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Alpízar Salazar M, Olguín Reyes SE, Medina Estévez A, Saturno Lobos JA, De Aldecoa Castillo JM, Carrera Aguas JC, Alaniz Monreal S, Navarro Rodríguez JA, Alpízar Sánchez DMF. Natural History of Metabolic Dysfunction-Associated Steatotic Liver Disease: From Metabolic Syndrome to Hepatocellular Carcinoma. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:88. [PMID: 39859069 PMCID: PMC11766802 DOI: 10.3390/medicina61010088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 12/30/2024] [Accepted: 01/04/2025] [Indexed: 01/27/2025]
Abstract
Introduction: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) stems from disrupted lipid metabolism in the liver, often linked to obesity, type 2 diabetes, and dyslipidemia. In Mexico, where obesity affects 36.9% of adults, MASLD prevalence has risen, especially with metabolic syndrome affecting 56.31% by 2018. MASLD can progress to Metabolic Dysfunction-Associated Steatohepatitis (MASH), affecting 5.27% globally, leading to severe complications like cirrhosis and hepatocellular carcinoma. Background: Visceral fat distribution varies by gender, impacting MASLD development due to hormonal influences. Insulin resistance plays a central role in MASLD pathogenesis, exacerbated by high-fat diets and specific fatty acids, leading to hepatic steatosis. Lipotoxicity from saturated fatty acids further damages hepatocytes, triggering inflammation and fibrosis progression in MASH. Diagnosing MASLD traditionally involves invasive liver biopsy, but non-invasive methods like ultrasound and transient elastography are preferred due to their safety and availability. These methods detect liver steatosis and fibrosis with reasonable accuracy, offering alternatives to biopsy despite varying sensitivity and specificity. Conclusions: MASLD as a metabolic disorder underscores its impact on public health, necessitating improved awareness and early management strategies to mitigate its progression to severe liver diseases.
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Affiliation(s)
- Melchor Alpízar Salazar
- Endocrinology, Specialized Center for Diabetes, Obesity and Prevention of Cardiovascular Diseases (CEDOPEC), Mexico City 11650, Mexico
| | - Samantha Estefanía Olguín Reyes
- Clinical Research, Specialized Center for Diabetes, Obesity and Prevention of Cardiovascular Diseases (CEDOPEC), Mexico City 11650, Mexico; (S.E.O.R.); (A.M.E.); (J.A.S.L.); (S.A.M.); (J.A.N.R.); (D.M.F.A.S.)
| | - Andrea Medina Estévez
- Clinical Research, Specialized Center for Diabetes, Obesity and Prevention of Cardiovascular Diseases (CEDOPEC), Mexico City 11650, Mexico; (S.E.O.R.); (A.M.E.); (J.A.S.L.); (S.A.M.); (J.A.N.R.); (D.M.F.A.S.)
| | - Julieta Alejandra Saturno Lobos
- Clinical Research, Specialized Center for Diabetes, Obesity and Prevention of Cardiovascular Diseases (CEDOPEC), Mexico City 11650, Mexico; (S.E.O.R.); (A.M.E.); (J.A.S.L.); (S.A.M.); (J.A.N.R.); (D.M.F.A.S.)
| | - Jesús Manuel De Aldecoa Castillo
- Clinical Nutrition, Specialized Center for Diabetes, Obesity and Prevention of Cardiovascular Diseases (CEDOPEC), Mexico City 11650, Mexico;
| | - Juan Carlos Carrera Aguas
- Clinical Nutrition, Specialized Center for Diabetes, Obesity and Prevention of Cardiovascular Diseases (CEDOPEC), Mexico City 11650, Mexico;
| | - Samary Alaniz Monreal
- Clinical Research, Specialized Center for Diabetes, Obesity and Prevention of Cardiovascular Diseases (CEDOPEC), Mexico City 11650, Mexico; (S.E.O.R.); (A.M.E.); (J.A.S.L.); (S.A.M.); (J.A.N.R.); (D.M.F.A.S.)
| | - José Antonio Navarro Rodríguez
- Clinical Research, Specialized Center for Diabetes, Obesity and Prevention of Cardiovascular Diseases (CEDOPEC), Mexico City 11650, Mexico; (S.E.O.R.); (A.M.E.); (J.A.S.L.); (S.A.M.); (J.A.N.R.); (D.M.F.A.S.)
| | - Dulce María Fernanda Alpízar Sánchez
- Clinical Research, Specialized Center for Diabetes, Obesity and Prevention of Cardiovascular Diseases (CEDOPEC), Mexico City 11650, Mexico; (S.E.O.R.); (A.M.E.); (J.A.S.L.); (S.A.M.); (J.A.N.R.); (D.M.F.A.S.)
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Wojtacha JJ, Morawin B, Wawrzyniak-Gramacka E, Tylutka A, de Freitas AKE, Zembron-Lacny A. Endothelial Dysfunction with Aging: Does Sex Matter? Int J Mol Sci 2024; 25:12203. [PMID: 39596269 PMCID: PMC11594464 DOI: 10.3390/ijms252212203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 10/31/2024] [Accepted: 11/10/2024] [Indexed: 11/28/2024] Open
Abstract
Oxidative stress and inflammation accompany endothelial dysfunction that results from the excessive or uncontrolled production of reactive oxygen and nitrogen species (RONS) in older adults. This study was designed to assess the usefulness of serum oxi-inflammatory component combinations in vascular disease prediction and prevention with regard to sex. Women (n = 145) and men (n = 50) aged 72.2 ± 7.8 years participated in this project. The females demonstrated the elevated production of hydrogen peroxide (H2O2) and nitric oxide (NO) responsible for intravascular low-density lipoprotein oxidation. NO generation was enhanced in the women, but its bioavailability was reduced, which was expressed by a high 3-nitrotyrosine (3-NitroT) concentration. The relation of NO/3-NitroT (rs = 0.811, p < 0.001) in the women and NO/3-NitroT (rs = -0.611, p < 0.001) in the men showed that sex determines endothelial dysfunction. RONS generation in the women simultaneously promoted endothelial regeneration, as demonstrated by a ~1.5-fold increase in circulating progenitor cells. Inflammation-specific variables, such as the neutrophil-to-lymphocyte ratio, the systemic immune inflammation index, and the neutrophil-to-high-density lipoprotein (HDL) ratio, were reduced in the women and showed their diagnostic utility for clinical prognosis in vascular dysfunction, especially the C-reactive-protein-to-HDL ratio (AUC = 0.980, specificity 94.7%, sensitivity 93.3%, OR = 252, 95% CI 65-967, p < 0.001). This study is the first to have revealed sex-specific changes in the oxi-inflammatory response, which can generate the risk of cardiovascular events at an older age.
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Affiliation(s)
- Jakub Jozue Wojtacha
- Department of Applied and Clinical Physiology, University of Zielona Gora, 28 Zyty Str., 65-417 Zielona Gora, Poland; (J.J.W.); (B.M.); (E.W.-G.); (A.T.)
| | - Barbara Morawin
- Department of Applied and Clinical Physiology, University of Zielona Gora, 28 Zyty Str., 65-417 Zielona Gora, Poland; (J.J.W.); (B.M.); (E.W.-G.); (A.T.)
| | - Edyta Wawrzyniak-Gramacka
- Department of Applied and Clinical Physiology, University of Zielona Gora, 28 Zyty Str., 65-417 Zielona Gora, Poland; (J.J.W.); (B.M.); (E.W.-G.); (A.T.)
| | - Anna Tylutka
- Department of Applied and Clinical Physiology, University of Zielona Gora, 28 Zyty Str., 65-417 Zielona Gora, Poland; (J.J.W.); (B.M.); (E.W.-G.); (A.T.)
| | - Ana Karyn Ehrenfried de Freitas
- School of Health Science, Positivo University, 5300 Professor Pedro Viriato Parigot de Souza Street, Campo Comprido, Curitiba 81280-330, PR, Brazil;
- Department of Cardiology, Hospital da Cruz Vermelha Brasileira Filial do Paraná, Av. Vicente Machado, 1280, R. Cap. Souza Franco, 50-Batel, Curitiba 80420-011, PR, Brazil
| | - Agnieszka Zembron-Lacny
- Department of Applied and Clinical Physiology, University of Zielona Gora, 28 Zyty Str., 65-417 Zielona Gora, Poland; (J.J.W.); (B.M.); (E.W.-G.); (A.T.)
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Barbosa LB, Gama IRDS, Vasconcelos NBR, Santos EAD, Ataide-Silva T, Ferreira HDS. Dietary patterns according to gender and ethnicity associated with metabolic syndrome: a systematic review and meta-analysis. CIENCIA & SAUDE COLETIVA 2024; 29:e03662023. [PMID: 39292035 DOI: 10.1590/1413-812320242910.03662023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Accepted: 09/26/2023] [Indexed: 09/19/2024] Open
Abstract
The objective of this systematic review (SR) with meta-analysis (MA) was to identify the dietary patterns of the population, regarding ethnicity and gender, and their association with the metabolic syndrome and its risk factors (MetS-RF). The literature search was performed using Medline, Scopus, Ebsco, SciELO, and BVS databases. Studies with adult participants that identified dietary patterns associated with MetS-RF were included. Pooled odds ratio (OR) and 95%CI were calculated using a random-effect, generic inverse variance method. Statistical heterogeneity and publication bias were explored. The dietary patterns were classified as healthy or unhealthy. Studies were categorized into three groups: Women (all ethnicities), Afro-descendant (men and women), and General Population (both genders and ethnicity). Among the articles found (n=8,496), 22 integrated the SR and 11 the MA. The adherence to the healthy dietary pattern was negatively associated (protective factor) with MetS-RF only in the General Population (OR=0.77; 95%CI: 0.61-0.98). Nevertheless, the unhealthy dietary pattern was associated with the higher prevalence of MetS-RF in all analyzed groups. It was concluded that an unhealthy eating pattern increases the chances of SM-RF in adults, regardless of gender and ethnicity.
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Affiliation(s)
- Lídia Bezerra Barbosa
- Faculdade de Nutrição, Universidade Federal de Alagoas (UFAL). Av. Lourival Melo Mota s/n, Tabuleiro do Martins. 57072-900 Maceió AL Brasil.
| | - Isabelle Rodrigues de Souza Gama
- Faculdade de Nutrição, Universidade Federal de Alagoas (UFAL). Av. Lourival Melo Mota s/n, Tabuleiro do Martins. 57072-900 Maceió AL Brasil.
| | | | | | - Thays Ataide-Silva
- Faculdade de Nutrição, Universidade Federal de Alagoas (UFAL). Av. Lourival Melo Mota s/n, Tabuleiro do Martins. 57072-900 Maceió AL Brasil.
| | - Haroldo da Silva Ferreira
- Faculdade de Nutrição, Universidade Federal de Alagoas (UFAL). Av. Lourival Melo Mota s/n, Tabuleiro do Martins. 57072-900 Maceió AL Brasil.
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Habib S. Team players in the pathogenesis of metabolic dysfunctions-associated steatotic liver disease: The basis of development of pharmacotherapy. World J Gastrointest Pathophysiol 2024; 15:93606. [PMID: 39220834 PMCID: PMC11362842 DOI: 10.4291/wjgp.v15.i4.93606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 05/14/2024] [Accepted: 07/23/2024] [Indexed: 08/22/2024] Open
Abstract
Nutrient metabolism is regulated by several factors. Social determinants of health with or without genetics are the primary regulator of metabolism, and an unhealthy lifestyle affects all modulators and mediators, leading to the adaptation and finally to the exhaustion of cellular functions. Hepatic steatosis is defined by presence of fat in more than 5% of hepatocytes. In hepatocytes, fat is stored as triglycerides in lipid droplet. Hepatic steatosis results from a combination of multiple intracellular processes. In a healthy individual nutrient metabolism is regulated at several steps. It ranges from the selection of nutrients in a grocery store to the last step of consumption of ATP as an energy or as a building block of a cell as structural component. Several hormones, peptides, and genes have been described that participate in nutrient metabolism. Several enzymes participate in each nutrient metabolism as described above from ingestion to generation of ATP. As of now several publications have revealed very intricate regulation of nutrient metabolism, where most of the regulatory factors are tied to each other bidirectionally, making it difficult to comprehend chronological sequence of events. Insulin hormone is the primary regulator of all nutrients' metabolism both in prandial and fasting states. Insulin exerts its effects directly and indirectly on enzymes involved in the three main cellular function processes; metabolic, inflammation and repair, and cell growth and regeneration. Final regulators that control the enzymatic functions through stimulation or suppression of a cell are nuclear receptors in especially farnesoid X receptor and peroxisome proliferator-activated receptor/RXR ligands, adiponectin, leptin, and adiponutrin. Insulin hormone has direct effect on these final modulators. Whereas blood glucose level, serum lipids, incretin hormones, bile acids in conjunction with microbiota are intermediary modulators which are controlled by lifestyle. The purpose of this review is to overview the key players in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) that help us understand the disease natural course, risk stratification, role of lifestyle and pharmacotherapy in each individual patient with MASLD to achieve personalized care and target the practice of precision medicine. PubMed and Google Scholar databases were used to identify publication related to metabolism of carbohydrate and fat in states of health and disease states; MASLD, cardiovascular disease and cancer. More than 1000 publications including original research and review papers were reviewed.
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Affiliation(s)
- Shahid Habib
- Department of Hepatology, Liver Institute PLLC, Tucson, AZ 85712, United States
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Carpentier AC. Tracers and Imaging of Fatty Acid and Energy Metabolism of Human Adipose Tissues. Physiology (Bethesda) 2024; 39:0. [PMID: 38113392 PMCID: PMC11283904 DOI: 10.1152/physiol.00012.2023] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 11/22/2023] [Accepted: 12/19/2023] [Indexed: 12/21/2023] Open
Abstract
White adipose tissue and brown adipose tissue (WAT and BAT) regulate fatty acid metabolism and control lipid fluxes to other organs. Dysfunction of these key metabolic processes contributes to organ insulin resistance and inflammation leading to chronic diseases such as type 2 diabetes, metabolic dysfunction-associated steatohepatitis, and cardiovascular diseases. Metabolic tracers combined with molecular imaging methods are powerful tools for the investigation of these pathogenic mechanisms. Herein, I review some of the positron emission tomography and magnetic resonance imaging methods combined with stable isotopic metabolic tracers to investigate fatty acid and energy metabolism, focusing on human WAT and BAT metabolism. I will discuss the complementary strengths offered by these methods for human investigations and current gaps in the field.
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Affiliation(s)
- André C Carpentier
- Department of Medicine, Division of Endocrinology, Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Quebec, Canada
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Nauli AM, Phan A, Tso P, Nauli SM. The effects of sex hormones on the size of intestinal lipoproteins. Front Physiol 2023; 14:1316982. [PMID: 38179142 PMCID: PMC10766372 DOI: 10.3389/fphys.2023.1316982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 12/08/2023] [Indexed: 01/06/2024] Open
Abstract
Larger intestinal lipoproteins are more likely to be retained longer in the intestinal wall, allowing more time for their fat to be hydrolyzed and subsequently taken up by the abdominal viscera. Since men generally accumulate more abdominal visceral fat than women, we sought to determine if males produce larger intestinal lipoproteins compared to females. Using the conscious lymph fistula mouse model, we discovered that the male mice indeed produced larger intestinal lipoproteins than the female mice when they were intraduodenally infused with lipid emulsion. We then employed our differentiated Caco-2 cell model with semipermeable membrane system to determine the effects of sex hormones on the size of intestinal lipoproteins. Lipoprotein size was quantitatively measured by calculating the ratio of triglycerides (TG)/Apolipoprotein B (ApoB) and by analyzing their transmission electron micrographs. Our studies showed that while there was no dose-dependent effect of estrogen and progesterone, testosterone significantly increased the size of lipoproteins. When these hormones were combined to resemble the physiological concentrations observed in males and the different ovarian cycle phases in premenopausal females, both the male and luteal groups had significantly larger lipoproteins than the ovulatory group; and the male group also had significantly larger lipoproteins than the follicular group. The ovulatory group secreted a significantly lower amount of TG than the male and luteal groups. ApoB was comparable among all these groups. These findings support our hypothesis that, through their testosterone effects, males are more likely to produce larger intestinal lipoproteins. Larger lipoproteins tend to remain longer in the intestinal wall and may facilitate fat uptake preferentially by the abdominal viscera. Our studies may partly explain why men are more prone to accumulating abdominal visceral fat, which is an independent predictor of mortality.
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Affiliation(s)
- Andromeda M. Nauli
- Department of Biomedical Sciences, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI, United States
| | - Ann Phan
- Desert Valley Hospital, Victorville, CA, United States
| | - Patrick Tso
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Surya M. Nauli
- Department of Biomedical and Pharmaceutical Sciences, Chapman University, Irvine, CA, United States
- Department of Medicine, University of California, Irvine, Irvine, CA, United States
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Borlaug BA, Jensen MD, Kitzman DW, Lam CSP, Obokata M, Rider OJ. Obesity and heart failure with preserved ejection fraction: new insights and pathophysiological targets. Cardiovasc Res 2023; 118:3434-3450. [PMID: 35880317 PMCID: PMC10202444 DOI: 10.1093/cvr/cvac120] [Citation(s) in RCA: 165] [Impact Index Per Article: 82.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 06/28/2022] [Accepted: 07/01/2022] [Indexed: 02/07/2023] Open
Abstract
Obesity and heart failure with preserved ejection fraction (HFpEF) represent two intermingling epidemics driving perhaps the greatest unmet health problem in cardiovascular medicine in the 21st century. Many patients with HFpEF are either overweight or obese, and recent data have shown that increased body fat and its attendant metabolic sequelae have widespread, protean effects systemically and on the cardiovascular system leading to symptomatic HFpEF. The paucity of effective therapies in HFpEF underscores the importance of understanding the distinct pathophysiological mechanisms of obese HFpEF to develop novel therapies. In this review, we summarize the current understanding of the cardiovascular and non-cardiovascular features of the obese phenotype of HFpEF, how increased adiposity might pathophysiologically contribute to the phenotype, and how these processes might be targeted therapeutically.
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Affiliation(s)
- Barry A Borlaug
- Department of Cardiovascular Diseases, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905, USA
| | | | - Dalane W Kitzman
- Department of Internal Medicine, Section on Cardiology, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | | | - Masaru Obokata
- Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Oliver J Rider
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, Oxford Centre for Clinical Magnetic Resonance Research, University of Oxford, Oxford, UK
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Palmer AK, Jensen MD. Metabolic changes in aging humans: current evidence and therapeutic strategies. J Clin Invest 2022; 132:158451. [PMID: 35968789 PMCID: PMC9374375 DOI: 10.1172/jci158451] [Citation(s) in RCA: 100] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Aging and metabolism are inextricably linked, and many age-related changes in body composition, including increased central adiposity and sarcopenia, have underpinnings in fundamental aging processes. These age-related changes are further exacerbated by a sedentary lifestyle and can be in part prevented by maintenance of activity with aging. Here we explore the age-related changes seen in individual metabolic tissues - adipose, muscle, and liver - as well as globally in older adults. We also discuss the available evidence for therapeutic interventions such as caloric restriction, resistance training, and senolytic and senomorphic drugs to maintain healthy metabolism with aging, focusing on data from human studies.
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Affiliation(s)
| | - Michael D. Jensen
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
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Jesuthasan A, Zhyzhneuskaya S, Peters C, Barnes AC, Hollingsworth KG, Sattar N, Lean MEJ, Taylor R, Al-Mrabeh AH. Sex differences in intraorgan fat levels and hepatic lipid metabolism: implications for cardiovascular health and remission of type 2 diabetes after dietary weight loss. Diabetologia 2022; 65:226-233. [PMID: 34657182 PMCID: PMC8660759 DOI: 10.1007/s00125-021-05583-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 07/29/2021] [Indexed: 11/08/2022]
Abstract
AIMS/HYPOTHESIS Type 2 diabetes confers a greater relative increase in CVD risk in women compared with men. We examined sex differences in intraorgan fat and hepatic VLDL1-triacylglycerol (VLDL1-TG) export before and after major dietary weight loss. METHODS A group with type 2 diabetes (n = 64, 30 male/34 female) and a group of healthy individuals (n = 25, 13 male/12 female) were studied. Intraorgan and visceral fat were quantified by magnetic resonance and VLDL1-TG export by intralipid infusion techniques. RESULTS Triacylglycerol content of the liver and pancreas was elevated in people with diabetes with no sex differences (liver 16.4% [9.3-25.0%] in women vs 11.9% [7.0-23.1%] in men, p = 0.57, and pancreas 8.3 ± 0.5% vs 8.5 ± 0.4%, p = 0.83, respectively). In the absence of diabetes, fat levels in both organs were lower in women than men (1.0% [0.9-1.7%] vs 4.5% [1.9-8.0%], p = 0.005, and 4.7 ± 0.4% vs 7.6 ± 0.5%, p< 0.0001, respectively). Women with diabetes had higher hepatic VLDL1-TG production rate and plasma VLDL1-TG than healthy women (559.3 ± 32.9 vs 403.2 ± 45.7 mg kg-1 day-1, p = 0.01, and 0.45 [0.26-0.77] vs 0.25 [0.13-0.33] mmol/l, p = 0.02), whereas there were no differences in men (548.8 ± 39.8 vs 506.7 ± 29.2 mg kg-1 day-1, p = 0.34, and 0.72 [0.53-1.15] vs 0.50 [0.32-0.68] mmol/l, p = 0.26). Weight loss decreased intraorgan fat and VLDL1-TG production rates regardless of sex, and these changes were accompanied by similar rates of diabetes remission (65.4% vs 71.0%) and CVD risk reduction (59.8% vs 41.5%) in women and men, respectively. CONCLUSIONS/INTERPRETATION In type 2 diabetes, women have liver and pancreas fat levels as high as those of men, associated with raised hepatic VLDL1-TG production rates. Dynamics of triacylglycerol turnover differ between sexes in type 2 diabetes and following weight loss. These changes may contribute to the disproportionately raised cardiovascular risk of women with diabetes.
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Affiliation(s)
- Aaron Jesuthasan
- Magnetic Resonance Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Sviatlana Zhyzhneuskaya
- Magnetic Resonance Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Carl Peters
- Magnetic Resonance Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Alison C Barnes
- Human Nutrition Research Centre, Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Kieren G Hollingsworth
- Magnetic Resonance Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Naveed Sattar
- Institute of Cardiovascular and Medical Science, University of Glasgow, Glasgow, UK
| | - Michael E J Lean
- School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, UK
| | - Roy Taylor
- Magnetic Resonance Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
| | - Ahmad H Al-Mrabeh
- Magnetic Resonance Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
- Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
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Viraragavan A, Willmer T, Patel O, Basson A, Johnson R, Pheiffer C. Cafeteria diet induces global and Slc27a3-specific hypomethylation in male Wistar rats. Adipocyte 2021; 10:108-118. [PMID: 33570456 PMCID: PMC7889207 DOI: 10.1080/21623945.2021.1886697] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Increased visceral adipose tissue (VAT) is associated with metabolic dysfunction, while subcutaneous adipose tissue (SAT) is considered protective. The mechanisms underlying these differences are not fully elucidated. This study aimed to investigate molecular differences in VAT and SAT of male Wistar rats fed a cafeteria diet (CD) or a standard rodent diet (STD) for three months. The expression of fatty acid metabolism genes was analysed by quantitative real-time PCR. Global and gene-specific DNA methylation was quantified using the Imprint® Methylated DNA Quantification Kit and pyrosequencing, respectively. Bodyweight, retroperitoneal fat mass, insulin resistance, leptin and triglyceride concentrations and adipocyte hypertrophy were higher in CD- compared to STD-fed rats. The expression of solute carrier family 27 member 3 (Slc27a3), a fatty acid transporter, was 9.6-fold higher in VAT and 6.3-fold lower in SAT of CD- versus STD-fed rats. Taqman probes confirmed increased Slc27a3 expression, while pyrosequencing showed Slc27a3 hypomethylation in VAT of CD- compared to STD-fed rats. The CD decreased global methylation in both VAT and SAT, although no depot differences were observed. Dysregulated fatty acid influx in VAT, in response to a CD, provides insight into the mechanisms underlying depot-differences in adipose tissue expansion during obesity and metabolic disease. Abbreviations: CD: cafeteria diet; E2F1: E2F Transcription Factor 1; EMSA: electrophoretic mobility shift assay; EGFR: epidermal growth factor receptor; GCF: GC-Rich Sequence DNA-Binding Factor; HOMA-IR: Homeostasis model for insulin resistance; NKX2-1: NK2 homeobox 1; PCR: Polymerase chain reaction; qRT-PCR: quantitative real-time PCR; RF: retroperitoneal fat; SAT: subcutaneous adipose tissue; Slc27a3: solute carrier family 27 member 3; STD: standard diet; TNFα: tumour necrosis factor alpha; TTS: transcriptional start site; T2D: Type 2 Diabetes; VAT: visceral adipose tissue; WT1 I: Wilms’ tumour protein 1
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Affiliation(s)
- Amsha Viraragavan
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, South Africa
- Department of Biochemistry and Microbiology, University of Zululand, Kwa-Dlangezwa, South Africa
| | - Tarryn Willmer
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, South Africa
- Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Tygerberg, South Africa
| | - Oelfah Patel
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, South Africa
- Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, University of Stellenbosch, Tygerberg, South Africa
| | - Albertus Basson
- Department of Biochemistry and Microbiology, University of Zululand, Kwa-Dlangezwa, South Africa
| | - Rabia Johnson
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, South Africa
- Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Tygerberg, South Africa
| | - Carmen Pheiffer
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, South Africa
- Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Tygerberg, South Africa
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Raajendiran A, Krisp C, Souza DPD, Ooi G, Burton PR, Taylor RA, Molloy MP, Watt MJ. Proteome analysis of human adipocytes identifies depot-specific heterogeneity at metabolic control points. Am J Physiol Endocrinol Metab 2021; 320:E1068-E1084. [PMID: 33843278 DOI: 10.1152/ajpendo.00473.2020] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Adipose tissue is a primary regulator of energy balance and metabolism. The distribution of adipose tissue depots is of clinical interest because the accumulation of upper-body subcutaneous (ASAT) and visceral adipose tissue (VAT) is associated with cardiometabolic diseases, whereas lower-body glutealfemoral adipose tissue (GFAT) appears to be protective. There is heterogeneity in morphology and metabolism of adipocytes obtained from different regions of the body, but detailed knowledge of the constituent proteins in each depot is lacking. Here, we determined the human adipocyte proteome from ASAT, VAT, and GFAT using high-resolution Sequential Window Acquisition of all Theoretical (SWATH) mass spectrometry proteomics. We quantified 4,220 proteins in adipocytes, and 2,329 proteins were expressed in all three adipose depots. Comparative analysis revealed significant differences between adipocytes from different regions (6% and 8% when comparing VAT vs. ASAT and GFAT, 3% when comparing the subcutaneous adipose tissue depots, ASAT and GFAT), with marked differences in proteins that regulate metabolic functions. The VAT adipocyte proteome was overrepresented with proteins of glycolysis, lipogenesis, oxidative stress, and mitochondrial dysfunction. The GFAT adipocyte proteome predicted the activation of peroxisome proliferator-activated receptor α (PPARα), fatty acid, and branched-chain amino acid (BCAA) oxidation, enhanced tricarboxylic acid (TCA) cycle flux, and oxidative phosphorylation, which was supported by metabolomic data obtained from adipocytes. Together, this proteomic analysis provides an important resource and novel insights that enhance the understanding of metabolic heterogeneity in the regional adipocytes of humans.NEW & NOTEWORTHY Adipocyte metabolism varies depending on anatomical location and the adipocyte protein composition may orchestrate this heterogeneity. We used SWATH proteomics in patient-matched human upper- (visceral and subcutaneous) and lower-body (glutealfemoral) adipocytes and detected 4,220 proteins and distinguishable regional proteomes. Upper-body adipocyte proteins were associated with glycolysis, de novo lipogenesis, mitochondrial dysfunction, and oxidative stress, whereas lower-body adipocyte proteins were associated with enhanced PPARα activation, fatty acid, and BCAA oxidation, TCA cycle flux, and oxidative phosphorylation.
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Affiliation(s)
- Arthe Raajendiran
- Department of Anatomy and Physiology, University of Melbourne, Melbourne, Victoria, Australia
- Department of Physiology, Monash University, Clayton, Victoria, Australia
- Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, University of Melbourne, Melbourne, Victoria, Australia
| | - Christoph Krisp
- Australian Proteome Analysis Facility, Macquarie University, New South Wales, Australia
| | - David P De Souza
- Metabolomics Australia, Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, Victoria, Australia
| | - Geraldine Ooi
- Faculty of Medicine, Nursing and Health Sciences, Centre for Obesity Research and Education, Monash University, Melbourne, Victoria, Australia
| | - Paul R Burton
- Faculty of Medicine, Nursing and Health Sciences, Centre for Obesity Research and Education, Monash University, Melbourne, Victoria, Australia
| | - Renea A Taylor
- Department of Physiology, Monash University, Clayton, Victoria, Australia
- Cancer Research Division, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia
| | - Mark P Molloy
- Australian Proteome Analysis Facility, Macquarie University, New South Wales, Australia
| | - Matthew J Watt
- Department of Anatomy and Physiology, University of Melbourne, Melbourne, Victoria, Australia
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12
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Carpentier AC. 100 th anniversary of the discovery of insulin perspective: insulin and adipose tissue fatty acid metabolism. Am J Physiol Endocrinol Metab 2021; 320:E653-E670. [PMID: 33522398 DOI: 10.1152/ajpendo.00620.2020] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Insulin inhibits systemic nonesterified fatty acid (NEFA) flux to a greater degree than glucose or any other metabolite. This remarkable effect is mainly due to insulin-mediated inhibition of intracellular triglyceride (TG) lipolysis in adipose tissues and is essential to prevent diabetic ketoacidosis, but also to limit the potential lipotoxic effects of NEFA in lean tissues that contribute to the development of diabetes complications. Insulin also regulates adipose tissue fatty acid esterification, glycerol and TG synthesis, lipogenesis, and possibly oxidation, contributing to the trapping of dietary fatty acids in the postprandial state. Excess NEFA flux at a given insulin level has been used to define in vivo adipose tissue insulin resistance. Adipose tissue insulin resistance defined in this fashion has been associated with several dysmetabolic features and complications of diabetes, but the mechanistic significance of this concept is not fully understood. This review focusses on the in vivo regulation of adipose tissue fatty acid metabolism by insulin and the mechanistic significance of the current definition of adipose tissue insulin resistance. One hundred years after the discovery of insulin and despite decades of investigations, much is still to be understood about the multifaceted in vivo actions of this hormone on adipose tissue fatty acid metabolism.
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Affiliation(s)
- André C Carpentier
- Division of Endocrinology, Department of Medicine, Centre de recherche du CHUS, Université de Sherbrooke, Sherbrooke, Quebec, Canada
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13
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Dehghan A, Vasan SK, Fielding BA, Karpe F. A prospective study of the relationships between change in body composition and cardiovascular risk factors across the menopause. Menopause 2021; 28:400-406. [PMID: 33534433 PMCID: PMC8284369 DOI: 10.1097/gme.0000000000001721] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 10/22/2020] [Accepted: 10/22/2020] [Indexed: 11/25/2022]
Abstract
OBJECTIVE Menopause increases the risk of cardiovascular disease (CVD) which in part has been attributed to the rise in cholesterol and blood pressure (BP). This study examined the hypothesis that menopausal changes in body composition and regional fat depots relate to the change in CVD risk factors. METHODS A prospective recall study was designed to capture premenopausal women to be re-examined soon after menopause. A total of 97 women from the Oxford Biobank underwent dual x-ray absorptiometry, blood biochemistry, and BP readings pre- and postmenopause. RESULTS Despite minimal changes in body weight over the 5.1 ± 0.9 year follow-up period, there was an increase in total fat mass and a decline in lean mass, where the proportional change of regional fat mass was the greatest for the visceral fat depot (+22%, P < 0.01). Plasma ApoB (+12%, P < 0.01) and C-reactive protein (+45%, P < 0.01) increased as did systolic (+7%, P < 0.001) and diastolic BP (+5%, P < 0.001). Plasma nonesterified fatty acids decreased (-20%, P < 0.05) which may reflect on a change in adipose tissue function across the menopause. PCSK-9 decreased (-26%, P < 0.01) which suggests a compensation for the postmenopausal reduction in low-density lipoprotein receptor activity. Using multilinear regression analyses the changes in ApoB and diastolic BP were associated with visceral fat mass change, but this association was lost when adjusted for total fat mass change. CONCLUSION The increase in CVD risk factor burden across menopause may not be driven by changes in body composition, rather by functional changes in end organs such as adipose tissue and liver.
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Affiliation(s)
- Aaron Dehghan
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK
| | - Senthil K. Vasan
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK
| | | | - Fredrik Karpe
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK
- NIHR Oxford Biomedical Centre, Oxford University Hospital Trust and University of Oxford, Oxford, UK
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Abstract
Although visceral fat is strongly correlated with the metabolic complications of obesity, the existing data indicate it is not the cause of these complications. Excess release of free fatty acids (FFA) from adipose tissue lipolysis can account for a sizable portion of the metabolic complications of obesity. In humans, upper-body subcutaneous adipose tissue accounts for most systemic FFA, whereas visceral fat contributes a modest portion of the excess amount to which the liver is exposed. This pattern is maintained in upper-body/visceral obesity, except that greater amounts of visceral fat expose the liver to more FFA from visceral adipose tissue lipolysis.
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Affiliation(s)
- Michael D Jensen
- Department of Endocrinology, Metabolism, Diabetes, & Nutrition, Mayo Clinic, 200 First Street Southwest, Room 5-194 Joseph, Rochester, MN 55905, USA.
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15
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Nauli AM, Matin S. Why Do Men Accumulate Abdominal Visceral Fat? Front Physiol 2019; 10:1486. [PMID: 31866877 PMCID: PMC6906176 DOI: 10.3389/fphys.2019.01486] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 11/21/2019] [Indexed: 12/18/2022] Open
Abstract
Men have a higher tendency to accumulate abdominal visceral fat compared to pre-menopausal women. The accumulation of abdominal visceral fat in men, which is a strong independent predictor of mortality, is mainly due to the higher dietary fat uptake by their abdominal visceral fat. Since dietary fat is absorbed by the enterocytes and transported to the circulation in the forms of chylomicrons and very low density lipoproteins (VLDLs), it is crucial to understand how these lipoproteins are different between men and women. The chylomicrons in men are generally bigger in size and more in quantity than those in women. During the postprandial state, these chylomicrons congest the lamina propria and the low-pressure lymphatics. In this paper, we propose that this congestion predisposes the chylomicron triglycerides to hydrolysis by lipoprotein lipase (LPL). The liberated fatty acids are then stored by the nearby abdominal visceral adipocytes, leading to the accumulation of abdominal visceral fat. These mechanisms perhaps explain why men, through their bigger and higher production of chylomicrons, are more likely to accumulate abdominal visceral fat than pre-menopausal women. This accumulation eventually leads to belly enlargement, which confers men their apple-shaped body.
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Affiliation(s)
- Andromeda M Nauli
- Department of Pharmaceutical Sciences, College of Pharmacy, Marshall B. Ketchum University, Fullerton, CA, United States
| | - Sahar Matin
- College of Pharmacy, Marshall B. Ketchum University, Fullerton, CA, United States
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16
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Malandrino N, Reynolds JC, Brychta RJ, Chen KY, Auh S, Gharib AM, Startzell M, Cochran EK, Brown RJ. Visceral fat does not contribute to metabolic disease in lipodystrophy. Obes Sci Pract 2019; 5:75-82. [PMID: 30847226 PMCID: PMC6381384 DOI: 10.1002/osp4.319] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2018] [Revised: 12/05/2018] [Accepted: 12/06/2018] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVES Lipodystrophies are characterized by regional or generalized loss of adipose tissue and severe metabolic complications. The role of visceral adipose tissue (VAT) in the development of metabolic derangements in lipodystrophy is unknown. The study aim was to investigate VAT contribution to metabolic disease in lipodystrophy versus healthy controls. METHODS Analysis of correlations between VAT volume and biomarkers of metabolic disease in 93 patients and 93 age/sex-matched healthy controls. RESULTS Patients with generalized lipodystrophy (n = 43) had lower VAT compared with matched controls, while those with partial lipodystrophy (n = 50) had higher VAT versus controls. Both groups with lipodystrophy had lower leg fat mass versus controls (p < 0.05 for all; unpaired t-test). In both generalized and partial lipodystrophy, there was no correlation between VAT and glucose, triglycerides or high-density lipoprotein cholesterol (p > 0.05 for all; Spearman correlation). In controls matched to patients with generalized or partial lipodystrophy, VAT correlated with glucose (R = 0.42 and 0.36), triglycerides (R = 0.36 and 0.60) and high-density lipoprotein cholesterol (R = -0.34 and -0.64) (p < 0.05 for all; Spearman correlation). CONCLUSIONS In contrast to healthy controls, metabolic derangements in lipodystrophy did not correlate with VAT volume. These data suggest that, in lipodystrophy, impaired peripheral subcutaneous fat deposition may exert a larger effect than VAT accumulation on the development of metabolic complications. Interventions aimed at increasing functional subcutaneous adipose tissue may provide metabolic benefit.
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Affiliation(s)
- N. Malandrino
- Diabetes, Endocrinology, and Obesity BranchNIDDK, NIHBethesdaMDUSA
| | - J. C. Reynolds
- Radiology and Imaging Sciences DepartmentClinical Center, NIHBethesdaMDUSA
| | - R. J. Brychta
- Diabetes, Endocrinology, and Obesity BranchNIDDK, NIHBethesdaMDUSA
| | - K. Y. Chen
- Diabetes, Endocrinology, and Obesity BranchNIDDK, NIHBethesdaMDUSA
| | - S. Auh
- Office of the DirectorNIDDK, NIHBethesdaMDUSA
| | - A. M. Gharib
- Biomedical and Metabolic Imaging BranchNIDDK, NIHBethesdaMDUSA
| | - M. Startzell
- Diabetes, Endocrinology, and Obesity BranchNIDDK, NIHBethesdaMDUSA
| | - E. K. Cochran
- Diabetes, Endocrinology, and Obesity BranchNIDDK, NIHBethesdaMDUSA
| | - R. J. Brown
- Diabetes, Endocrinology, and Obesity BranchNIDDK, NIHBethesdaMDUSA
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17
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Søndergaard E, Nielsen S. VLDL triglyceride accumulation in skeletal muscle and adipose tissue in type 2 diabetes. Curr Opin Lipidol 2018; 29:42-47. [PMID: 29135689 DOI: 10.1097/mol.0000000000000471] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE OF REVIEW Insulin resistance is closely linked to accumulation of lipid outside adipose tissue (ectopic fat storage). VLDL particles transport lipids from the liver to peripheral tissues. However, whether abnormalities in VLDL-triglyceride storage in muscle and adipose tissue exist in type 2 diabetes has previously been unknown, primarily because of methodological difficulties. Here, we review recent research on VLDL-triglyceride storage. RECENT FINDINGS In a recent study, men with type 2 diabetes had increased skeletal muscle VLDL-triglyceride storage compared to weight-matched nondiabetic men, potentially leading to intramyocellular triglyceride accumulation. In contrast, studies of adipose tissue VLDL-triglyceride storage have shown similar storage capacity in men with and without diabetes, both in the postabsorptive and the postprandial period. In the initial submission, studies have failed to show associations between lipoprotein lipase activity, considered the rate-limiting step in storage of lipids from lipoproteins, and VLDL-TG storage in both muscle and adipose tissue. SUMMARY Differences in muscle VLDL-triglyceride storage may lead to ectopic fat storage and contribute to the development of type 2 diabetes, whereas the ability to store VLDL-triglyceride in adipose tissue is preserved in type 2 diabetes.
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Affiliation(s)
- Esben Søndergaard
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus C
- Danish Diabetes Academy, Odense University Hospital, Odense C, Denmark
| | - Søren Nielsen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus C
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18
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Schrauwen-Hinderling VB, Carpentier AC. Molecular imaging of postprandial metabolism. J Appl Physiol (1985) 2017; 124:504-511. [PMID: 28495844 DOI: 10.1152/japplphysiol.00212.2017] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Disordered postprandial metabolism of energy substrates is one of the main defining features of prediabetes and contributes to the development of several chronic diseases associated with obesity, such as type 2 diabetes and cardiovascular diseases. Postprandial energy metabolism has been studied using classical isotopic tracer approaches that are limited by poor access to splanchnic metabolism and highly dynamic and complex exchanges of energy substrates involving multiple organs and systems. Advances in noninvasive molecular imaging modalities, such as PET and MRI/magnetic resonance spectroscopy (MRS), have recently allowed important advances in our understanding of postprandial energy metabolism in humans. The present review describes some of these recent advances, with particular focus on glucose and fatty acid metabolism in the postprandial state, and discusses current gaps in knowledge and new perspectives of application of PET and MRI/MRS for the investigation and treatment of human metabolic diseases.
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Affiliation(s)
- Vera B Schrauwen-Hinderling
- Department of Radiology and Human Biology and Human Movement Sciences, Maastricht University Medical Center , Maastricht , The Netherlands
| | - André C Carpentier
- Department of Medicine, Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke , Sherbrooke, Québec , Canada
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19
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Søndergaard E, Andersen IR, Sørensen LP, Gormsen LC, Nielsen S. Lipoprotein lipase activity does not predict very low-density lipoprotein-triglyceride fatty acid oxidation during exercise. Scand J Med Sci Sports 2017; 27:474-481. [PMID: 28207959 DOI: 10.1111/sms.12859] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/13/2017] [Indexed: 11/30/2022]
Abstract
Exercise lowers plasma triglyceride levels, but the physiological mechanisms remain not fully elucidated. Lipoprotein lipase (LPL) is a key enzyme in facilitating fatty acid uptake from lipoproteins. As exercise increases the efficiency of very low-density lipoprotein-triglyceride (VLDL-TG) oxidation, we hypothesized that muscle LPL activity would be a rate-limiting step and predict VLDL-TG Fatty acids oxidation during exercise. Sixteen healthy, lean subjects (eight men and eight women) were examined before and during an acute exercise bout (90 minutes at 50% of VO2-max). Heparin-releasable LPL activity was measured in muscle and adipose tissue biopsies. Breath 14 CO2 was measured after a primed-constant infusion of ex vivo labeled [14 C]-triolein VLDL-TG. Fractional VLDL-TG storage was measured in adipose tissue biopsies. Exercise did not affect muscle LPL activity (P=.30). No association was observed between muscle LPL activity and VLDL-TG oxidation, neither in the basal state (P=.17) nor during exercise (P=.83). Exercise did not affect upper body or lower body adipose tissue LPL activity (both P=.92). The basal adipose tissue fractional VLDL-TG storage (abdominal.13%±9%; femoral 17%±10% (P=.18)) was not associated with upper body (P=.56) or lower body (P=.44) subcutaneous adipose tissue LPL activity. Muscle LPL activity does not predict VLDL-TG oxidation during rest or exercise. In addition, adipose tissue LPL activity was not associated with VLDL-TG storage during rest. This suggests that LPL activity is present in excess of what is required to facilitate lipid uptake for oxidation during both rest and exercise.
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Affiliation(s)
- E Søndergaard
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.,The Danish Diabetes Academy, Odense, Denmark
| | - I R Andersen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - L P Sørensen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - L C Gormsen
- Department of Nuclear Medicine and PET center, Aarhus University Hospital, Aarhus, Denmark
| | - S Nielsen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
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20
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Andersen IR, Søndergaard E, Sørensen LP, Nellemann B, Gormsen LC, Jensen MD, Nielsen S. Increased VLDL-TG Fatty Acid Storage in Skeletal Muscle in Men With Type 2 Diabetes. J Clin Endocrinol Metab 2017; 102:831-839. [PMID: 27898284 DOI: 10.1210/jc.2016-2979] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Accepted: 11/28/2016] [Indexed: 12/19/2022]
Abstract
CONTEXT Lipoprotein lipase (LPL) activity is considered the rate-limiting step of very-low-density-lipoprotein triglycerides (VLDL-TG) tissue storage, and has been suggested to relate to the development of obesity as well as insulin resistance and type 2 diabetes. OBJECTIVE The objective of the study was to assess the relationship between the quantitative storage of VLDL-TG fatty acids and LPL activity and other storage factors in muscle and adipose tissue. In addition, we examine whether such relations were influenced by type 2 diabetes. DESIGN We recruited 23 men (12 with type 2 diabetes, 11 nondiabetic) matched for age and body mass index. Postabsorptive VLDL-TG muscle and subcutaneous adipose tissue (abdominal and leg) quantitative storage was measured using tissue biopsies in combination with a primed-constant infusion of ex vivo triolein labeled [1-14C]VLDL-TG and a bolus infusion of ex vivo triolein labeled [9,10-3H]VLDL-TG. Biopsies were analyzed for LPL activity and cellular storage factors. RESULTS VLDL-TG storage rate was significantly greater in men with type 2 diabetes compared with nondiabetic men in muscle tissue (P = 0.02). We found no significant relationship between VLDL-TG storage rate and LPL activity or other storage factors in muscle or adipose tissue. However, LPL activity correlated with fractional VLDL-TG storage in abdominal fat (P = 0.04). CONCLUSIONS Men with type 2 diabetes have increased VLDL-TG storage in muscle tissue, potentially contributing to increased intramyocellular triglyceride and ectopic lipid deposition. Neither muscle nor adipose tissue storage rates were related to LPL activity. This argues against LPL as a rate-limiting step in the postabsorptive quantitative storage of VLDL-TG.
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Affiliation(s)
| | - Esben Søndergaard
- Departments of Endocrinology and Internal Medicine and
- Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota 55905; and
- Danish Diabetes Academy, 5000 Odense, Denmark
| | | | | | - Lars C Gormsen
- Department of Nuclear Medicine and PET Center, Aarhus University Hospital, 8000 Aarhus, Denmark
| | - Michael D Jensen
- Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota 55905; and
| | - Søren Nielsen
- Departments of Endocrinology and Internal Medicine and
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21
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Abstract
PURPOSE OF REVIEW Experimental evidences are strong for a role of long-chain saturated fatty acids in the development of insulin resistance and type 2 diabetes. Ectopic accretion of triglycerides in lean organs is a characteristic of prediabetes and type 2 diabetes and has been linked to end-organ complications. The contribution of disordered dietary fatty acid (DFA) metabolism to lean organ overexposure and lipotoxicity is still unclear, however. DFA metabolism is very complex and very difficult to study in vivo in humans. RECENT FINDINGS We have recently developed a novel imaging method using PET with oral administration of 14-R,S-F-fluoro-6-thia-heptadecanoic acid (FTHA) to quantify organ-specific DFA partitioning. Our studies thus far confirmed impaired storage of DFA per volume of fat mass in abdominal adipose tissues of individuals with prediabetes. They also highlighted the increased channeling of DFA toward the heart, associated with subclinical reduction in cardiac systolic and diastolic function in individuals with prediabetes. SUMMARY In the present review, we summarize previous work on DFA metabolism in healthy and prediabetic states and discuss these in the light of our novel findings using PET imaging of DFA metabolism. We herein provide an integrated view of abnormal organ-specific DFA partitioning in prediabetes in humans.
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Affiliation(s)
- Christophe Noll
- Division of Endocrinology, Department of Medicine, Centre de recherche du CHUS, Université de Sherbrooke, Sherbrooke, Quebec, Canada
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22
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Laforenza U, Bottino C, Gastaldi G. Mammalian aquaglyceroporin function in metabolism. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2015; 1858:1-11. [PMID: 26456554 DOI: 10.1016/j.bbamem.2015.10.004] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 10/05/2015] [Accepted: 10/07/2015] [Indexed: 11/26/2022]
Abstract
Aquaglyceroporins are integral membrane proteins that are permeable to glycerol as well as water. The movement of glycerol from a tissue/organ to the plasma and vice versa requires the presence of different aquaglyceroporins that can regulate the entrance or the exit of glycerol across the plasma membrane. Actually, different aquaglyceroporins have been discovered in the adipose tissue, small intestine, liver, kidney, heart, skeletal muscle, endocrine pancreas and capillary endothelium, and their differential expression could be related to obesity and the type 2 diabetes. Here we describe the expression and function of different aquaglyceroporins in physiological condition and in obesity and type 2 diabetes, suggesting they are potential therapeutic targets for metabolic disorders.
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Affiliation(s)
| | - Cinzia Bottino
- Department of Molecular Medicine, University of Pavia, Italy
| | - Giulia Gastaldi
- Department of Molecular Medicine, University of Pavia, Italy
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Laforest S, Labrecque J, Michaud A, Cianflone K, Tchernof A. Adipocyte size as a determinant of metabolic disease and adipose tissue dysfunction. Crit Rev Clin Lab Sci 2015; 52:301-13. [DOI: 10.3109/10408363.2015.1041582] [Citation(s) in RCA: 118] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Abstract
Body fat distribution, especially visceral fat accumulation, may contribute more than total fat mass per se to the development of metabolic and cardiovascular disorders. Early prevention highly improves health outcomes later in life, especially when considering such cumulative conditions as atherosclerosis. However, as these processes emerge to be partly reversible, dietary and lifestyle interventions at any age and health condition are greatly beneficial. Given the worldwide abundance of metabolic and cardiovascular disorders, the identification and implementation of strategies for preventing or reducing the accumulation of morbid fat tissues is of great importance for preventing and regressing atherosclerosis. This review focuses on dietary strategies and specific food components that were demonstrated to alter body fat distribution and regression of atherosclerosis. Different properties of various adipose depots (superficial subcutaneous, deep subcutaneous and visceral fat depots) and their contribution to metabolic and cardiovascular disorders are briefly discussed. Visceral obesity and atherosclerosis should be approached as modifiable rather than ineluctable conditions.
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25
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Moore Simas TA, Corvera S, Lee MM, Zhang N, Leung K, Olendzki B, Barton B, Rosal MC. Understanding multifactorial influences on the continuum of maternal weight trajectories in pregnancy and early postpartum: study protocol, and participant baseline characteristics. BMC Pregnancy Childbirth 2015; 15:71. [PMID: 25885002 PMCID: PMC4389494 DOI: 10.1186/s12884-015-0490-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Accepted: 02/25/2015] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND Maternal and offspring immediate and long-term health are affected by pregnancy weight gain and maternal weight. This study was designed to determine feasibility of: 1) recruiting a socio-economically and racially/ethnically diverse sample of pregnant women into a longitudinal observational study, including consenting the women for serial biologic specimen evaluations; 2) implementing comprehensive assessments (including biologic, anthropometric, behavioral, cognitive/psychosocial and socio-demographic, and cultural measures) at multiple time points over the study period, including collecting biologic specimens at planned and unplanned pregnancy delivery times; and 3) retaining the sample for one year into the postpartum period. Additionally, the study will provide preliminary data of associations among hypothesized predictors, mediators and moderators of pregnancy and post-partum maternal and infant weight trajectories. The study was conceptualized under a Biopsychosocial Model using a lifespan approach. Study protocol and baseline characteristics are described. METHODS/DESIGN We sought to recruit a sample of 100 healthy women age 18-45 years, between 28-34 weeks gestation, with singleton pregnancies, enrolled in care prior to 17 weeks gestation. Women provide written consent for face-to-face (medical history, anthropometrics, biologic specimens), and paper-and-pencil assessments, at five time points: baseline (third trimester), delivery-associated, and 6-weeks, 3-months and 6-months postpartum. Additional telephone-based assessments (diet, physical activity and breastfeeding) administered baseline and three-months postpartum. Infant weights are collected until 1-year of life. We seek to retain 80% of participants at six-months postpartum and 80% of offspring at 12-months. 110 women were recruited. Sample characteristics include: mean age 28.3 years, BMI 25.7 kg/m(2), and gestational age at baseline visit of 32.5 weeks. One-third of cohort was non-white, over a quarter were Latina, and almost a quarter were non-US born. The cohort majority was multigravida, had graduated high school and/or had higher levels of education, and worked outside the home. DISCUSSION Documentation of study feasibility and preliminary data for theory-driven hypothesis of maternal and child factors associated with weight trajectories will support future large scale longitudinal studies of risk and protective factors for maternal and child health. This research will also inform intervention targets facilitating healthy maternal and child weight.
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Affiliation(s)
- Tiffany A Moore Simas
- Department of Obstetrics & Gynecology, Division of Research, University of Massachusetts Medical School/UMass Memorial Health Care, Memorial Campus - 119 Belmont Street, Worcester, MA, 01605, USA.
| | - Silvia Corvera
- Department of Medicine, Program in Molecular Medicine, University of Massachusetts Medical School, Biotech 2 - 373 Plantation Street, Worcester, MA, 01605, USA.
| | - Mary M Lee
- Department of Pediatrics, University of Massachusetts Medical School/UMass Memorial Health Care, University Campus - 55 Lake Avenue, Worcester, MA, 01655, USA.
| | - NingNing Zhang
- Department of Pediatrics, University of Massachusetts Medical School/UMass Memorial Health Care, University Campus - 55 Lake Avenue, Worcester, MA, 01655, USA.
| | - Katherine Leung
- Department of Obstetrics & Gynecology, Division of Research, University of Massachusetts Medical School/UMass Memorial Health Care, Memorial Campus - 119 Belmont Street, Worcester, MA, 01605, USA.
| | - Barbara Olendzki
- Department of Medicine, Division of Preventive and Behavioral Medicine, University of Massachusetts Medical School, University Campus - 55 Lake Avenue, Worcester, MA, 01655, USA.
| | - Bruce Barton
- Department of Quantitative Health Sciences, University of Massachusetts Medical School, University Campus - 55 Lake Avenue, Worcester, MA, 01655, USA.
| | - Milagros C Rosal
- Department of Medicine, Division of Preventive and Behavioral Medicine, University of Massachusetts Medical School, University Campus - 55 Lake Avenue, Worcester, MA, 01655, USA.
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26
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Bucci M, Karmi AC, Iozzo P, Fielding BA, Viljanen A, Badeau RM, Borra R, Saunavaara V, Pham T, Hannukainen JC, Kalliokoski K, Haaparanta-Solin M, Viljanen T, Parkkola R, Frayn KN, Nuutila P. Enhanced fatty acid uptake in visceral adipose tissue is not reversed by weight loss in obese individuals with the metabolic syndrome. Diabetologia 2015; 58:158-64. [PMID: 25331375 DOI: 10.1007/s00125-014-3402-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2014] [Accepted: 09/15/2014] [Indexed: 11/26/2022]
Abstract
AIMS/HYPOTHESIS Obesity causes an imbalance in fat mass distribution between visceral and subcutaneous adipose tissue (AT) depots. We tested the hypothesis that this relates to increased NEFA uptake between these depots in obese compared with healthy participants. Second, we hypothesised that a diet very low in energy (very low calorie diet [VLCD]) decreases fat mass in obese participants and that this is associated with the decline in NEFA uptake. METHODS NEFA uptake in AT depots was measured with [(18)F]-fluoro-6-thia-heptadecanoic acid ((18)F-FTHA) and positron emission tomography (PET) in 18 obese participants with the metabolic syndrome before and after a 6 week VLCD. Whole body fat oxidation was measured using indirect calorimetry and [U-(13)C]palmitate. Sixteen non-obese participants were controls. RESULTS Obese participants had >100% higher (p < 0.0001) NEFA uptake in the visceral and subcutaneous abdominal AT depots than controls. VLCD decreased AT mass in all regions (12% to 21%), but NEFA uptake was decreased significantly (18%; p < 0.006) only in the femoral AT. Whole body carbohydrate oxidation decreased, while fat oxidation increased. CONCLUSIONS/INTERPRETATION The data demonstrate that weight loss caused by VLCD does not affect abdominal fasting NEFA uptake rates. We found that visceral fat takes up more NEFAs than subcutaneous AT depots, even after weight loss.
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Affiliation(s)
- Marco Bucci
- Turku PET Centre, University of Turku and Turku University Hospital, P.O. Box 52, FI-20521, Turku, Finland,
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Dennedy MC, Vidal-Puig A. Review Article: An Adipocentric View of the Metabolic Syndrome and Cardiovascular Disease. CURRENT CARDIOVASCULAR RISK REPORTS 2014. [DOI: 10.1007/s12170-014-0379-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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28
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Dietary patterns, abdominal visceral adipose tissue, and cardiometabolic risk factors in African Americans: the Jackson heart study. Obesity (Silver Spring) 2013. [PMID: 23592674 PMCID: PMC3478414 DOI: 10.1038/oby.2012.145] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Dietary behavior is an important lifestyle factor to impact an individual’s risk of developing cardiovascular disease (CVD). However, the influence of specific dietary factors on CVD risk for African Americans remains unclear. We conducted a cross-sectional study of 1775 participants from Jackson Heart Study (JHS) Exam 2 (between 2006 and 2009) who were free of hypertension, diabetes and CVD at the baseline (between 2001 and 2004). Dietary intakes were documented using a validated food-frequency questionnaire (FFQ) and dietary patterns were generated by factor analysis. Three major dietary patterns were identified: a “southern”, a “fast food” and a “prudent” pattern. After adjustment for age, sex, smoking and alcohol status, education level and physical activity, high “southern” pattern score was associated with an increased odds ratio (OR) for high abdominal visceral adipose tissue (VAT) (OR:1.80, 95%CI:1.1–3.0, p=0.02), hypertension (OR:1.42, 95%CI:1.1–1.9, p=0.02), diabetes (OR:2.03, 95%CI:1.1–3.9, p=0.03) and metabolic syndrome (OR:2.16, 95%CI:1.3–3.6, p=0.004). Similar associations were also observed in the “fast food” pattern (p ranges 0.03–0.0001). The “prudent” pattern was significantly associated, in a protective direction, with hypertension (OR 0.69, 95%CI 0.5–0.9, p=0.02). In conclusion, dietary patterns, especially the “southern” pattern, identified from a regional specific FFQ in this Deep South African Americans, are correlated with abdominal VAT and cardiometabolic risk factors.
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29
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Association between plasma nonesterified fatty acids species and adipose tissue fatty acid composition. PLoS One 2013; 8:e74927. [PMID: 24098359 PMCID: PMC3788793 DOI: 10.1371/journal.pone.0074927] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2013] [Accepted: 08/06/2013] [Indexed: 12/18/2022] Open
Abstract
Fatty acid composition of adipose tissue (AT) is an established long-term biomarker for fatty acid (FA) intake and status, but AT samples are not easily available. Nonesterified FA composition in plasma (pNEFA) may be a good indicator of AT FA composition, because pNEFA are mainly generated by AT lipolysis. We investigated the correlation of 42 pNEFA and subcutaneous as well as visceral AT FA in 27 non-diabetic women with a median BMI of 36 kg/m2 (Q0.25: 25 kg/m2; Q0.75: 49 kg/m2). Close correlations of pNEFA and AT FA were found for odd-chain FA (15∶0 r = 0.838 and 0.862 for subcutaneous and visceral AT, respectively) and omega-3 FA (22∶6 r = 0.719/0.535), while no significant or low correlations were found for other FA including 18∶1 (r = 0.384/0.325) and 20∶4 (r = 0.386/0.266). Close correlations of pNEFA and AT FA were found for essential fatty acids, like 18∶2 (r = 0.541/0.610) and 20∶5 (r = 0.561/0.543). The lower correlation for some pNEFA species with AT FA indicates that the variation of most pNEFA is significantly affected by other FA sources and flux of FA to tissue, in addition to release from AT. A relevant influence of BMI on the level of correlation was shown for saturated FA. NEFA analysis in fasted plasma can serve as a virtual AT biopsy for some FA, and as a biomarker for intake of dairy products and sea fish.
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30
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Almandoz JP, Singh E, Howell LA, Grothe K, Vlazny DT, Smailovic A, Irving BA, Nelson RH, Miles JM. Spillover of Fatty acids during dietary fat storage in type 2 diabetes: relationship to body fat depots and effects of weight loss. Diabetes 2013; 62:1897-903. [PMID: 23349503 PMCID: PMC3661646 DOI: 10.2337/db12-1407] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Spillover of lipoprotein lipase-generated fatty acids from chylomicrons into the plasma free fatty acid (FFA) pool is an important source of FFA and reflects inefficiency in dietary fat storage. We measured spillover in 13 people with type 2 diabetes using infusions of a [(3)H]triolein-labeled lipid emulsion and [U-(13)C]oleate during continuous feeding, before and after weight loss. Body fat was measured with dual energy X-ray absorptiometry and computed tomography. Participants lost ∼14% of body weight. There was an ∼38% decrease in meal-suppressed FFA concentration (P < 0.0001) and an ∼23% decrease in oleate flux (P = 0.007). Fractional spillover did not change (P = NS). At baseline, there was a strong negative correlation between spillover and leg fat (r = -0.79, P = 0.001) and a positive correlation with the trunk-to-leg fat ratio (R = 0.56, P = 0.047). These correlations disappeared after weight loss. Baseline leg fat (R = -0.61, P = 0.027) but not trunk fat (R = -0.27, P = 0.38) negatively predicted decreases in spillover with weight loss. These results indicate that spillover, a measure of inefficiency in dietary fat storage, is inversely associated with lower body fat in type 2 diabetes.
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Affiliation(s)
- Jaime P. Almandoz
- Endocrine Research Unit, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota
| | - Ekta Singh
- Endocrine Research Unit, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota
| | - Lisa A. Howell
- Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota
| | - Karen Grothe
- Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota
| | - Danielle T. Vlazny
- Endocrine Research Unit, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota
| | - Almira Smailovic
- Endocrine Research Unit, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota
| | - Brian A. Irving
- Endocrine Research Unit, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota
| | - Robert H. Nelson
- Endocrine Research Unit, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota
| | - John M. Miles
- Endocrine Research Unit, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota
- Corresponding author: John M. Miles,
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Tchkonia T, Thomou T, Zhu Y, Karagiannides I, Pothoulakis C, Jensen MD, Kirkland JL. Mechanisms and metabolic implications of regional differences among fat depots. Cell Metab 2013; 17:644-656. [PMID: 23583168 PMCID: PMC3942783 DOI: 10.1016/j.cmet.2013.03.008] [Citation(s) in RCA: 484] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Fat distribution is closely linked to metabolic disease risk. Distribution varies with sex, genetic background, disease state, certain drugs and hormones, development, and aging. Preadipocyte replication and differentiation, developmental gene expression, susceptibility to apoptosis and cellular senescence, vascularity, inflammatory cell infiltration, and adipokine secretion vary among depots, as do fatty-acid handling and mechanisms of enlargement with positive-energy and loss with negative-energy balance. How interdepot differences in these molecular, cellular, and pathophysiological properties are related is incompletely understood. Whether fat redistribution causes metabolic disease or whether it is a marker of underlying processes that are primarily responsible is an open question.
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Affiliation(s)
| | - Thomas Thomou
- Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
| | - Yi Zhu
- Robert and Arlene Kogod Center on Aging
| | - Iordanes Karagiannides
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, Department of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
| | - Charalabos Pothoulakis
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, Department of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
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32
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Carpentier AC. The 2012 CDA-CIHR INMD young investigator award lecture: dysfunction of adipose tissues and the mechanisms of ectopic fat deposition in type 2 diabetes. Can J Diabetes 2013; 37:109-14. [PMID: 24070801 DOI: 10.1016/j.jcjd.2013.03.026] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Revised: 03/12/2013] [Accepted: 03/12/2013] [Indexed: 12/20/2022]
Abstract
Ectopic fat deposition in skeletal muscles, liver, heart, and other tissues has been closely linked with the development of lean tissues' insulin resistance and progression toward type 2 diabetes mellitus. Mechanisms of overexposure of these tissues to fatty acids include increased de novo lipogenesis, impaired fatty acid oxidation and increased fatty acid flux to these organs. White adipose tissues are the main organs responsible for the regulation of circulating fatty acids. It has been clearly demonstrated that pre-diabetes individuals and individuals with diabetes display impaired adipose tissue dietary fatty acid storage that may lead to increased circulating flux and exaggerated lean tissue fatty acid exposure. Additionally, brown adipose tissue depots are less metabolically active in individuals with type 2 diabetes. We have developed a series of novel in vivo investigative tools using positron emission tomography to comprehensively assess postprandial interorgan fatty acid partitioning and white and brown adipose tissue metabolism in subjects with pre-diabetes and type 2 diabetes. Our findings shed new lights into the sophisticated mechanisms that regulate fatty acid partitioning and energy homeostasis during the development of type 2 diabetes. New links between abnormal dietary fatty acid metabolism and early myocardial metabolic and functional defects are now being uncovered in humans with the hope to find novel ways to predict and avoid the devastating complications of diabetes.
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Affiliation(s)
- André C Carpentier
- CIHR-GSK Chair in Diabetes Department of Medicine, Division of Endocrinology, Université de Sherbrooke, Centre de recherche clinique Étienne-Le Bel, Centre hospitalier universitaire de Sherbrooke, Sherbrooke, Québec, Canada.
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33
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Liu J, Hickson DA, Musani SK, Talegawkar SA, Carithers TC, Tucker KL, Fox CS, Taylor HA. Dietary patterns, abdominal visceral adipose tissue, and cardiometabolic risk factors in African Americans: the Jackson heart study. Obesity (Silver Spring) 2013; 21:644-51. [PMID: 23592674 PMCID: PMC3478414 DOI: 10.1002/oby.20265] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2011] [Accepted: 05/11/2012] [Indexed: 12/21/2022]
Abstract
OBJECTIVE To examine the relative association of abdominal visceral adipose tissue (VAT) with cardiometabolic risk factors between African and European Americans. DESIGN AND METHODS We conducted a cross-sectional study of 2035 African Americans from Jackson Heart Study (JHS) and 3170 European Americans from Framingham Heart Study (FHS) who underwent computed tomography assessment of VAT and subcutaneous adipose tissue (SAT). The FHS participants were weighted to match the age distribution of the JHS participants and the metabolic risk factors were examined by study groups in relation to VAT. RESULTS JHS participants had higher rates of obesity, hypertension, diabetes and metabolic syndrome than FHS participants (all p = 0.001). The associations were weaker in JHS women for VAT with blood pressure, triglycerides, HDL-C, and total cholesterol (pinteraction = 0.03 to 0.001) than FHS women. In contrast, JHS men had stronger associations for VAT with high triglycerides, low HDL, and metabolic syndrome (all pinteraction = 0.001) compared to FHS men. Similar associations and gender patterns existed for SAT with most metabolic risk factors. CONCLUSIONS The relative association between VAT and cardiometabolic risk factors is weaker in JHS women compared to FHS women, whereas stronger association with triglycerides and HDL were observed in JHS men.
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Affiliation(s)
- Jiankang Liu
- Jackson Heart Study, University of Mississippi Medical Center, Jackson State University, Jackson, Mississippi, USA.
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34
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Gupta N, Jensen MD. Clinical effects of high-fat meals and weight gain due to high-fat feeding. INTERNATIONAL JOURNAL OF OBESITY SUPPLEMENTS 2012; 2:S51-5. [PMID: 27152154 DOI: 10.1038/ijosup.2012.23] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Overfeeding high-fat (HF) meals results in both short-term and long-term effects that vary depending upon adiposity status (obese vs nonobese) and family history of type 2 diabetes. Although more than 4 weeks of overeating produces mild insulin resistance, whether the same is true of a single, HF meal is not clear. We reviewed overfeeding studies of 4-8 weeks duration, studies of single HF meals and our own (unpublished) plasma insulin and glucose concentration data from 59 nonobese and 15 overweight/obese volunteers who consumed either a normal-fat (NF) breakfast or a breakfast matched for carbohydrate and protein, but with an additional 80 g of monounsaturated fat (HF). Four to eight weeks of overfeeding a HF diet causes an ∼10% reduction in insulin sensitivity. Some authors report that a single HF meal is associated with greater postprandial insulin concentrations, whereas other investigators have not confirmed such a response. We found that plasma glucose concentrations peaked later following a HF breakfast than a NF breakfast in both obese and nonobese adults and that daytime plasma insulin concentrations were not uniformly increased following a HF breakfast. We conclude that a single HF meal delays the postprandial peak in glucose concentrations, likely due to delayed gastric emptying. This will confound attempts to use insulinemia as a marker of insulin resistance. After 4-8 weeks of overeating a HF diet accompanied by 2-4 kg of fat gain, insulin sensitivity decreases by ∼10%. Although we could not demonstrate that baseline insulin resistance predicts visceral fat gain with overfeeding, normal-weight relatives of type 2 diabetes mellitus do tend to gain more weight and become more insulin resistant than those without a positive family history of type 2 diabetes mellitus. In summary, short-term weight gain from HF diets induces relatively mild metabolic disorders.
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Affiliation(s)
- N Gupta
- Mayo Clinic, Endocrine Research Unit , Rochester, MN, USA
| | - M D Jensen
- Mayo Clinic, Endocrine Research Unit , Rochester, MN, USA
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Labbé SM, Grenier-Larouche T, Noll C, Phoenix S, Guérin B, Turcotte EE, Carpentier AC. Increased myocardial uptake of dietary fatty acids linked to cardiac dysfunction in glucose-intolerant humans. Diabetes 2012; 61:2701-10. [PMID: 23093657 PMCID: PMC3478552 DOI: 10.2337/db11-1805] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Impaired cardiac systolic and diastolic function has been observed in preclinical models and in subjects with type 2 diabetes. Using a recently validated positron emission tomography (PET) imaging method with 14(R,S)-[(¹⁸F]-fluoro-6-thia-heptadecanoic acid to quantify organ-specific dietary fatty acid partitioning, we demonstrate in this study that overweight and obese subjects with impaired glucose tolerance (IGT⁺) display significant increase in fractional myocardial dietary fatty acid uptake over the first 6 h postprandial compared with control individuals (IGT⁻). Measured by [¹¹C]acetate with PET, IGT⁺ subjects have a significant increase in myocardial oxidative index. IGT⁺ subjects have significantly reduced left ventricular stroke volume and ejection fraction (LVEF) and tend to display impaired diastolic function, as assessed by PET ventriculography. We demonstrate an inverse relationship between increased myocardial dietary fatty acid partitioning and LVEF. Fractional dietary fatty acid uptake is reduced in subcutaneous abdominal and visceral adipose tissues in IGT⁺ directly associated with central obesity. Fractional dietary fatty acid uptake in skeletal muscles or liver is, however, similar in IGT⁺ versus IGT⁻. The current study demonstrates, for the first time, that excessive myocardial partitioning of dietary fatty acids occurs in prediabetic individuals and is associated with early impairment of left ventricular function and increased myocardial oxidative metabolism.
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Affiliation(s)
- Sébastien M. Labbé
- Department of Medicine, Division of Endocrinology, Centre de Recherche Clinique Etienne-LeBel, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Thomas Grenier-Larouche
- Department of Medicine, Division of Endocrinology, Centre de Recherche Clinique Etienne-LeBel, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Christophe Noll
- Department of Medicine, Division of Endocrinology, Centre de Recherche Clinique Etienne-LeBel, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Serge Phoenix
- Department of Medicine, Division of Endocrinology, Centre de Recherche Clinique Etienne-LeBel, Université de Sherbrooke, Sherbrooke, Québec, Canada
- Department of Nuclear Medicine and Radiobiology, Centre de Recherche Clinique Etienne-LeBel, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Brigitte Guérin
- Department of Nuclear Medicine and Radiobiology, Centre de Recherche Clinique Etienne-LeBel, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Eric E. Turcotte
- Department of Nuclear Medicine and Radiobiology, Centre de Recherche Clinique Etienne-LeBel, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - André C. Carpentier
- Department of Medicine, Division of Endocrinology, Centre de Recherche Clinique Etienne-LeBel, Université de Sherbrooke, Sherbrooke, Québec, Canada
- Corresponding author: André C. Carpentier,
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Søndergaard E, Gormsen LC, Nellemann B, Jensen MD, Nielsen S. Body composition determines direct FFA storage pattern in overweight women. Am J Physiol Endocrinol Metab 2012; 302:E1599-604. [PMID: 22510710 DOI: 10.1152/ajpendo.00015.2012] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Direct FFA storage in adipose tissue is a recently appreciated pathway for postabsorptive lipid storage. We evaluated the effect of body fat distribution on direct FFA storage in women with different obesity phenotypes. Twenty-eight women [10 upper body overweight/obese (UBO; WHR >0.85, BMI >28 kg/m(2)), 11 lower body overweight/obese (LBO; WHR <0.80, BMI >28 kg/m(2)), and 7 lean (BMI <25 kg/m(2))] received an intravenous bolus dose of [9,10-(3)H]palmitate- and [1-(14)C]triolein-labeled VLDL tracer followed by upper body subcutaneous (UBSQ) and lower body subcutaneous (LBSQ) fat biopsies. Regional fat mass was assessed by combining DEXA and CT scanning. We report greater fractional storage of FFA in UBSQ fat in UBO women compared with lean women (P < 0.01). The LBO women had greater storage per 10(6) fat cells in LBSQ adipocytes compared with UBSQ adipocytes (P = 0.04), whereas the other groups had comparable storage in UBSQ and LBSQ adipocytes. Fractional FFA storage was significantly associated with fractional VLDL-TG storage in both UBSQ (P < 0.01) and LBSQ (P = 0.03) adipose tissue. In conclusion, UBO women store a greater proportion of FFA in the UBSQ depot compared with lean women. In addition, LBO women store FFA more efficiently in LBSQ fat cells compared with UBSQ fat cells, which may play a role in development of their LBO phenotype. Finally, direct FFA storage and VLDL-TG fatty acid storage are correlated, indicating they may share a common rate-limiting pathway for fatty acid storage in adipose tissue.
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Affiliation(s)
- E Søndergaard
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark
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Votruba SB, Jensen MD. Short-term regional meal fat storage in nonobese humans is not a predictor of long-term regional fat gain. Am J Physiol Endocrinol Metab 2012; 302:E1078-83. [PMID: 22338076 PMCID: PMC3361980 DOI: 10.1152/ajpendo.00414.2011] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Although body fat distribution strongly predicts metabolic health outcomes related to excess weight, little is known about the factors an individual might exhibit that predict a particular fat distribution pattern. We utilized the meal fatty acid tracer-adipose biopsy technique to assess upper and lower body subcutaneous (UBSQ and LBSQ, respectively) meal fat storage in lean volunteers who then were overfed to gain weight. Meal fatty acid storage in UBSQ and LBSQ adipose tissue, as well as daytime substrate oxidation (indirect calorimetry), was measured in 28 nonobese volunteers [n = 15 men, body mass index = 22.1 ± 2.5 (SD)] before and after an ∼8-wk period of supervised overfeeding (weight gain = 4.6 ± 2.2 kg, fat gain = 3.8 ± 1.7 kg). Meal fat storage (mg/g adipose tissue lipid) in UBSQ (visit 1: 0.78 ± 0.34 and 1.04 ± 0.71 for women and men, respectively, P = 0.22; visit 2: 0.71 ± 0.24 and 0.90 ± 0.37 for women and men, respectively, P = 0.08) and LBSQ (visit 1: 0.60 ± 0.23 and 0.48 ± 0.29 for women and men, respectively, P = 0.25; visit 2: 0.62 ± 0.24 and 0.65 ± 0.23 for women and men, respectively, P = 0.67) adipose tissue did not differ between men and women at either visit. Fractional meal fatty acid storage in UBSQ (0.31 ± 0.15) or LBSQ (0.19 ± 0.13) adipose tissue at visit 1 did not predict the percent change in regional body fat in response to overfeeding. These data indicate that meal fat uptake trafficking in the short term (24 h) is not predictive of body fat distribution patterns. In general, UBSQ adipose tissue appears to be a favored depot for meal fat deposition in both sexes, and redistribution of meal fatty acids likely takes place at later time periods.
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Carpentier AC, Labbé SM, Grenier-Larouche T, Noll C. Abnormal dietary fatty acid metabolic partitioning in insulin resistance and Type 2 diabetes. ACTA ACUST UNITED AC 2011. [DOI: 10.2217/clp.11.60] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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Søndergaard E, Nellemann B, Sørensen LP, Gormsen LC, Christiansen JS, Ernst E, Dueholm M, Nielsen S. Similar VLDL-TG storage in visceral and subcutaneous fat in obese and lean women. Diabetes 2011; 60:2787-91. [PMID: 21911742 PMCID: PMC3198059 DOI: 10.2337/db11-0604] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE Excess visceral fat accumulation is associated with the metabolic disturbances of obesity. Differential lipid redistribution through lipoproteins may affect body fat distribution. This is the first study to investigate VLDL-triglyceride (VLDL-TG) storage in visceral fat. RESEARCH DESIGN AND METHODS Nine upper-body obese (UBO; waist circumference >88 cm) and six lean (waist circumference <80 cm) women scheduled for elective tubal ligation surgery were studied. VLDL-TG storage in visceral, upper-body subcutaneous (UBSQ), and lower-body subcutaneous (LBSQ) fat were measured with [9,10-(3)H]-triolein-labeled VLDL. RESULTS VLDL-TG storage in visceral fat accounted for only ~0.8% of VLDL-TG turnover in UBO and lean women, respectively. A significantly larger proportion of VLDL-TG turnover was stored in UBSQ (~5%) and LBSQ (~4%) fat. The VLDL-TG fractional storage was similar in UBO and lean women for all regional depots. VLDL-TG fractional storage and VLDL-TG concentration were correlated in UBO women in UBSQ fat (r = 0.68, P = 0.04), whereas an inverse association was observed for lean women in visceral (r = -0.89, P = 0.02) and LBSQ (r = -0.87, P = 0.02) fat. CONCLUSIONS VLDL-TG storage efficiency is similar in all regional fat depots, and trafficking of VLDL-TG into different adipose tissue depots is similar in UBO and lean women. Postabsorptive VLDL-TG storage is unlikely to be of major importance in the development of preferential upper-body fat distribution in obese women.
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Affiliation(s)
- Esben Søndergaard
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Birgitte Nellemann
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Lars P. Sørensen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Lars C. Gormsen
- Department of Clinical Physiology and Nuclear Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Jens S. Christiansen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Erik Ernst
- Department of Gynecology and Obstetrics, Aarhus University Hospital, Aarhus, Denmark
| | - Margit Dueholm
- Department of Gynecology and Obstetrics, Aarhus University Hospital, Aarhus, Denmark
| | - Søren Nielsen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
- Corresponding author: Søren Nielsen,
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Ali AH, Koutsari C, Mundi M, Stegall MD, Heimbach JK, Taler SJ, Nygren J, Thorell A, Bogachus LD, Turcotte LP, Bernlohr D, Jensen MD. Free fatty acid storage in human visceral and subcutaneous adipose tissue: role of adipocyte proteins. Diabetes 2011; 60:2300-7. [PMID: 21810594 PMCID: PMC3161316 DOI: 10.2337/db11-0219] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
OBJECTIVE Because direct adipose tissue free fatty acid (FFA) storage may contribute to body fat distribution, we measured FFA (palmitate) storage rates and fatty acid (FA) storage enzymes/proteins in omental and abdominal subcutaneous fat. RESEARCH DESIGN AND METHODS Elective surgery patients received a bolus of [1-(14)C]palmitate followed by omental and abdominal subcutaneous fat biopsies to measure direct FFA storage. Long chain acyl-CoA synthetase (ACS) and diacylglycerol acyltransferase activities, CD36, fatty acid-binding protein, and fatty acid transport protein 1 were measured. RESULTS Palmitate tracer storage (dpm/g adipose lipid) and calculated palmitate storage rates were greater in omental than abdominal subcutaneous fat in women (1.2 ± 0.8 vs. 0.7 ± 0.4 μmol · kg adipose lipid(-1) · min(-1), P = 0.005) and men (0.7 ± 0.2 vs. 0.2 ± 0.1, P < 0.001), and both were greater in women than men (P < 0.0001). Abdominal subcutaneous adipose tissue palmitate storage rates correlated with ACS activity (women: r = 0.66, P = 0.001; men: r = 0.70, P = 0.007); in men, CD36 was also independently related to palmitate storage rates. The content/activity of FA storage enzymes/proteins in omental fat was dramatically lower in those with more visceral fat. In women, only omental palmitate storage rates were correlated (r = 0.54, P = 0.03) with ACS activity. CONCLUSIONS Some adipocyte FA storage factors correlate with direct FFA storage, but sex differences in this process in visceral fat do not account for sex differences in visceral fatness. The reduced storage proteins in those with greater visceral fat suggest that the storage factors we measured are not a predominant cause of visceral adipose tissue accumulation.
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Affiliation(s)
- Asem H. Ali
- Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota
- National Institute of Diabetes and Digestive and Kidney Diseases & National Institute of Child Health and Human Development, Bethesda, Maryland
| | | | - Manpreet Mundi
- Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota
| | - Mark D. Stegall
- Department of Surgery, Division of Transplantation Surgery and the William J. von Liebig Transplant Center, Mayo Clinic, Rochester, Minnesota
| | - Julie K. Heimbach
- Department of Surgery, Division of Transplantation Surgery and the William J. von Liebig Transplant Center, Mayo Clinic, Rochester, Minnesota
| | - Sandra J. Taler
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - Jonas Nygren
- Department of Surgery, Ersta Hospital and Karolinska Institutet, Department of Clinical Sciences, Danderyds Hospital, Stockholm, Sweden
| | - Anders Thorell
- Department of Surgery, Ersta Hospital and Karolinska Institutet, Department of Clinical Sciences, Danderyds Hospital, Stockholm, Sweden
| | - Lindsey D. Bogachus
- Department of Biological Sciences, College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California
| | - Lorraine P. Turcotte
- Department of Biological Sciences, College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California
| | - David Bernlohr
- Biochemistry, Molecular Biology & Biophysics, University of Minnesota, Minneapolis, Minnesota
| | - Michael D. Jensen
- Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota
- Corresponding author: Michael D. Jensen,
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Allred CC, Krennmayr T, Koutsari C, Zhou L, Ali AH, Jensen MD. A novel ELISA for measuring CD36 protein in human adipose tissue. J Lipid Res 2010; 52:408-15. [PMID: 21115967 DOI: 10.1194/jlr.m008995] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
CD36 is a transmembrane protein present in many tissues that is believed to facilitate inward fatty acid transport. Western blotting is the most widely used method to measure tissue CD36 protein content, but it is time consuming, technically demanding, and semiquantitative. To more precisely measure adipose tissue CD36 content we developed an enzyme linked immunosorbent assay (ELISA) after establishing that: 1) the anti-CD36 antibodies gave a single distinct band on traditional Western blots, and 2) the vast majority of adipocyte CD36 resides in the plasma membrane. By using serial dilutions of each sample and including a calibrator sample and quality control sample on each plate, we could achieve inter- and intra-assay variability of ∼ 10%. We found that CD36 content in omental and abdominal subcutaneous adipose tissue varied over a 2-5-fold range depending upon the means of data expression (per units of tissue protein, weight, or lipid). Omental CD36 content in women decreased markedly (P = 0.01) as a function of fat cell size. For the most part, tissue CD36 content was not correlated with CD36 mRNA. This ELISA method for tissue CD36 content should enhance research into the role of this protein on tissue fatty acid uptake.
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Affiliation(s)
- Carolyn C Allred
- Endocrine Research Unit, Division of Endocrinology, Mayo Clinic, Rochester, MN, USA
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McQuaid SE, Humphreys SM, Hodson L, Fielding BA, Karpe F, Frayn KN. Femoral adipose tissue may accumulate the fat that has been recycled as VLDL and nonesterified fatty acids. Diabetes 2010; 59:2465-73. [PMID: 20682685 PMCID: PMC3279526 DOI: 10.2337/db10-0678] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE Gluteo-femoral, in contrast to abdominal, fat accumulation appears protective against diabetes and cardiovascular disease. Our objective was to test the hypothesis that this reflects differences in the ability of the two depots to sequester fatty acids, with gluteo-femoral fat acting as a longer-term "sink." RESEARCH DESIGN AND METHODS A total of 12 healthy volunteers were studied after an overnight fast and after ingestion of a mixed meal. Blood samples were taken from veins draining subcutaneous femoral and abdominal fat and compared with arterialized blood samples. Stable isotope-labeled fatty acids were used to trace specific lipid fractions. In 36 subjects, adipose tissue blood flow in the two depots was monitored with (133)Xe. RESULTS Blood flow increased in response to the meal in both depots, and these responses were correlated (r(s) = 0.44, P < 0.01). Nonesterified fatty acid (NEFA) release was suppressed after the meal in both depots; it was lower in femoral fat than in abdominal fat (P < 0.01). Plasma triacylglycerol (TG) extraction by femoral fat was also lower than that by abdominal fat (P = 0.05). Isotopic tracers showed that the difference was in chylomicron-TG extraction. VLDL-TG extraction and direct NEFA uptake were similar in the two depots. CONCLUSIONS Femoral fat shows lower metabolic fluxes than subcutaneous abdominal fat, but differs in its relative preference for extracting fatty acids directly from the plasma NEFA and VLDL-TG pools compared with chylomicron-TG.
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Affiliation(s)
- Siobhán E. McQuaid
- Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford, U.K
| | - Sandy M. Humphreys
- Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford, U.K
| | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford, U.K
| | - Barbara A. Fielding
- Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford, U.K
| | - Fredrik Karpe
- Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford, U.K
- National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Oxford Radcliffe Hospitals, Oxford, U.K
| | - Keith N. Frayn
- Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford, U.K
- Corresponding author: Keith N. Frayn,
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Nellemann B, Gormsen LC, Christiansen JS, Jensen MD, Nielsen S. Postabsorptive VLDL-TG fatty acid storage in adipose tissue in lean and obese women. Obesity (Silver Spring) 2010; 18:1304-11. [PMID: 19875996 PMCID: PMC2893248 DOI: 10.1038/oby.2009.370] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Adipose tissue lipoprotein lipase (LPL) is a necessary enzyme for storage of very-low-density lipoprotein-triglyceride (VLDL-TG), but whether it is a rate-determining step is unknown. To test this hypothesis we included 10 upper-body obese (UBO), 11 lower-body obese (LBO), and 8 lean women. We infused ex vivo-labeled VLDL-(14)C-TG and then performed adipose tissue biopsies to understand the relationship between VLDL-TG storage and LPL activity in femoral and upper-body subcutaneous fat. Both fractional tracer storage and rate of storage of the VLDL-TG tracer were evaluated. VLDL-TG storage was also examined as a function of regional adipose tissue blood flow (ATBF), insulin, VLDL-TG turnover, regional fat mass, fat-free mass (FFM), and fat cell size. LPL activity per adipocyte was significantly greater in obese than lean women but not significantly different per gram lipid. Both VLDL-TG fractional tracer storage per kg lipid and VLDL-TG storage rate per kg lipid were similar in abdominal and femoral fat in all three groups and were not significantly different between groups. Multiple regression analysis identified FFM and femoral fat mass as significant independent predictors of VLDL-TG fractional tracer storage and insulin as a significant predictor of VLDL-TG fatty acid storage rate. LPL activity, ATBF, and VLDL-TG turnover did not predict VLDL-TG storage. We conclude that lower FFM and greater plasma insulin are associated with greater VLDL-TG deposition in abdominal subcutaneous and femoral fat. Greater femoral fat mass signals greater femoral VLDL-TG storage. We suggest that the differences in VLDL-TG storage in abdominal and femoral fat that occur with progressive obesity are regulated through mechanisms other than LPL activity.
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Melhorn SJ, Krause EG, Scott KA, Mooney MR, Johnson JD, Woods SC, Sakai RR. Acute exposure to a high-fat diet alters meal patterns and body composition. Physiol Behav 2010; 99:33-9. [PMID: 19835896 DOI: 10.1016/j.physbeh.2009.10.004] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2009] [Revised: 09/24/2009] [Accepted: 10/06/2009] [Indexed: 01/07/2023]
Abstract
Weight gain and adiposity are often attributed to the overconsumption of unbalanced, high-fat diets however, the pattern of consumption can also contribute to associated body weight and compositional changes. The present study explored the rapid alterations in meal patterns of normal-weight rats given continuous access to high-fat diet and examined body weight and composition changes compared to chow fed controls. Ten Long-Evans rats were implanted with subcutaneous microchips for meal pattern analysis. Animals were body weight matched and separated into two groups: high-fat or chow fed. Each group was maintained on their assigned diet for nine days and monitored for 22 h each day for meal pattern behavior. Body weight was evaluated every other day, and body composition measures were taken prior and following diet exposure. High-fat fed animals gained more weight and adipose tissue than chow fed controls and displayed a reduced meal frequency and increased meal size. Furthermore, meal size was significantly correlated with the gain of adipose tissue. Together, these results suggest that consumption of a high-fat diet can rapidly alter meal patterns, which in turn contribute to the development of adiposity.
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Affiliation(s)
- Susan J Melhorn
- Department of Psychiatry, Program in Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA.
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Giroud S, Perret M, Gilbert C, Zahariev A, Goudable J, Le Maho Y, Oudart H, Momken I, Aujard F, Blanc S. Dietary palmitate and linoleate oxidations, oxidative stress, and DNA damage differ according to season in mouse lemurs exposed to a chronic food deprivation. Am J Physiol Regul Integr Comp Physiol 2009; 297:R950-9. [DOI: 10.1152/ajpregu.00214.2009] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
This study investigated the extent to which the increase in torpor expression in the grey mouse lemur, due to graded food restriction, is modulated by a trade-off between a whole body sparing of polyunsaturated dietary fatty acids and the related oxidative stress generated during daily torpor. We measured changes in torpor frequency, total energy expenditure (TEE), linoleate (polyunsaturated fatty acid) and palmitate (saturated fatty acid) oxidation, hexanoyl-lysine (HEL; the product of linoleate peroxidation), and 8-hydroxydeoxyguanosine (8OHdG; a marker of DNA damage). Animals under summer-acclimated long days (LD) or winter-acclimated short days (SD) were exposed to a 40% (LD40 and SD40) and 80% (LD80 and SD80) 35-day calorie restriction (CR). During CR, all groups reduced their body mass, but LD80 animals reached survival-threatened levels at day 22 and were then excluded from the CR trial. Only SD mouse lemurs increased their torpor frequency with CR and displayed a decrease in their TEE adjusted for fat-free mass. After CR, SD40 mouse lemurs shifted the dietary fatty acid oxidation toward palmitate and spared linoleate. Such a shift was not observed in LD animals and during severe CR, during which oxidation of both dietary fatty acids was increased. Concomitantly, HEL increased in both LD40 and SD80 groups, whereas DNA damage was only seen in SD80 food-restricted animals. HEL correlated positively with linoleate oxidation confirming in vivo the substrate/product relationship demonstrated in vitro, and negatively with TEE adjusted for fat-free mass, suggesting higher oxidative stress associated with increased torpor expression. This suggests a seasonal-dependant, cost-benefit trade-off between maximizing torpor propensity and minimizing oxidative stress that is associated with a shift toward sparing of dietary polyunsaturated fatty acids that is dependent upon the expression of a winter phenotype.
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Affiliation(s)
- Sylvain Giroud
- Institut Pluridisciplinaire Hubert Curien–Département d'Ecologie, Physiologie, Ethologie Unité Mixte de Recherche 7178 Centre National de la Recherche Scientifique, Université de Strasbourg, Strasbourg
- Mécanismes Adaptatifs et Evolution, Unité Mixte de Recherche 7179 Centre National de la Recherche Scientifique, Muséum National d'Histoire Naturelle, Brunoy
| | - Martine Perret
- Mécanismes Adaptatifs et Evolution, Unité Mixte de Recherche 7179 Centre National de la Recherche Scientifique, Muséum National d'Histoire Naturelle, Brunoy
| | - Caroline Gilbert
- Institut Pluridisciplinaire Hubert Curien–Département d'Ecologie, Physiologie, Ethologie Unité Mixte de Recherche 7178 Centre National de la Recherche Scientifique, Université de Strasbourg, Strasbourg
- Université Henri Poincaré, Nancy Université, Vandoeuvre-Les-Nancy; and
| | - Alexandre Zahariev
- Institut Pluridisciplinaire Hubert Curien–Département d'Ecologie, Physiologie, Ethologie Unité Mixte de Recherche 7178 Centre National de la Recherche Scientifique, Université de Strasbourg, Strasbourg
| | - Joëlle Goudable
- Institut des Sciences Pharmaceutiques et Biologiques–Faculté de Pharmacie and Fédération de Biochimie, Hôpital E. Herriot, Lyon, France
| | - Yvon Le Maho
- Institut Pluridisciplinaire Hubert Curien–Département d'Ecologie, Physiologie, Ethologie Unité Mixte de Recherche 7178 Centre National de la Recherche Scientifique, Université de Strasbourg, Strasbourg
| | - Hugues Oudart
- Institut Pluridisciplinaire Hubert Curien–Département d'Ecologie, Physiologie, Ethologie Unité Mixte de Recherche 7178 Centre National de la Recherche Scientifique, Université de Strasbourg, Strasbourg
| | - Iman Momken
- Institut Pluridisciplinaire Hubert Curien–Département d'Ecologie, Physiologie, Ethologie Unité Mixte de Recherche 7178 Centre National de la Recherche Scientifique, Université de Strasbourg, Strasbourg
| | - Fabienne Aujard
- Mécanismes Adaptatifs et Evolution, Unité Mixte de Recherche 7179 Centre National de la Recherche Scientifique, Muséum National d'Histoire Naturelle, Brunoy
| | - Stéphane Blanc
- Institut Pluridisciplinaire Hubert Curien–Département d'Ecologie, Physiologie, Ethologie Unité Mixte de Recherche 7178 Centre National de la Recherche Scientifique, Université de Strasbourg, Strasbourg
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Koutsari C, Ali AH, Nair KS, Rizza RA, O'Brien P, Khosla S, Jensen MD. Fatty acid metabolism in the elderly: effects of dehydroepiandrosterone and testosterone replacement in hormonally deficient men and women. J Clin Endocrinol Metab 2009; 94:3414-23. [PMID: 19567532 PMCID: PMC2741706 DOI: 10.1210/jc.2009-0165] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
CONTEXT Aging, low dehydroepiandrosterone (DHEA), and testosterone are associated with increased adiposity and metabolic risk. Treatment with these hormones may improve these abnormalities. OBJECTIVE The objective of the study was to determine effects of aging, DHEA, or testosterone replacement on adiposity, meal fat partitioning, and postabsorptive lipolysis. DESIGN This was a cross-sectional, 2-yr, double-blind, randomized, placebo-controlled trial. SETTING The study was conducted in the general community. PATIENTS Elderly women and men (>or=60 yr) with low DHEA sulfate (women and men) and bioavailable testosterone (men) concentrations and young adults. INTERVENTIONS Thirty elderly women each received 50 mg DHEA or placebo daily for 2 yr. Thirty elderly men received 75 mg DHEA, 29 received 5 mg testosterone (patch), and 32 received placebo daily for 2 yr. Thirty young women and 32 young men served as controls. MAIN OUTCOME MEASURES In vivo measures of meal fat storage into sc fat, postabsorptive lipolysis, and regional adiposity at baseline and after treatment. RESULTS At baseline, the elderly had more body fat, greater systemic lipolysis (women, P = 0.0003; men, P < 0.0001) adjusted for resting energy expenditure, greater meal fat oxidation (women, P = 0.026; men, P = 0.0025), and less meal fat storage in sc fat (women, P = 0.0139; men, P= 0.0006). Although testosterone treatment increased meal fat storage into upper- vs. lower-body fat in elderly men, neither hormone affected regional adiposity, meal fat oxidation, or systemic lipolysis. CONCLUSIONS Aging, in the context of low DHEA sulfate (women and men) and bioavailable testosterone (men) concentrations, is associated with changes in meal fat partitioning and postabsorptive lipolysis that are not corrected by DHEA and only partly corrected by testosterone replacement.
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Shi H, Seeley RJ, Clegg DJ. Sexual differences in the control of energy homeostasis. Front Neuroendocrinol 2009; 30:396-404. [PMID: 19341761 PMCID: PMC4517605 DOI: 10.1016/j.yfrne.2009.03.004] [Citation(s) in RCA: 171] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2008] [Revised: 03/09/2009] [Accepted: 03/17/2009] [Indexed: 12/20/2022]
Abstract
The prevalence of obesity has reached epidemic proportion with enormous costs in both human lives and healthcare dollars spent. Obesity-related metabolic disorders are much lower in premenopausal women than men; however, there is a dramatic increase following menopause in women. The health risks associated with obesity vary depending on the location of adipose tissue. Adipose tissue distributed in the abdominal visceral carry a much greater risk for metabolic disorders than does adipose tissue distributed subcutaneously. There are distinct sex-dependent differences in the regional fat distribution, women carry more fat subcutaneously whereas men carry more fat viscerally. Males and females differ with respect to their regulation of energy homeostasis. Peripheral adiposity hormones such as leptin and insulin as well as sex hormones directly influence energy balance. Sexual dimorphisms in energy balance, body fat distribution, and the role sex hormones have in mediating these differences are the focus of this review.
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Affiliation(s)
- Haifei Shi
- Obesity Research Center, University of Cincinnati, Cincinnati, OH, USA
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Abstract
Body fat distribution modulates risk for type 2 diabetes mellitus. We evaluated potentially involved metabolic risk factors. In a population of 282 male and 157 female healthy subjects (data from the San Antonio and the European Group of Insulin Resistance (EGIR) study cohorts), we evaluated associations between body fat distribution (assessed by waist and hip circumference) and parameters of lipid- and glucose metabolism, including clamp measurements of insulin sensitivity. After stratification for BMI, fasting triglycerides were lower in the presence of a large hip, and higher in a large waist. Persons with the largest BMI (3rd tertile) showed a difference in triglyceride levels of 1.5 vs. 2.4 mmol/l in large vs. small hip circumference groups (P < 0.038), and a difference of 1.5 vs. 1.2 mmol/l in large vs. small waist circumference groups (P < 0.025). A similar analysis did not reveal a difference in insulin sensitivity. Linear regression analyses confirmed the findings; they revealed negative associations between triglycerides and hip, and (for women borderline statistically significant) positive associations between triglycerides and waist, after adjustment for BMI, mutual confounding, and age (beta +/- s.e.; men: -0.48 +/- 0.005, P < 0.001, and 0.21 +/- 0.005, P < 0.05; women: -0.78 +/- 0.007, P < 0.001, and 0.24 +/- 0.005, P < 0.065), respectively. Linear regression analyses revealed similar opposite associations with high-density lipoprotein (HDL)-cholesterol, though not with glucose, insulin, or insulin sensitivity as measured with the clamp method. In our study population of healthy persons, body fat distribution is associated with fasting triglycerides and HDL-cholesterol, and not with insulin sensitivity. Metabolic risk of unfavorable body fat distribution may be modulated by lower triglyceride storage capacity.
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Affiliation(s)
- Johannes B Ruige
- Ghent University Hospital, Department of Endocrinology, Ghent, Belgium
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Hou XG, Moser S, Sarr MG, Thompson GB, Que FG, Jensen MD. Visceral and subcutaneous adipose tissue diacylglycerol acyltransferase activity in humans. Obesity (Silver Spring) 2009; 17:1129-34. [PMID: 19197254 PMCID: PMC2721480 DOI: 10.1038/oby.2008.659] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Diacylglycerol acyltransferase (DGAT) could be a rate limiting step in triglyceride (TG) synthesis as it is the final step in this pathway. As such, between depot differences in DGAT activity could influence regional fat storage. DGAT activity and in vitro rates of direct free fatty acid (FFA) storage were measured in abdominal subcutaneous and omental adipose tissue samples from 12 nonobese (BMI<30 kg/m2) and 23 obese men and women (BMI>30 kg/m2) undergoing elective surgery. DGAT activity was greater in omental than in abdominal subcutaneous adipose tissue from nonobese patients (2.0+/-0.9 vs. 0.9+/-0.3 pmol/min/mg lipid, respectively, P=0.003), but not from obese patients (1.4+/-0.6 vs. 1.7+/-0.7 pmol/min/mg lipid, respectively, P=0.10). DGAT activity per unit adipose weight was negatively correlated with adipocyte size (P<0.01) and positively correlated with direct FFA storage in omental (P<0.001) but not in abdominal subcutaneous fat. Tissue DGAT activity varies as a function of adipocyte size, but this relationship differs between visceral and abdominal subcutaneous fat in obese and nonobese humans. Our results are consistent with the hypothesis that interindividual variations in DGAT activity may be an important regulatory step in visceral adipose tissue FFA uptake/storage.
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Affiliation(s)
- Xin Guo Hou
- Endocrine Research Unit, Division of Endocrinology, Department of Surgery, Mayo Clinic, Rochester, Minnesota, USA
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50
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Effect of plasma triglyceride metabolism on lipid storage in adipose tissue: studies using genetically engineered mouse models. Biochim Biophys Acta Mol Cell Biol Lipids 2009; 1791:479-85. [PMID: 19168150 DOI: 10.1016/j.bbalip.2008.12.015] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2008] [Revised: 12/11/2008] [Accepted: 12/23/2008] [Indexed: 01/15/2023]
Abstract
The obesity epidemic is associated with an increased incidence of type 2 diabetes, cardiovascular morbidity and various types of cancer. A better insight into the molecular mechanisms that underlie adipogenesis and obesity may result in novel therapeutic handles to fight obesity and these associated diseases. Adipogenesis is determined by the balance between uptake of fatty acids (FA) from plasma into adipocytes, intracellular FA oxidation versus esterification of FA into triglycerides (TG), lipolysis of TG by intracellular lipases, and secretion of FA from adipocytes. Here, we review the mechanisms that are specifically involved in the entry of FA into adipose tissue. In plasma, these originating FA are either present as TG within apoB-containing lipoproteins (i.e. chylomicrons and VLDL) or as free FA bound to albumin. Kinetic studies, however, have revealed that TG are the major source of FA entering adipose tissue, both in the fed and fasted condition. In fact, studies with genetically engineered mice have revealed that the activity of lipoprotein lipase (LPL) is a major determinant for the development of obesity. As a general rule, high fat diet-induced adipogenesis is aggravated by stimulated LPL activity (e.g. by adipose tissue-specific overexpression of LPL or deficiency for apoCIII), and attenuated by inhibited LPL activity (e.g. by adipose-specific deficiency for LPL, overexpression of apoCI or angptl4, or by deficiency for apoE or the VLDL receptor). In addition, we describe that the trans-membrane transport of FA and cytoplasmic binding of FA in adipocytes can also dramatically affect adipogenesis. The relevance of these findings for human pathophysiology is discussed.
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