in identifying insulin resistance and establish valid cutoff values. This cross-sectional study used the data of 11,378 adults, derived from the United States National Health and Nutrition Examination Survey (1999-2016). Insulin resistance was defined as a homeostasis model assessment-insulin resistance value above the 75th percentile for each sex and race/ethnicities. The area under the curves (AUCs) were as follows: VAI, 0.735; LAP, 0.796; TyG index, 0.723; TyG-BMI, 0.823, and; TyG-WC, 0.822. The AUCs for TyG-BMI and TyG-WC were significantly higher than those for VAI, LAP, and TyG index (vs. TyG-BMI, p < 0.001; vs. TyG-WC, p < 0.001). The cutoff values were as follows: VAI: men 1.65, women 1.65; LAP: men 42.5, women 42.5; TyG index: men 4.665, women 4.575; TyG-BMI: men 135.5, women 135.5; and TyG-WC: men 461.5, women 440.5. Given that lipid indices can be easily calculated with routine laboratory tests, these values may be useful markers for insulin resistance risk assessments in clinical settings.
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Affiliation(s)
- Juncheol Lee
- grid.413897.00000 0004 0624 2238Department of Emergency Medicine, Armed Forces Capital Hospital, Seongnam, Republic of Korea
| | - Bongyoung Kim
- grid.49606.3d0000 0001 1364 9317Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Wonhee Kim
- grid.256753.00000 0004 0470 5964Department of Emergency Medicine, Hallym University, Chuncheon, Republic of Korea
| | - Chiwon Ahn
- grid.254224.70000 0001 0789 9563Department of Emergency Medicine, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Hyun Young Choi
- grid.256753.00000 0004 0470 5964Department of Emergency Medicine, Hallym University, Chuncheon, Republic of Korea
| | - Jae Guk Kim
- grid.256753.00000 0004 0470 5964Department of Emergency Medicine, Hallym University, Chuncheon, Republic of Korea
| | - Jihoon Kim
- grid.256753.00000 0004 0470 5964Department of Thoracic and Cardiovascular Surgery, Hallym University College of Medicine, Chuncheon, Republic of Korea
| | - Hyungoo Shin
- grid.412145.70000 0004 0647 3212Department of Emergency Medicine, College of Medicine, Hanyang University Guri Hospital, Guri, Republic of Korea
| | - Jun Goo Kang
- grid.256753.00000 0004 0470 5964Department of Internal Medicine, Hallym University, Chuncheon, Republic of Korea ,grid.256753.00000 0004 0470 5964Division of Endocrinology and Metabolism, Hallym University College of Medicine, 1, Hallymdaehak-gil, Chuncheon-si, Gangwon-do 24252 Republic of Korea
| | - Shinje Moon
- grid.256753.00000 0004 0470 5964Department of Internal Medicine, Hallym University, Chuncheon, Republic of Korea ,grid.256753.00000 0004 0470 5964Division of Endocrinology and Metabolism, Hallym University College of Medicine, 1, Hallymdaehak-gil, Chuncheon-si, Gangwon-do 24252 Republic of Korea
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Goossens GH, Jocken JWE, Blaak EE. Sexual dimorphism in cardiometabolic health: the role of adipose tissue, muscle and liver. Nat Rev Endocrinol 2021; 17:47-66. [PMID: 33173188 DOI: 10.1038/s41574-020-00431-8] [Citation(s) in RCA: 200] [Impact Index Per Article: 50.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/02/2020] [Indexed: 12/11/2022]
Abstract
Obesity is associated with many adverse health effects, such as an increased cardiometabolic risk. Despite higher adiposity for a given BMI, premenopausal women are at lower risk of cardiometabolic disease than men of the same age. This cardiometabolic advantage in women seems to disappear after the menopause or when type 2 diabetes mellitus develops. Sexual dimorphism in substrate supply and utilization, deposition of excess lipids and mobilization of stored lipids in various key metabolic organs (such as adipose tissue, skeletal muscle and the liver) are associated with differences in tissue-specific insulin sensitivity and cardiometabolic risk profiles between men and women. Moreover, lifestyle-related factors and epigenetic and genetic mechanisms seem to affect metabolic complications and disease risk in a sex-specific manner. This Review provides insight into sexual dimorphism in adipose tissue distribution, adipose tissue, skeletal muscle and liver substrate metabolism and tissue-specific insulin sensitivity in humans, as well as the underlying mechanisms, and addresses the effect of these sex differences on cardiometabolic health. Additionally, this Review highlights the implications of sexual dimorphism in the pathophysiology of obesity-related cardiometabolic risk for the development of sex-specific prevention and treatment strategies.
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Affiliation(s)
- Gijs H Goossens
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, Netherlands.
| | - Johan W E Jocken
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, Netherlands
| | - Ellen E Blaak
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, Netherlands.
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29
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Shen Y, Chen W, Han L, Bian Q, Fan J, Cao Z, Jin X, Ding T, Xian Z, Guo Z, Zhang W, Ju D, Mei X. VEGF-B antibody and interleukin-22 fusion protein ameliorates diabetic nephropathy through inhibiting lipid accumulation and inflammatory responses. Acta Pharm Sin B 2021; 11:127-142. [PMID: 33532185 PMCID: PMC7838033 DOI: 10.1016/j.apsb.2020.07.002] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 06/13/2020] [Accepted: 07/02/2020] [Indexed: 01/17/2023] Open
Abstract
Diabetic nephropathy (DN) is considered the primary causes of end-stage renal disease (ESRD) and is related to abnormal glycolipid metabolism, hemodynamic abnormalities, oxidative stress and chronic inflammation. Antagonism of vascular endothelial growth factor B (VEGF-B) could efficiently ameliorate DN by reducing renal lipotoxicity. However, this pharmacological strategy is far from satisfactory, as it ignores numerous pathogenic factors, including anomalous reactive oxygen species (ROS) generation and inflammatory responses. We found that the upregulation of VEGF-B and downregulation of interleukin-22 (IL-22) among DN patients were significantly associated with the progression of DN. Thus, we hypothesized that a combination of a VEGF-B antibody and IL-22 could protect against DN not only by regulating glycolipid metabolism but also by reducing the accumulation of inflammation and ROS. To meet these challenges, a novel anti-VEGFB/IL22 fusion protein was developed, and its therapeutic effects on DN were further studied. We found that the anti-VEGFB/IL22 fusion protein reduced renal lipid accumulation by inhibiting the expression of fatty acid transport proteins and ameliorated inflammatory responses via the inhibition of renal oxidative stress and mitochondrial dysfunction. Moreover, the fusion protein could also improve diabetic kidney disease by increasing insulin sensitivity. Collectively, our findings indicate that the bifunctional VEGF-B antibody and IL-22 fusion protein could improve the progression of DN, which highlighted a novel therapeutic approach to DN.
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Key Words
- ACR, urine albumin-to-creatinine ratio
- ADFP, adipocyte differentiation-related protein
- AGEs, advanced glycation end products
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- BUN, blood urea nitrogen
- Ccr, creatinine clearance rate
- DN, diabetic nephropathy
- Diabetic nephropathy
- ECM, extracellular matrix
- ESRD, end-stage renal disease
- FA, fatty acid
- FATPs, fatty acid transport proteins
- Fusion protein
- GBM, glomerular basement membrane
- GSEA, gene set enrichment analysis
- H&E, hematoxylin & eosin
- HbA1c%, glycosylated hemoglobin
- IL-22, interleukin-22
- Interleukin-22
- KEGG, Kyoto Encyclopedia of Genes and Genomes
- NAC, N-acetyl-l-cysteine
- NLRP3, NOD-like receptor family pyrin domain-containing protein 3
- NRP-1, neuropilin-1
- PAS, periodic acid-Schiff
- ROS, reactive oxygen species
- SDS-PAGE, SDS-polyacrylamide gel electrophoresis
- TEM, transmission electron microscopy
- VEGF-B, vascular endothelial growth factor B
- VEGFR, vascular endothelial growth factor receptor
- Vascular endothelial growth factor B
- eGFR, estimated glomerular filtration rate
- β2-MG, β2 microglobulin
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Affiliation(s)
- Yilan Shen
- Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Wei Chen
- Department of Biological Medicines, Fudan University School of Pharmacy, Shanghai 201203, China
- Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
| | - Lei Han
- Department of Biological Medicines, Fudan University School of Pharmacy, Shanghai 201203, China
| | - Qi Bian
- Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Jiajun Fan
- Department of Biological Medicines, Fudan University School of Pharmacy, Shanghai 201203, China
| | - Zhonglian Cao
- Department of Biological Medicines, Fudan University School of Pharmacy, Shanghai 201203, China
| | - Xin Jin
- Department of Biological Medicines, Fudan University School of Pharmacy, Shanghai 201203, China
| | - Tao Ding
- Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Zongshu Xian
- Department of Biological Medicines, Fudan University School of Pharmacy, Shanghai 201203, China
| | - Zhiyong Guo
- Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Wei Zhang
- Department of Nephrology, Shanghai Yangpu Hospital of TCM, Shanghai 200090, China
| | - Dianwen Ju
- Department of Biological Medicines, Fudan University School of Pharmacy, Shanghai 201203, China
- Corresponding authors. Tel.: +86 21 31161407 (Xiaobin Mei), +86 21 51980037 (Dianwen Ju).
| | - Xiaobin Mei
- Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
- Corresponding authors. Tel.: +86 21 31161407 (Xiaobin Mei), +86 21 51980037 (Dianwen Ju).
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Lambadiari V, Kountouri A, Maratou E, Liatis S, Dimitriadis GD, Karpe F. Case Report: Metreleptin Treatment in a Patient With a Novel Mutation for Familial Partial Lipodystrophy Type 3, Presenting With Uncontrolled Diabetes and Insulin Resistance. Front Endocrinol (Lausanne) 2021; 12:684182. [PMID: 34168618 PMCID: PMC8217860 DOI: 10.3389/fendo.2021.684182] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 05/18/2021] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Familial partial lipodystrophy type 3 (FPLD3) is a very rare autosomal dominant genetic disorder which is caused by mutations in the peroxisome proliferator activated receptor gamma (PPARG) gene. It is characterized by a partial loss of adipose tissue leading to subnormal leptin secretion and metabolic complications. Metreleptin, a synthetic analogue of human leptin, is an effective treatment for generalized lipodystrophies, but the evidence for efficacy in patients with FPLD3 is scarce. CASE PRESENTATION We present a 61-year-old woman, initially misdiagnosed as type 1 diabetes since the age of 29, with severe insulin resistance, who gradually displayed a more generalized form of lipoatrophy and extreme hypertriglyceridemia, hypertension and multiple manifestations of cardiovascular disease. She was found to carry a novel mutation leading to PPARGGlu157Gly variant. After six months of metreleptin treatment, HbA1c decreased from 10 to 7.9% and fasting plasma triglycerides were dramatically reduced from 2.919 mg/dl to 198 mg/dl. CONCLUSIONS This case highlights the importance of early recognition of FPLD syndromes otherwise frequently observed as difficult-to-classify and manages diabetes cases, in order to prevent cardiovascular complications. Metreleptin may be an effective treatment for FPLD3.
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Affiliation(s)
- Vaia Lambadiari
- Second Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece
- *Correspondence: Vaia Lambadiari,
| | - Aikaterini Kountouri
- Second Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece
| | - Eirini Maratou
- Department of Clinical Biochemistry, Medical School, National and Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece
| | - Stavros Liatis
- First Department of Propaedeutic and Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - George D. Dimitriadis
- Medical School, Sector of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Fredrik Karpe
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford and National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), Oxford University Hospital Trusts, Oxford, United Kingdom
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Zammouri J, Vatier C, Capel E, Auclair M, Storey-London C, Bismuth E, Mosbah H, Donadille B, Janmaat S, Fève B, Jéru I, Vigouroux C. Molecular and Cellular Bases of Lipodystrophy Syndromes. Front Endocrinol (Lausanne) 2021; 12:803189. [PMID: 35046902 PMCID: PMC8763341 DOI: 10.3389/fendo.2021.803189] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 12/09/2021] [Indexed: 12/14/2022] Open
Abstract
Lipodystrophy syndromes are rare diseases originating from a generalized or partial loss of adipose tissue. Adipose tissue dysfunction results from heterogeneous genetic or acquired causes, but leads to similar metabolic complications with insulin resistance, diabetes, hypertriglyceridemia, nonalcoholic fatty liver disease, dysfunctions of the gonadotropic axis and endocrine defects of adipose tissue with leptin and adiponectin deficiency. Diagnosis, based on clinical and metabolic investigations, and on genetic analyses, is of major importance to adapt medical care and genetic counseling. Molecular and cellular bases of these syndromes involve, among others, altered adipocyte differentiation, structure and/or regulation of the adipocyte lipid droplet, and/or premature cellular senescence. Lipodystrophy syndromes frequently present as systemic diseases with multi-tissue involvement. After an update on the main molecular bases and clinical forms of lipodystrophy, we will focus on topics that have recently emerged in the field. We will discuss the links between lipodystrophy and premature ageing and/or immuno-inflammatory aggressions of adipose tissue, as well as the relationships between lipomatosis and lipodystrophy. Finally, the indications of substitutive therapy with metreleptin, an analog of leptin, which is approved in Europe and USA, will be discussed.
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Affiliation(s)
- Jamila Zammouri
- Sorbonne University, Inserm UMR_S 938, Saint-Antoine Research Centre, Cardiometabolism and Nutrition University Hospital Institute (ICAN), Paris, France
| | - Camille Vatier
- Sorbonne University, Inserm UMR_S 938, Saint-Antoine Research Centre, Cardiometabolism and Nutrition University Hospital Institute (ICAN), Paris, France
- Endocrinology Department, Assistance Publique-Hôpitaux de Paris, Saint-Antoine Hospital, National Reference Centre for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), Paris, France
| | - Emilie Capel
- Sorbonne University, Inserm UMR_S 938, Saint-Antoine Research Centre, Cardiometabolism and Nutrition University Hospital Institute (ICAN), Paris, France
| | - Martine Auclair
- Sorbonne University, Inserm UMR_S 938, Saint-Antoine Research Centre, Cardiometabolism and Nutrition University Hospital Institute (ICAN), Paris, France
| | - Caroline Storey-London
- Assistance Publique-Hôpitaux de Paris, Robert Debré Hospital, Pediatric Endocrinology Department, National Competence Centre for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), Paris, France
| | - Elise Bismuth
- Assistance Publique-Hôpitaux de Paris, Robert Debré Hospital, Pediatric Endocrinology Department, National Competence Centre for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), Paris, France
| | - Héléna Mosbah
- Sorbonne University, Inserm UMR_S 938, Saint-Antoine Research Centre, Cardiometabolism and Nutrition University Hospital Institute (ICAN), Paris, France
- Endocrinology Department, Assistance Publique-Hôpitaux de Paris, Saint-Antoine Hospital, National Reference Centre for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), Paris, France
| | - Bruno Donadille
- Sorbonne University, Inserm UMR_S 938, Saint-Antoine Research Centre, Cardiometabolism and Nutrition University Hospital Institute (ICAN), Paris, France
- Endocrinology Department, Assistance Publique-Hôpitaux de Paris, Saint-Antoine Hospital, National Reference Centre for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), Paris, France
| | - Sonja Janmaat
- Sorbonne University, Inserm UMR_S 938, Saint-Antoine Research Centre, Cardiometabolism and Nutrition University Hospital Institute (ICAN), Paris, France
- Endocrinology Department, Assistance Publique-Hôpitaux de Paris, Saint-Antoine Hospital, National Reference Centre for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), Paris, France
| | - Bruno Fève
- Sorbonne University, Inserm UMR_S 938, Saint-Antoine Research Centre, Cardiometabolism and Nutrition University Hospital Institute (ICAN), Paris, France
- Endocrinology Department, Assistance Publique-Hôpitaux de Paris, Saint-Antoine Hospital, National Reference Centre for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), Paris, France
| | - Isabelle Jéru
- Sorbonne University, Inserm UMR_S 938, Saint-Antoine Research Centre, Cardiometabolism and Nutrition University Hospital Institute (ICAN), Paris, France
- Endocrinology Department, Assistance Publique-Hôpitaux de Paris, Saint-Antoine Hospital, National Reference Centre for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), Paris, France
- Genetics Department, Assistance Publique-Hôpitaux de Paris, La Pitié-Salpêtrière Hospital, Paris, France
| | - Corinne Vigouroux
- Sorbonne University, Inserm UMR_S 938, Saint-Antoine Research Centre, Cardiometabolism and Nutrition University Hospital Institute (ICAN), Paris, France
- Endocrinology Department, Assistance Publique-Hôpitaux de Paris, Saint-Antoine Hospital, National Reference Centre for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), Paris, France
- Genetics Department, Assistance Publique-Hôpitaux de Paris, La Pitié-Salpêtrière Hospital, Paris, France
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Li X, Wang H. Multiple organs involved in the pathogenesis of non-alcoholic fatty liver disease. Cell Biosci 2020; 10:140. [PMID: 33372630 PMCID: PMC7720519 DOI: 10.1186/s13578-020-00507-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 11/27/2020] [Indexed: 02/08/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) represents the leading cause of chronic liver disease worldwide and the anticipated health burden is huge. There are limited therapeutic approaches for NAFLD now. It’s imperative to get a better understanding of the disease pathogenesis if new treatments are to be discovered. As the hepatic manifestation of metabolic syndrome, this disease involves complex interactions between different organs and regulatory pathways. It’s increasingly clear that brain, gut and adipose tissue all contribute to NAFLD pathogenesis and development, in view of their roles in energy homeostasis. In the present review, we try to summarize currently available data regarding NAFLD pathogenesis and to lay a particular emphasis on the inter-organ crosstalk evidence.
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Affiliation(s)
- Xiaoyan Li
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China. .,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, 230032, China.
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33
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Lightbourne M, Wolska A, Abel BS, Rother KI, Walter M, Kushchayeva Y, Auh S, Shamburek RD, Remaley AT, Muniyappa R, Brown RJ. Apolipoprotein CIII and Angiopoietin-like Protein 8 are Elevated in Lipodystrophy and Decrease after Metreleptin. J Endocr Soc 2020; 5:bvaa191. [PMID: 33442570 DOI: 10.1210/jendso/bvaa191] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Indexed: 02/08/2023] Open
Abstract
Context Lipodystrophy syndromes cause hypertriglyceridemia that improves with leptin treatment using metreleptin. Mechanisms causing hypertriglyceridemia and improvements after metreleptin are incompletely understood. Objective Determine relationship of circulating lipoprotein lipase (LPL) modulators with hypertriglyceridemia in healthy controls and in patients with lipodystrophy before and after metreleptin. Methods Cross-sectional comparison of patients with lipodystrophy (generalized lipodystrophy n = 3; partial lipodystrophy n = 11) vs age/sex-matched healthy controls (n = 28), and longitudinal analyses in patients before and after 2 weeks and 6 months of metreleptin. The study was carried out at the National Institutes of Health, Bethesda, Maryland. Outcomes were LPL stimulators apolipoprotein (apo) C-II and apoA-V and inhibitors apoC-III and angiopoietin-like proteins (ANGPTLs) 3, 4, and 8; ex vivo activation of LPL by plasma. Results Patients with lipodystrophy were hypertriglyceridemic and had higher levels of all LPL stimulators and inhibitors vs controls except for ANGPTL4, with >300-fold higher ANGPTL8, 4-fold higher apoC-III, 3.5-fold higher apoC-II, 1.9-fold higher apoA-V, 1.6-fold higher ANGPTL3 (P < .05 for all). At baseline, all LPL modulators except ANGPLT4 positively correlated with triglycerides. Metreleptin decreased apoC-II and apoC-III after 2 weeks and 6 months, and decreased ANGPTL8 after 6 months (P < 0.05 for all). Plasma from patients with lipodystrophy caused higher ex vivo LPL activation vs hypertriglyceridemic control plasma (P < .0001), which did not change after metreleptin. Conclusion Elevations in LPL inhibitors apoC-III and ANGPTL8 may contribute to hypertriglyceridemia in lipodystrophy, and may mediate reductions in circulating and hepatic triglycerides after metreleptin. These therefore are strong candidates for therapies to lower triglycerides in these patients.
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Affiliation(s)
- Marissa Lightbourne
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Anna Wolska
- Lipoprotein Metabolism Laboratory, Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Brent S Abel
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Kristina I Rother
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Mary Walter
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Yevgeniya Kushchayeva
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Sungyoung Auh
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Robert D Shamburek
- Cardiovascular Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Alan T Remaley
- Lipoprotein Metabolism Laboratory, Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Ranganath Muniyappa
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Rebecca J Brown
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
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Goedeke L, Peng L, Montalvo-Romeral V, Butrico GM, Dufour S, Zhang XM, Perry RJ, Cline GW, Kievit P, Chng K, Petersen KF, Shulman GI. Controlled-release mitochondrial protonophore (CRMP) reverses dyslipidemia and hepatic steatosis in dysmetabolic nonhuman primates. Sci Transl Med 2020; 11:11/512/eaay0284. [PMID: 31578240 DOI: 10.1126/scitranslmed.aay0284] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 09/13/2019] [Indexed: 12/21/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is estimated to affect up to one-third of the general population, and new therapies are urgently required. Our laboratory previously developed a controlled-release mitochondrial protonophore (CRMP) that is functionally liver-targeted and promotes oxidation of hepatic triglycerides. Although we previously demonstrated that CRMP safely reverses hypertriglyceridemia, fatty liver, hepatic inflammation, and fibrosis in diet-induced rodent models of obesity, there remains a critical need to assess its safety and efficacy in a model highly relevant to humans. Here, we evaluated the impact of longer-term CRMP treatment on hepatic mitochondrial oxidation and on the reversal of hypertriglyceridemia, NAFLD, and insulin resistance in high-fat, fructose-fed cynomolgus macaques (n = 6) and spontaneously obese dysmetabolic rhesus macaques (n = 12). Using positional isotopomer nuclear magnetic resonance tracer analysis (PINTA), we demonstrated that acute CRMP treatment (single dose, 5 mg/kg) increased rates of hepatic mitochondrial fat oxidation by 40%. Six weeks of CRMP treatment reduced hepatic triglycerides in both nonhuman primate models independently of changes in body weight, food intake, body temperature, or adverse reactions. CRMP treatment was also associated with a 20 to 30% reduction in fasting plasma triglycerides and low-density lipoprotein (LDL)-cholesterol in dysmetabolic nonhuman primates. Oral administration of CRMP reduced endogenous glucose production by 18%, attributable to a 20% reduction in hepatic acetyl-coenzyme A (CoA) content [as assessed by whole-body β-hydroxybutyrate (β-OHB) turnover] and pyruvate carboxylase flux. Collectively, these studies provide proof-of-concept data to support the development of liver-targeted mitochondrial uncouplers for the treatment of metabolic syndrome in humans.
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Affiliation(s)
- Leigh Goedeke
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA
| | - Liang Peng
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA
| | | | - Gina M Butrico
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA
| | - Sylvie Dufour
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA
| | - Xian-Man Zhang
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA
| | - Rachel J Perry
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA.,Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT 06510, USA
| | - Gary W Cline
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA
| | - Paul Kievit
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, USA
| | - Keefe Chng
- Crown Bioscience Louisiana Inc., New Iberia, LA 70560, USA
| | - Kitt Falk Petersen
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA
| | - Gerald I Shulman
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA. .,Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT 06510, USA
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35
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Martínez-Sánchez N. There and Back Again: Leptin Actions in White Adipose Tissue. Int J Mol Sci 2020; 21:ijms21176039. [PMID: 32839413 PMCID: PMC7503240 DOI: 10.3390/ijms21176039] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/17/2020] [Accepted: 08/18/2020] [Indexed: 12/13/2022] Open
Abstract
Leptin is a hormone discovered almost 30 years ago with important implications in metabolism. It is primarily produced by white adipose tissue (WAT) in proportion to the amount of fat. The discovery of leptin was a turning point for two principle reasons: on one hand, it generated promising expectations for the treatment of the obesity, and on the other, it changed the classical concept that white adipose tissue was simply an inert storage organ. Thus, adipocytes in WAT produce the majority of leptin and, although its primary role is the regulation of fat stores by controlling lipolysis and lipogenesis, this hormone also has implications in other physiological processes within WAT, such as apoptosis, browning and inflammation. Although a massive number of questions related to leptin actions have been answered, the necessity for further clarification facilitates constantly renewing interest in this hormone and its pathways. In this review, leptin actions in white adipose tissue will be summarized in the context of obesity.
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Baykal AP, Parks EJ, Shamburek R, Syed-Abdul MM, Chacko S, Cochran E, Startzell M, Gharib AM, Ouwerkerk R, Abd-Elmoniem KZ, Walter PJ, Walter M, Muniyappa R, Chung ST, Brown RJ. Leptin decreases de novo lipogenesis in patients with lipodystrophy. JCI Insight 2020; 5:137180. [PMID: 32573497 DOI: 10.1172/jci.insight.137180] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 06/10/2020] [Indexed: 01/14/2023] Open
Abstract
De novo lipogenesis (DNL) plays a role in the development of hepatic steatosis. In humans with lipodystrophy, reduced adipose tissue causes lower plasma leptin, insulin resistance, dyslipidemia, and ectopic triglyceride (TG) accumulation. We hypothesized that recombinant leptin (metreleptin) for 6 months in 11 patients with lipodystrophy would reduce DNL by decreasing insulin resistance and glycemia, thus reducing circulating TG and hepatic TG. The percentage of TG in TG-rich lipoprotein particle (TRLP-TG) derived from DNL (%DNL) was measured by deuterium incorporation from body water into palmitate. At baseline, DNL was elevated, similar to levels previously shown in obesity-associated nonalcoholic fatty liver disease (NAFLD). After metreleptin, DNL decreased into the normal range. Similarly, absolute DNL (TRLP-TG × %DNL) decreased by 88% to near-normal levels. Metreleptin improved peripheral insulin sensitivity (hyperinsulinemic-euglycemic clamp) and lowered hemoglobin A1c and hepatic TG. Both before and after metreleptin, DNL positively correlated with insulin resistance, insulin doses, and hepatic TG, supporting the hypothesis that hyperinsulinemia stimulates DNL and that elevated DNL is integral to the pathogenesis of lipodystrophy-associated NAFLD. These data suggest that leptin-mediated improvement in insulin sensitivity increases clearance of blood glucose by peripheral tissues, reduces hepatic carbohydrate flux, and lowers insulinemia, resulting in DNL reductions and improvements in hepatic steatosis and dyslipidemia.
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Affiliation(s)
- Annah P Baykal
- National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Elizabeth J Parks
- Department of Nutrition and Exercise Physiology, School of Medicine, University of Missouri, Columbia, Missouri, USA
| | - Robert Shamburek
- National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA
| | - Majid M Syed-Abdul
- Department of Nutrition and Exercise Physiology, School of Medicine, University of Missouri, Columbia, Missouri, USA
| | - Shaji Chacko
- Department of Pediatrics, Children's Nutrition Research Center, US Department of Agriculture/Agricultural Research Service, Baylor College of Medicine, Houston, Texas, USA
| | - Elaine Cochran
- National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Megan Startzell
- National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Ahmed M Gharib
- National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Ronald Ouwerkerk
- National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Khaled Z Abd-Elmoniem
- National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Peter J Walter
- National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Mary Walter
- National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Ranganath Muniyappa
- National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Stephanie T Chung
- National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Rebecca J Brown
- National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
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Hendley MA, Isely C, Murphy KP, Hall HE, Annamalai P, Gower RM. Scaffold Implant Into the Epididymal Adipose Tissue Protects Mice From High Fat Diet Induced Ectopic Lipid Accumulation and Hyperinsulinemia. Front Bioeng Biotechnol 2020; 8:562. [PMID: 32612981 PMCID: PMC7308717 DOI: 10.3389/fbioe.2020.00562] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 05/11/2020] [Indexed: 12/18/2022] Open
Abstract
Ectopic lipid accumulation, the deposition of lipids in lean tissue, is linked to type 2 diabetes through an association with insulin resistance. It occurs when adipose tissue fails to meet lipid storage needs and there is lipid spillover into tissues not equipped to store them. Ectopic lipid contributes to organ dysfunction because lipids can interfere with insulin signaling and other signaling pathways. Clinical studies indicate that decreasing ectopic lipids through diet and exercise is effective in treating type 2 diabetes; however, its prevalence continues to rise. We propose that strategies to improve lipid handling in the adipose tissue would be adjunctive to healthy lifestyle modification and may address difficulties in treating type 2 diabetes and other syndromes spurred by ectopic lipid. Herein, we investigate biomaterial implants as a means to increase lipid utilization in adipose tissue through the recruitment of highly metabolic cells. Poly(lactide-co-glycolide) scaffolds were implanted into the epididymal fat of mice fed a high fat diet that overwhelms the adipose tissue and promotes ectopic lipid accumulation. Over 5 weeks, mice with scaffolds gained less weight compared to mice without scaffolds and were protected from hyperinsulinemia. These effects correlated with a 53% decrease in triglyceride in the gastrocnemius and a 25% decrease in the liver. Scaffolds increased CPT1A protein levels in the epididymal fat and histology revealed high expression of CTP1A in the cells infiltrating the scaffold relative to the rest of the fat pad. In addition, lacing the scaffold with resveratrol increased CPT1A expression in the epididymal fat over scaffolds with no drug; however, this did not result in further decreases in weight gain or ectopic lipid. Mechanistically, we propose that the cellular activity caused by scaffold implant mitigates the lipid load imposed by the high fat diet and leads to a substantial decrease in lipid accumulation in the muscle and liver. In conclusion, this study establishes that a tissue engineering approach to modulate lipid utilization in the epididymal fat tissue can mitigate ectopic lipid accumulation in mice fed a high fat diet with positive effects on weight gain and whole-body insulin resistance.
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Affiliation(s)
- Michael A Hendley
- Biomedical Engineering Program, University of South Carolina, Columbia, SC, United States
| | - Christopher Isely
- Department of Chemical Engineering, University of South Carolina, Columbia, SC, United States
| | - Kendall P Murphy
- Department of Chemical Engineering, University of South Carolina, Columbia, SC, United States
| | - Hayley E Hall
- Biomedical Engineering Program, University of South Carolina, Columbia, SC, United States
| | - Prakasam Annamalai
- Department of Chemical Engineering, University of South Carolina, Columbia, SC, United States
| | - R Michael Gower
- Biomedical Engineering Program, University of South Carolina, Columbia, SC, United States.,Department of Chemical Engineering, University of South Carolina, Columbia, SC, United States
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38
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You D, Lyn-Cook LE, Gatti DM, Bell N, Mayeux PR, James LP, Mattes WB, Larson GJ, Harrill AH. Nitrosative Stress and Lipid Homeostasis as a Mechanism for Zileuton Hepatotoxicity and Resistance in Genetically Sensitive Mice. Toxicol Sci 2020; 175:220-235. [PMID: 32170957 PMCID: PMC7253212 DOI: 10.1093/toxsci/kfaa037] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Zileuton is an orally active inhibitor of leukotriene synthesis for maintenance treatment of asthma, for which clinical usage has been associated with idiosyncratic liver injury. Mechanistic understanding of zileuton toxicity is hampered by the rarity of the cases and lack of an animal model. A promising model for mechanistic study of rare liver injury is the Diversity Outbred (J:DO) mouse population, with genetic variation similar to that found in humans. In this study, female DO mice were administered zileuton or vehicle daily for 7 days (i.g.). Serum liver enzymes were elevated in the zileuton group, with marked interindividual variability in response. Zileuton exposure-induced findings in susceptible DO mice included microvesicular fatty change, hepatocellular mitosis, and hepatocellular necrosis. Inducible nitric oxide synthase and nitrotyrosine abundance were increased in livers of animals with necrosis and those with fatty change, implicating nitrosative stress as a possible injury mechanism. Conversely, DO mice lacking adverse liver pathology following zileuton exposure experienced decreased hepatic concentrations of resistin and increased concentrations of insulin and leptin, providing potential clues into mechanisms of toxicity resistance. Transcriptome pathway analysis highlighted mitochondrial dysfunction and altered fatty acid oxidation as key molecular perturbations associated with zileuton exposure, and suggested that interindividual differences in cytochrome P450 metabolism, glutathione-mediated detoxification, and farnesoid X receptor signaling may contribute to zileuton-induced liver injury (ZILI). Taken together, DO mice provided a platform for investigating mechanisms of toxicity and resistance in context of ZILI which may lead to targeted therapeutic interventions.
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Affiliation(s)
- Dahea You
- Division of the National Toxicology Program, The National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709
| | - Lascelles E Lyn-Cook
- Graduate Program in Interdisciplinary Biomedical Sciences, The University of Arkansas for Medical Sciences and Arkansas Children’s Research Institute, Little Rock, Arkansas 72205
| | | | - Natalie Bell
- Division of the National Toxicology Program, The National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709
- East Carolina University, Greenville, North Carolina 27858
| | | | - Laura P James
- Department of Pediatrics, The University of Arkansas for Medical Sciences and Arkansas Children’s Research Institute, Little Rock, Arkansas 27705
| | - William B Mattes
- Division of Systems Biology, The National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas 72079
| | - Gary J Larson
- Social & Scientific Systems, Inc., Durham, North Carolina 27703
| | - Alison H Harrill
- Division of the National Toxicology Program, The National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709
- Department of Environmental and Occupational Health, The University of Arkansas for Medical Sciences and Arkansas Children’s Research Institute, Little Rock, Arkansas 72205
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Abstract
PURPOSE OF REVIEW In this brief review, we highlight studies that have contributed to our current understanding of glucose homeostasis by the central nervous system (CNS) leptin-melanocortin system, particularly proopiomelanocortin neurons and melanocortin-4 receptors (MC4R). RECENT FINDINGS Leptin deficiency is associated with insulin resistance and impaired glucose metabolism whereas leptin administration improves tissue glucose uptake/oxidation and reduces hepatic glucose output. These antidiabetic effects of leptin have been demonstrated in experimental animals and humans, even when circulating insulin levels are barely detectable. Recent evidence suggests that these antidiabetic actions of leptin are mediated, in large part, by stimulation of leptin receptors (LRs) in the CNS and require activation of proopiomelanocortin (POMC) neurons and MC4R. These chronic antidiabetic effects of the CNS leptin-melanocortin system appear to be independent of autonomic nervous system and pituitary-thyroid-adrenal (PTA) axis mechanisms. The powerful antidiabetic actions of the CNS leptin-melanocortin system are capable of normalizing plasma glucose even in the absence of insulin and involve interactions of multiple neuronal populations and intracellular signaling pathways. Although the links between the CNS leptin-melanocortin system and its chronic effects on peripheral tissue glucose metabolism are still uncertain, they are independent of insulin action, activation of the autonomic nervous system, or the PTA axis. Unraveling the pathways that contribute to the powerful antidiabetic effects of the CNS leptin-melanocortin system may provide novel therapeutic approaches for diabetes mellitus.
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Affiliation(s)
- Alexandre A da Silva
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, and Cardiovascular-Renal Research Center, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216-4505, USA.
| | - Jussara M do Carmo
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, and Cardiovascular-Renal Research Center, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216-4505, USA
| | - John E Hall
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, and Cardiovascular-Renal Research Center, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216-4505, USA
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40
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Gözüküçük M, Yarcı Gürsoy A, Destegül E, Taşkın S, Şatıroğlu H. Adiponectin and leptin levels in normal weight women with polycystic ovary syndrome. Horm Mol Biol Clin Investig 2020; 41:/j/hmbci.ahead-of-print/hmbci-2020-0016/hmbci-2020-0016.xml. [DOI: 10.1515/hmbci-2020-0016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 04/08/2020] [Indexed: 12/17/2022]
Abstract
Abstract
Objectives
Since polycystic ovarian syndrome (PCOS) is prevalent in reproductive women with obesity and insulin resistance, adipocytokines are often accused and investigated for pathophysiology. The aim of this study was to evaluate the adiponectin and leptin levels in normal-weight women with PCOS.
Methods
Forty women with PCOS and 40 age and body mass index (BMI) matched controls were included in the study. Adiponectin and leptin levels in addition to other biochemical parameters were measured.
Results
Leptin levels were statistically significantly higher in the study group compared to the control group (6.53 ± 2.670 vs 3.37 ± 2.002 ng/mL, p < 0.001 respectively). Although Adiponectin levels were lower in the study group compared to the control group (28.89 ± 16.124 μg/mL vs 31.05 ± 20.507, p = 0.714 respectively) the difference did not reach statistical significance. Leptin levels were positively correlated with fasting glucose, fasting insulin, free testosterone levels and homeostatic model assessment of insulin resistance (HOMA-IR) values. Adiponectin levels were negatively correlated with BMI.
Conclusions
Adiponectin and leptin have been suggested to play a crucial role in the pathogenesis of PCOS. Different adipocytokine levels in the normal weight PCOS group compared to age and BMI matched controls support the idea that adipose tissue in this group of women has some distinctive features not only in high BMI subgroup but also in normal weight subgroup.
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Affiliation(s)
- Murat Gözüküçük
- Sağlık Bakanlığı Ankara Eğitim ve Araştırma Hastanesi Sakarya Mh , Ulucanlar Cd , No:89 Altındağ , Ankara , Turkey
| | - Aslı Yarcı Gürsoy
- Ufuk University Faculty of Medicine , Department of Obstetrics and Gynecology , Ankara , Turkey
| | - Emre Destegül
- Adana City Hospital , Department of Obstetrics and Gynecology , Adana , Turkey
| | - Salih Taşkın
- Ankara University Faculty of Medicine , Department of Obstetrics and Gynecology , Ankara , Turkey
| | - Hakan Şatıroğlu
- Ankara University Faculty of Medicine , Department of Obstetrics and Gynecology , Ankara , Turkey
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41
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Sangwung P, Petersen KF, Shulman GI, Knowles JW. Mitochondrial Dysfunction, Insulin Resistance, and Potential Genetic Implications. Endocrinology 2020; 161:bqaa017. [PMID: 32060542 PMCID: PMC7341556 DOI: 10.1210/endocr/bqaa017] [Citation(s) in RCA: 121] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Revised: 01/30/2020] [Accepted: 02/13/2020] [Indexed: 02/06/2023]
Abstract
Insulin resistance (IR) is fundamental to the development of type 2 diabetes (T2D) and is present in most prediabetic (preDM) individuals. Insulin resistance has both heritable and environmental determinants centered on energy storage and metabolism. Recent insights from human genetic studies, coupled with comprehensive in vivo and ex vivo metabolic studies in humans and rodents, have highlighted the critical role of reduced mitochondrial function as a predisposing condition for ectopic lipid deposition and IR. These studies support the hypothesis that reduced mitochondrial function, particularly in insulin-responsive tissues such as skeletal muscle, white adipose tissue, and the liver, is inextricably linked to tissue and whole body IR through the effects on cellular energy balance. Here we discuss these findings as well as address potential mechanisms that serve as the nexus between mitochondrial malfunction and IR.
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Affiliation(s)
- Panjamaporn Sangwung
- Stanford Division of Cardiovascular Medicine and Cardiovascular Institute, Stanford University, Stanford, California
- Stanford Diabetes Research Center, Stanford University, Stanford, California
| | - Kitt Falk Petersen
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut
- Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, Connecticut
- Yale Diabetes Research Center, Yale School of Medicine, New Haven, Connecticut
| | - Gerald I Shulman
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut
- Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, Connecticut
- Yale Diabetes Research Center, Yale School of Medicine, New Haven, Connecticut
| | - Joshua W Knowles
- Stanford Division of Cardiovascular Medicine and Cardiovascular Institute, Stanford University, Stanford, California
- Stanford Diabetes Research Center, Stanford University, Stanford, California
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42
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Brenot A, Hutson I, Harris C. Epithelial-adipocyte interactions are required for mammary gland development, but not for milk production or fertility. Dev Biol 2020; 458:153-163. [PMID: 31697938 PMCID: PMC6995771 DOI: 10.1016/j.ydbio.2019.11.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 10/01/2019] [Accepted: 11/01/2019] [Indexed: 02/07/2023]
Abstract
To investigate the role of adipose tissue in reproductive function and mammary gland development and function, we have examined lipodystrophic (LD) mice. LD mice of both sexes are sterile, but fertility can be restored with leptin injections. Mammary glands from lipodystrophic mice were rudimentary and lacked terminal end buds. Leptin-injected LD mice were able to become pregnant, showed normal pregnancy-associated glandular proliferation despite a smaller glandular area, were able to produce a small amount of milk that had grossly normal content of milk proteins and neutral lipids, but could not sustain pups to weaning. In order to separate the individual requirements for 1) adipokines such as leptin, 2) estradiol, and 3) physical epithelial-adipocyte interactions, we performed a series of experiments with both lipodystrophic mice and ob (obese mice with a mutation in the lep gene encoding the adipokine leptin) mice that received either estradiol treatment or preadipocyte transplant. The resulting fat pad did not rescue the defect in mammary gland development in lipodystrophic mice. The defect also could not be rescued with estradiol pellets. Ob/ob mice, like LD mice, lack leptin and estradiol, but retain adipose tissue. Ob mice have defective mammary gland development. However, in striking contrast to what was observed in lipodystrophic mice, reconstitution of a WT fat pad in ob mice rescued the defect in mammary gland development. Estradiol treatment did not rescue mammary gland development in ob mice. Therefore direct interaction between mammary gland epithelia and adipocytes is a requirement for full invasion and expansion of the gland, but is not required for glandular proliferation during pregnancy and milk production.
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Affiliation(s)
- Audrey Brenot
- Department of Medicine, Divisions of Hematology and Oncology, 660 South Euclid Avenue, Washington University School of Medicine, St. Louis, MO, 63110, United States
| | - Irina Hutson
- Department of Medicine, Divisions of Endocrinology, Metabolism and Lipid Research, 660 South Euclid Avenue, Washington University School of Medicine, St. Louis, MO, 63110, United States
| | - Charles Harris
- Department of Medicine, Divisions of Endocrinology, Metabolism and Lipid Research, 660 South Euclid Avenue, Washington University School of Medicine, St. Louis, MO, 63110, United States; Medicine Service, Division of Endocrinology, St. Louis VA Medical Center, 915 N Grand Avenue, St. Louis, MO, 63106, United States.
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43
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Zouhar P, Rakipovski G, Bokhari MH, Busby O, Paulsson JF, Conde-Frieboes KW, Fels JJ, Raun K, Andersen B, Cannon B, Nedergaard J. UCP1-independent glucose-lowering effect of leptin in type 1 diabetes: only in conditions of hypoleptinemia. Am J Physiol Endocrinol Metab 2020; 318:E72-E86. [PMID: 31743040 PMCID: PMC6985793 DOI: 10.1152/ajpendo.00253.2019] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The possibility to use leptin therapeutically for lowering glucose levels in patients with type 1 diabetes has attracted interest. However, earlier animal models of type 1 diabetes are severely catabolic with very low endogenous leptin levels, unlike most patients with diabetes. Here, we aim to test glucose-lowering effects of leptin in novel, more human-like murine models. We examined the glucose-lowering potential of leptin in diabetic models of two types: streptozotocin-treated mice and mice treated with the insulin receptor antagonist S961. To prevent hypoleptinemia, we used combinations of thermoneutral temperature and high-fat feeding. Leptin fully normalized hyperglycemia in standard chow-fed streptozotocin-treated diabetic mice. However, more humanized physiological conditions (high-fat diets or thermoneutral temperatures) that increased adiposity - and thus also leptin levels - in the diabetic mice abrogated the effects of leptin, i.e., the mice developed leptin resistance also in this respect. The glucose-lowering effect of leptin was not dependent on the presence of the uncoupling protein-1 and was not associated with alterations in plasma insulin, insulin-like growth factor 1, food intake or corticosterone but fully correlated with decreased plasma glucagon levels and gluconeogenesis. An important implication of these observations is that the therapeutic potential of leptin as an additional treatment in patients with type 1 diabetes is probably limited. This is because such patients are treated with insulin and do not display low leptin levels. Thus, the potential for a glucose-lowering effect of leptin would already have been attained with standard insulin therapy, and further effects on blood glucose level through additional leptin cannot be anticipated.
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Affiliation(s)
- Petr Zouhar
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
- Department of Adipose Tissue Biology, Institute of Physiology CAS, Prague, the Czech Republic
| | | | - Muhammad Hamza Bokhari
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
| | - Oliver Busby
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
| | | | | | | | - Kirsten Raun
- Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark
| | | | - Barbara Cannon
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
| | - Jan Nedergaard
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
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Akhtar DH, Iqbal U, Vazquez-Montesino LM, Dennis BB, Ahmed A. Pathogenesis of Insulin Resistance and Atherogenic Dyslipidemia in Nonalcoholic Fatty Liver Disease. J Clin Transl Hepatol 2019; 7:362-370. [PMID: 31915606 PMCID: PMC6943204 DOI: 10.14218/jcth.2019.00028] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 10/08/2019] [Accepted: 11/08/2019] [Indexed: 12/18/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the developed world, with a global prevalence of around 25%. NAFLD is considered to be the hepatic manifestation of metabolic syndrome and is strongly associated with obesity, insulin resistance and dyslipidemia. Insulin resistance plays a pivotal role in the development of NAFLD-related dyslipidemia, which ultimately increases the risk of premature cardiovascular diseases, a leading cause of morbidity and mortality in patients with NAFLD. Insulin affects hepatic glucose and lipid metabolism by hepatic or extrahepatic pathways. Aside from insulin resistance, several other factors also contribute to the pathogenesis of atherogenic dyslipidemia in patients with NAFLD. These include diet composition, gut microbiota and genetic factors, to name a few. The identification of potentially modifiable risk factors of NAFLD is of importance, so as to target those who may benefit from lifestyle changes and to help develop targeted therapies that decrease the risk of cardiovascular diseases in patients with NAFLD.
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Affiliation(s)
- Daud H. Akhtar
- Department of Medicine, University of British Columbia Faculty of Medicine, Vancouver BC, Canada
| | - Umair Iqbal
- Department of Medicine, Geisinger Commonwealth School of Medicine, Danville, PA, USA
- *Correspondence to: Umair Iqbal, Department of Medicine, Geisinger Commonwealth School of Medicine, Danville, PA 17821, USA. Tel: +1-570-271-6211, E-mail:
| | | | - Brittany B. Dennis
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton ON, Canada
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Aijaz Ahmed
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
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do Carmo JM, da Silva AA, Gava FN, Moak SP, Dai X, Hall JE. Impact of leptin deficiency compared with neuronal-specific leptin receptor deletion on cardiometabolic regulation. Am J Physiol Regul Integr Comp Physiol 2019; 317:R552-R562. [PMID: 31411897 DOI: 10.1152/ajpregu.00077.2019] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The main goal of this study was to compare the impact of total body leptin deficiency with neuronal-specific leptin receptor (LR) deletion on metabolic and cardiovascular regulation. Liver fat, diacylglycerol acyltransferase-2 (DGTA2), and CD36 protein content were measured in wild-type (WT), nervous system LR-deficient (LR/Nestin-Cre), and leptin deficient (ob/ob) mice. Blood pressure (BP) and heart rate (HR) were recorded by telemetry, and motor activity (MA) and oxygen consumption (V̇o2) were monitored at 24 wk of age. Female and male LR/Nestin-Cre and ob/ob mice were heavier than WT mice (62 ± 5 and 61 ± 3 vs. 31 ± 1 g) and hyperphagic (6.2 ± 0.5 and 6.1 ± 0.7 vs. 3.5 ± 1.0 g/day), with reduced V̇o2 (27 ± 1 and 33 ± 1 vs 49 ± 3 ml·kg-1·min-1) and decreased MA (3 ± 1 and 7 ± 2 vs 676 ± 105 cm/h). They were also hyperinsulinemic and hyperglycemic compared with WT mice. LR/Nestin-Cre mice had high levels of plasma leptin, while ob/ob mice had undetectable leptin levels. Despite comparable obesity, LR/Nestin-Cre mice had lower liver fat content, DGTA2, and CD36 protein levels than ob/ob mice. Male WT, LR/Nestin-Cre, and ob/ob mice exhibited similar BP (111 ± 3, 110 ± 1 and 109 ± 2 mmHg). Female LR/Nestin-Cre and ob/ob mice, however, had higher BP than WT females despite similar metabolic phenotypes compared with male LR/Nestin-Cre and ob/ob mice. These results indicate that although nervous system LRs play a crucial role in regulating body weight and glucose homeostasis, peripheral LRs regulate liver fat deposition. In addition, our results suggest potential sex differences in the impact of obesity on BP regulation.
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Affiliation(s)
- Jussara M do Carmo
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi
| | - Alexandre A da Silva
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi
| | - Fabio N Gava
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi
| | - Sydney P Moak
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi
| | - Xuemei Dai
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi
| | - John E Hall
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi
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Perry RJ, Resch JM, Douglass AM, Madara JC, Rabin-Court A, Kucukdereli H, Wu C, Song JD, Lowell BB, Shulman GI. Leptin's hunger-suppressing effects are mediated by the hypothalamic-pituitary-adrenocortical axis in rodents. Proc Natl Acad Sci U S A 2019; 116:13670-13679. [PMID: 31213533 PMCID: PMC6613139 DOI: 10.1073/pnas.1901795116] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Leptin informs the brain about sufficiency of fuel stores. When insufficient, leptin levels fall, triggering compensatory increases in appetite. Falling leptin is first sensed by hypothalamic neurons, which then initiate adaptive responses. With regard to hunger, it is thought that leptin-sensing neurons work entirely via circuits within the central nervous system (CNS). Very unexpectedly, however, we now show this is not the case. Instead, stimulation of hunger requires an intervening endocrine step, namely activation of the hypothalamic-pituitary-adrenocortical (HPA) axis. Increased corticosterone then activates AgRP neurons to fully increase hunger. Importantly, this is true for 2 forms of low leptin-induced hunger, fasting and poorly controlled type 1 diabetes. Hypoglycemia, which also stimulates hunger by activating CNS neurons, albeit independently of leptin, similarly recruits and requires this pathway by which HPA axis activity stimulates AgRP neurons. Thus, HPA axis regulation of AgRP neurons is a previously underappreciated step in homeostatic regulation of hunger.
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Affiliation(s)
- Rachel J Perry
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520
| | - Jon M Resch
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
| | - Amelia M Douglass
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
| | - Joseph C Madara
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
| | - Aviva Rabin-Court
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520
| | - Hakan Kucukdereli
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
| | - Chen Wu
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
| | - Joongyu D Song
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520
| | - Bradford B Lowell
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
- Program in Neuroscience, Harvard Medical School, Boston, MA 02215
| | - Gerald I Shulman
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520;
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520
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Savage DB, Watson L, Carr K, Adams C, Brage S, Chatterjee KK, Hodson L, Boesch C, Kemp GJ, Sleigh A. Accumulation of saturated intramyocellular lipid is associated with insulin resistance. J Lipid Res 2019; 60:1323-1332. [PMID: 31048405 PMCID: PMC6602127 DOI: 10.1194/jlr.m091942] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 03/11/2019] [Indexed: 12/17/2022] Open
Abstract
Intramyocellular lipid (IMCL) accumulation has been linked to both insulin-resistant and insulin-sensitive (athletes) states. Biochemical analysis of intramuscular triglyceride composition is confounded by extramyocellular triglycerides in biopsy samples, and hence the specific composition of IMCLs is unknown in these states. 1H magnetic resonance spectroscopy (MRS) can be used to overcome this problem. Thus, we used a recently validated 1H MRS method to compare the compositional saturation index (CH2:CH3) and concentration independent of the composition (CH3) of IMCLs in the soleus and tibialis anterior muscles of 16 female insulin-resistant lipodystrophic subjects with that of age- and gender-matched athletes (n = 14) and healthy controls (n = 41). The IMCL CH2:CH3 ratio was significantly higher in both muscles of the lipodystrophic subjects compared with controls but was similar in athletes and controls. IMCL CH2:CH3 was dependent on the IMCL concentration in the controls and, after adjusting the compositional index for quantity (CH2:CH3adj), could distinguish lipodystrophics from athletes. This CH2:CH3adj marker had a stronger relationship with insulin resistance than IMCL concentration alone and was inversely related to VO2max The association of insulin resistance with the accumulation of saturated IMCLs is consistent with a potential pathogenic role for saturated fat and the reported benefits of exercise and diet in insulin-resistant states.
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Affiliation(s)
- David B Savage
- Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, United Kingdom
| | - Laura Watson
- National Institute for Health Research/Wellcome Trust Clinical Research Facility, Cambridge University Hospitals NHS Foundation Trust Cambridge Biomedical Campus, Cambridge, United Kingdom
| | - Katie Carr
- National Institute for Health Research/Wellcome Trust Clinical Research Facility, Cambridge University Hospitals NHS Foundation Trust Cambridge Biomedical Campus, Cambridge, United Kingdom
| | - Claire Adams
- Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, United Kingdom
| | - Soren Brage
- MRC Epidemiology Unit University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
| | - Krishna K Chatterjee
- Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, United Kingdom
- National Institute for Health Research/Wellcome Trust Clinical Research Facility, Cambridge University Hospitals NHS Foundation Trust Cambridge Biomedical Campus, Cambridge, United Kingdom
| | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Chris Boesch
- Department of Clinical Research and Radiology AMSM, University Bern, Bern, Switzerland
| | - Graham J Kemp
- Department of Musculoskeletal Biology University of Liverpool and MRC-Arthritis Research UK Centre for Integrated Research into Musculoskeletal Ageing, Liverpool, United Kingdom
| | - Alison Sleigh
- Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, United Kingdom
- National Institute for Health Research/Wellcome Trust Clinical Research Facility, Cambridge University Hospitals NHS Foundation Trust Cambridge Biomedical Campus, Cambridge, United Kingdom
- Wolfson Brain Imaging Centre University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
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Hackl MT, Fürnsinn C, Schuh CM, Krssak M, Carli F, Guerra S, Freudenthaler A, Baumgartner-Parzer S, Helbich TH, Luger A, Zeyda M, Gastaldelli A, Buettner C, Scherer T. Brain leptin reduces liver lipids by increasing hepatic triglyceride secretion and lowering lipogenesis. Nat Commun 2019; 10:2717. [PMID: 31222048 PMCID: PMC6586634 DOI: 10.1038/s41467-019-10684-1] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 05/24/2019] [Indexed: 12/31/2022] Open
Abstract
Hepatic steatosis develops when lipid influx and production exceed the liver's ability to utilize/export triglycerides. Obesity promotes steatosis and is characterized by leptin resistance. A role of leptin in hepatic lipid handling is highlighted by the observation that recombinant leptin reverses steatosis of hypoleptinemic patients with lipodystrophy by an unknown mechanism. Since leptin mainly functions via CNS signaling, we here examine in rats whether leptin regulates hepatic lipid flux via the brain in a series of stereotaxic infusion experiments. We demonstrate that brain leptin protects from steatosis by promoting hepatic triglyceride export and decreasing de novo lipogenesis independently of caloric intake. Leptin's anti-steatotic effects are generated in the dorsal vagal complex, require hepatic vagal innervation, and are preserved in high-fat-diet-fed rats when the blood brain barrier is bypassed. Thus, CNS leptin protects from ectopic lipid accumulation via a brain-vagus-liver axis and may be a therapeutic strategy to ameliorate obesity-related steatosis.
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Affiliation(s)
- Martina Theresa Hackl
- Department of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria
| | - Clemens Fürnsinn
- Department of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria
| | - Christina Maria Schuh
- Department of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria
| | - Martin Krssak
- Department of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria
- Department of Biomedical Imaging and Image-Guided Therapy, High-Field MR Center, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria
- Christian Doppler Laboratory for Clinical Molecular MR Imaging, MOLIMA, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Fabrizia Carli
- Institute of Clinical Physiology, National Research Council, Via G. Moruzzi 1, 56124, Pisa, Italy
| | - Sara Guerra
- Institute of Clinical Physiology, National Research Council, Via G. Moruzzi 1, 56124, Pisa, Italy
- Institute of Life Sciences, Sant'Anna School of Advanced Studies, Via Santa Cecilia 3, 56127, Pisa, Italy
| | - Angelika Freudenthaler
- Department of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria
| | - Sabina Baumgartner-Parzer
- Department of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria
| | - Thomas H Helbich
- Department of Biomedical Imaging and Image-Guided Therapy, Division of Molecular and Gender Imaging, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria
| | - Anton Luger
- Department of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria
| | - Maximilian Zeyda
- Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria
| | - Amalia Gastaldelli
- Institute of Clinical Physiology, National Research Council, Via G. Moruzzi 1, 56124, Pisa, Italy
- Institute of Life Sciences, Sant'Anna School of Advanced Studies, Via Santa Cecilia 3, 56127, Pisa, Italy
| | - Christoph Buettner
- Departments of Medicine and Neuroscience, and Diabetes, Obesity and Metabolism Institute (DOMI), Icahn School of Medicine at Mt Sinai, One Gustave L. Levy Pl, New York, NY, 10029, USA
| | - Thomas Scherer
- Department of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria.
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Kinzer AB, Shamburek RD, Lightbourne M, Muniyappa R, Brown RJ. Advanced Lipoprotein Analysis Shows Atherogenic Lipid Profile That Improves After Metreleptin in Patients with Lipodystrophy. J Endocr Soc 2019; 3:1503-1517. [PMID: 31620670 DOI: 10.1210/js.2019-00103] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 06/04/2019] [Indexed: 01/12/2023] Open
Abstract
Context Patients with lipodystrophy have dyslipidemia and insulin resistance. Leptin treatment with metreleptin in lipodystrophy decreases insulin resistance and lowers triglycerides without changing high-density lipoprotein. Detailed measurement of lipoprotein particles with nuclear magnetic resonance (NMR) spectroscopy can offer insights into cardiovascular disease (CVD) risk and lipid metabolism beyond a standard lipid panel. We hypothesized that patients with lipodystrophy would have a more atherogenic lipid profile than controls at baseline, which would be ameliorated with metreleptin treatment. Objective To characterize the lipoprotein profile in patients with lipodystrophy compared with controls and to evaluate effects of metreleptin treatment. Design Setting Patients and Intervention Patients with lipodystrophy (N = 17) were studied before and after metreleptin for 2 weeks and 6 months and compared with 51 insulin-sensitive sex-matched controls. Main Outcome Measures Lipoprotein profiles were measured by NMR with the LP4 deconvolution algorithm, which reports triglyceride-rich lipoprotein particles (TRLPs), high-density lipoprotein particles (HDLPs), and low-density lipoprotein particles (LDLPs). Results Patients with lipodystrophy had elevated large TRLPs and smaller HDLPs and LDLPs compared with controls. Five patients with lipodystrophy had chylomicrons, compared with zero controls. Metreleptin decreased the size and concentration of TRLPs, eliminated chylomicrons in all but one patient, decreased LDLPs, and increased LDLP size. Metreleptin treatment did not have major effects on HDLPs. Conclusions Patients with lipodystrophy had an atherogenic lipoprotein profile at baseline consistent with elevated CVD risk, which improved after metreleptin treatment. The presence of fasting chylomicrons in a subset of patients with lipodystrophy suggests saturation of chylomicron clearance by lipoprotein lipase.
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Affiliation(s)
- Alexandra B Kinzer
- National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland
| | | | - Marissa Lightbourne
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland
| | - Ranganath Muniyappa
- National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland
| | - Rebecca J Brown
- National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland
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Lee HL, Waldman MA, Auh S, Balow JE, Cochran EK, Gorden P, Brown RJ. Effects of metreleptin on proteinuria in patients with lipodystrophy. J Clin Endocrinol Metab 2019; 104:4169-4177. [PMID: 30990519 PMCID: PMC6688455 DOI: 10.1210/jc.2019-00200] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 04/10/2019] [Indexed: 01/22/2023]
Abstract
CONTEXT Patients with lipodystrophy have high prevalence of proteinuria. OBJECTIVE To assess kidney disease in patients with generalized (GLD) versus partial lipodystrophy (PLD), and effects metreleptin on proteinuria in patients with lipodystrophy. DESIGN/SETTING/PATIENTS/INTERVENTION Prospective, open-label studies of metreleptin treatment in patients with GLD and PLD at the National Institutes of Health, Bethesda, MD. OUTCOME MEASURES 24-hour urinary albumin and protein excretion rates, estimated glomerular filtration rate (eGFR), and creatinine clearance (CrCl) were measured at baseline and during up to 24 months of metreleptin treatment. Patients with increases in medications affecting outcome measures were excluded. RESULTS At baseline, patients with GLD had significantly greater albuminuria, proteinuria, eGFR, and CrCl compared to patients with PLD. CrCl was above the normal range in 69% of patients with GLD, and 39% with PLD (P=0.02). With up to 24 months of metreleptin treatment, there were significant reductions in albuminuria and proteinuria in patients with GLD, but not in those with PLD. No changes in eGFR or CrCl were observed in patients with GLD or PLD during metreleptin treatment. CONCLUSIONS Patients with GLD had significantly greater proteinuria than those with PLD, which improved with metreleptin treatment. The mechanisms leading to proteinuria in lipodystrophy and improvements in proteinuria with metreleptin are not clear. Hyperfiltration was also more common in GLD versus PLD but did not change with metreleptin.
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Affiliation(s)
- Ho Lim Lee
- Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Meryl A Waldman
- Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Sungyoung Auh
- Office of the Clinical Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - James E Balow
- Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Elaine K Cochran
- Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Phillip Gorden
- Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Rebecca J Brown
- Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
- Correspondence and Reprint Requests: Rebecca J. Brown, MD, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10-CRC, Room 6-5942, 10 Center Drive, Bethesda, Maryland 20892. E-mail:
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