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Arefin TM, Börchers S, Olekanma D, Cramer SR, Sotzen MR, Zhang N, Skibicka KP. Sex-specific signatures of GLP-1 and amylin on resting state brain activity and functional connectivity in awake rats. Neuropharmacology 2025; 269:110348. [PMID: 39914619 PMCID: PMC11926989 DOI: 10.1016/j.neuropharm.2025.110348] [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: 10/08/2024] [Revised: 12/16/2024] [Accepted: 02/04/2025] [Indexed: 02/13/2025]
Abstract
Gut-produced glucagon-like peptide-1 (GLP-1) and pancreas-made amylin robustly reduce food intake by directly or indirectly affecting brain activity. While for both peptides a direct action in the hindbrain and the hypothalamus is likely, few studies examined their impact on whole brain activity in rodents and did so evaluating male rodents under anesthesia. However, both sex and anesthesia may significantly alter the influence of feeding controlling molecules on brain activity. Therefore, we investigated the effect of GLP-1 and amylin on brain activity and functional connectivity (FC) in awake adult male and female rats using resting-state functional magnetic resonance imaging (rsfMRI). We further examined the relationship between the altered brain activity or connectivity and subsequent food intake in response to amylin or GLP-1. We observed sex divergent effects of amylin and GLP-1 on the brain activity and FC patterns. Most importantly correlation analysis between FC and feeding behavior revealed that different brain areas potentially drive reduced food intake in male and female rats. Our findings underscore the distributed and distinctly sex divergent neural network engaged by each of these anorexic peptides and suggest that different brain areas may be the primary drivers of the feeding outcome in male and female rats. Moreover, prominent activity and connectivity alterations observed in brain areas not typically associated with feeding behavior in both sexes may either indicate novel feeding centers or alternatively suggest the involvement of these substances in behaviors beyond feeding and metabolism. The latter question is of potential translational significance as analogues of both amylin and GLP-1 are clinically utilized.
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Affiliation(s)
- Tanzil M Arefin
- Huck Institutes of Life Science, Pennsylvania State University, State College, PA, USA; Department of Biomedical Engineering, Pennsylvania State University, University Park, USA; Center for Neurotechnology in Mental Health Research, Pennsylvania State University, University Park, USA; Department of Neuroscience, University of Rochester Medical Center, Rochester, NY, USA; Center for Advanced Brain Imaging and Neurophysiology, University of Rochester Medical Center, Rochester, NY, USA
| | - Stina Börchers
- Nutritional Sciences, Pennsylvania State University, University Park, PA, USA; Institute of Neuroscience and Physiology, University of Gothenburg, Sweden
| | - Doris Olekanma
- Nutritional Sciences, Pennsylvania State University, University Park, PA, USA; Huck Institutes of Life Science, Pennsylvania State University, State College, PA, USA; The Neuroscience Graduate Program, Pennsylvania State University, University Park, USA
| | - Samuel R Cramer
- Huck Institutes of Life Science, Pennsylvania State University, State College, PA, USA; The Neuroscience Graduate Program, Pennsylvania State University, University Park, USA
| | - Morgan R Sotzen
- Nutritional Sciences, Pennsylvania State University, University Park, PA, USA; Huck Institutes of Life Science, Pennsylvania State University, State College, PA, USA
| | - Nanyin Zhang
- Huck Institutes of Life Science, Pennsylvania State University, State College, PA, USA; Department of Biomedical Engineering, Pennsylvania State University, University Park, USA; Center for Neurotechnology in Mental Health Research, Pennsylvania State University, University Park, USA
| | - Karolina P Skibicka
- Nutritional Sciences, Pennsylvania State University, University Park, PA, USA; Huck Institutes of Life Science, Pennsylvania State University, State College, PA, USA; Institute of Neuroscience and Physiology, University of Gothenburg, Sweden.
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2
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Hankir MK, Lutz TA. Novel neural pathways targeted by GLP-1R agonists and bariatric surgery. Pflugers Arch 2025; 477:171-185. [PMID: 39644359 PMCID: PMC11761532 DOI: 10.1007/s00424-024-03047-3] [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: 10/17/2024] [Revised: 11/18/2024] [Accepted: 11/19/2024] [Indexed: 12/09/2024]
Abstract
The glucagon-like peptide 1 receptor (GLP-1R) agonist semaglutide has revolutionized the treatment of obesity, with other gut hormone-based drugs lined up that show even greater weight-lowering ability in obese patients. Nevertheless, bariatric surgery remains the mainstay treatment for severe obesity and achieves unparalleled weight loss that generally stands the test of time. While their underlying mechanisms of action remain incompletely understood, it is clear that the common denominator between GLP-1R agonists and bariatric surgery is that they suppress food intake by targeting the brain. In this Review, we highlight recent preclinical studies using contemporary neuroscientific techniques that provide novel concepts in the neural control of food intake and body weight with reference to endogenous GLP-1, GLP-1R agonists, and bariatric surgery. We start in the periphery with vagal, intestinofugal, and spinal sensory nerves and then progress through the brainstem up to the hypothalamus and finish at non-canonical brain feeding centers such as the zona incerta and lateral septum. Further defining the commonalities and differences between GLP-1R agonists and bariatric surgery in terms of how they target the brain may not only help bridge the gap between pharmacological and surgical interventions for weight loss but also provide a neural basis for their combined use when each individually fails.
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Affiliation(s)
- Mohammed K Hankir
- Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland
- School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
| | - Thomas A Lutz
- Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland.
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Krieger JP, Daniels D, Lee S, Mastitskaya S, Langhans W. Glucagon-Like Peptide-1 Links Ingestion, Homeostasis, and the Heart. Compr Physiol 2025; 15:e7. [PMID: 39887844 PMCID: PMC11790259 DOI: 10.1002/cph4.7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 11/02/2024] [Accepted: 11/05/2024] [Indexed: 02/01/2025]
Abstract
Glucagon-like peptide-1 (GLP-1), a hormone released from enteroendocrine cells in the distal small and large intestines in response to nutrients and other stimuli, not only controls eating and insulin release, but is also involved in drinking control as well as renal and cardiovascular functions. Moreover, GLP-1 functions as a central nervous system peptide transmitter, produced by preproglucagon (PPG) neurons in the hindbrain. Intestinal GLP-1 inhibits eating by activating vagal sensory neurons directly, via GLP-1 receptors (GLP-1Rs), but presumably also indirectly, by triggering the release of serotonin from enterochromaffin cells. GLP-1 enhances glucose-dependent insulin release via a vago-vagal reflex and by direct action on beta cells. Finally, intestinal GLP-1 acts on the kidneys to modulate electrolyte and water movements, and on the heart, where it provides numerous benefits, including anti-inflammatory, antiatherogenic, and vasodilatory effects, as well as protection against ischemia/reperfusion injury and arrhythmias. Hindbrain PPG neurons receive multiple inputs and project to many GLP-1R-expressing brain areas involved in reward, autonomic functions, and stress. PPG neuron-derived GLP-1 is involved in the termination of large meals and is implicated in the inhibition of water intake. This review details GLP-1's roles in these interconnected systems, highlighting recent findings and unresolved issues, and integrating them to discuss the physiological and pathological relevance of endogenous GLP-1 in coordinating these functions. As eating poses significant threats to metabolic, fluid, and immune homeostasis, the body needs mechanisms to mitigate these challenges while sustaining essential nutrient intake. Endogenous GLP-1 plays a crucial role in this "ingestive homeostasis."
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Affiliation(s)
- Jean-Philippe Krieger
- Jean-Philippe Krieger, Institute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of Zurich, Winterthurerstr. 260, 8057 Zurich
| | - Derek Daniels
- Department of Biological Sciences and the Center for Ingestive Behavior Research, University at Buffalo, the State University of New York, Buffalo NY 14260 USA
| | - Shin Lee
- Shin J. Lee, Neurimmune AG, Wagistrasse 18, 8952 Schlieren, Switzerland
| | - Svetlana Mastitskaya
- Department of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Wolfgang Langhans
- Physiology and Behavior Laboratory, Dept. of Health Sciences and Technology, ETH Zurich, 8603 Schwerzenbach, Switzerland
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Rossetti CL, Andrade IS, Fonte Boa LF, Neves MB, Fassarella LB, Bertasso IM, Souza MDGCD, Bouskela E, Lisboa PC, Takyia CM, Trevenzoli IH, Fortunato RS, Carvalho DPD. Liraglutide prevents body and fat mass gain in ovariectomized Wistar rats. Mol Cell Endocrinol 2024; 594:112374. [PMID: 39306226 DOI: 10.1016/j.mce.2024.112374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 09/03/2024] [Accepted: 09/18/2024] [Indexed: 09/29/2024]
Abstract
Estrogens exert beneficial metabolic effects by reducing food intake and enhancing energy expenditure through both central and peripheral mechanisms. The decrease of estrogen, as occurs in ovariectomy (OVX), leads to metabolic disturbances, such as increased body weight, adipose tissue mass, basal blood glucose, and impaired glucose tolerance. These effects can be reversed by reintroducing estrogen. GLP-1 and its receptor agonists, known for their antihyperglycemic properties, also exhibit anorexigenic effects. Besides that, research indicates that GLP-1 analogs can induce metabolic changes peripherally, such as increased fatty acid oxidation and inhibited lipogenesis. Given the shared metabolic actions of GLP-1 and estrogens, we explored whether liraglutide, a GLP-1 agonist, could mitigate the metabolic effects of estrogen deficiency. We tested this hypothesis using ovariectomized rats, a model that simulates menopausal estrogen deficiency, and treated them with either liraglutide or 17β-Estradiol benzoate for 21 days. Ovariectomy resulted in elevated DPP-IV activity in both plasma and inguinal white adipose tissue (iWAT). While estrogen replacement effectively countered the DPP-IV increase in both plasma and iWAT, liraglutide only prevented the rise in iWAT DPP-IV activity. Liraglutide prevented body weight and fat mass gain after ovariectomy to the same extent as estradiol treatment. This can be explained by the lower food intake and food efficiency caused by estradiol and liraglutide. However, liraglutide was associated with increased pro-inflammatory cytokines and inflammatory cells in white adipose tissue. Further research is crucial to fully understand the potential benefits and risks of using GLP-1 receptor agonists in the context of menopause.
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Affiliation(s)
- Camila Lüdke Rossetti
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil; Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, USA
| | - Iris Soares Andrade
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Luiz Fernando Fonte Boa
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Marcelo Barbosa Neves
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Larissa Brito Fassarella
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Iala Milene Bertasso
- Laboratorio de Fisiologia Endócrina, Instituto de Biologia, Universidade Do Estado Do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Maria das Graças Coelho de Souza
- Laboratório de Pesquisa Clínica e Experimental em Biologia Vascular (BioVasc), Universidade Do Estado Do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Eliete Bouskela
- Laboratório de Pesquisa Clínica e Experimental em Biologia Vascular (BioVasc), Universidade Do Estado Do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Patrícia Cristina Lisboa
- Laboratorio de Fisiologia Endócrina, Instituto de Biologia, Universidade Do Estado Do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Christina Maeda Takyia
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil; Programa de Pós-Graduação em Ciências Cirúrgicas, Faculdade de Medicina, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Isis Hara Trevenzoli
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Rodrigo Soares Fortunato
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil.
| | - Denise Pires de Carvalho
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil
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Knakker B, Inkeller J, Kovács P, Lendvai B, Hernádi I. GLP-1 receptor agonist exenatide uncouples food intake from hedonic and anticipatory regulation in non-human primates: insights from an operant meal schedule paradigm. Neuropsychopharmacology 2024; 50:410-418. [PMID: 39232188 PMCID: PMC11631970 DOI: 10.1038/s41386-024-01981-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 08/15/2024] [Accepted: 08/26/2024] [Indexed: 09/06/2024]
Abstract
Glucagon-like peptide 1 (GLP-1), a neuroendocrine signal of energy balance and satiety, has a major role in regulating food intake behaviour. Here we investigated the effects of the GLP-1 agonist exenatide on palatability-driven feeding regulation in adult male rhesus macaques (n = 5) using a novel operant food intake paradigm with four meal schedule conditions where two types of pellets with different palatability values were offered as meal in all combinations in two consecutive daily feeding sessions (S1 and S2). In control conditions, a strong, palatability-driven anticipatory effect was found in S1, followed by a complementary positive contrast effect in S2. After acute subcutaneous treatment with 1 µg/kg dose of exenatide 1 h before S1, food intake decreased to the same very low level in all meal schedule conditions in S1, completely erasing the previously observed anticipatory effect. Conversely, exenatide induced hypoglycaemia in an anticipatory meal schedule dependent pattern. Interestingly, the previously observed positive contrast effect was spared in S2, with a weaker residual effect specifically on the consumption of the more palatable pellet type. To conclude, the food intake reducing effects of exenatide may temporally evolve from strong anorectic to weak anhedonic modulations, where hedonic experience and anticipation during the early anorectic phase is conserved but uncoupled from food intake behaviour.
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Affiliation(s)
- Balázs Knakker
- Grastyán E. Translational Research Centre, University of Pécs, Pécs, Hungary
| | - Judit Inkeller
- Grastyán E. Translational Research Centre, University of Pécs, Pécs, Hungary
| | - Péter Kovács
- Department of Pharmacology and Drug Safety Research, Gedeon Richter Plc., Budapest, Hungary
- VRG Therapeutics, Füvészkert utca 3., Budapest, 1083, Hungary
| | - Balázs Lendvai
- Department of Pharmacology and Drug Safety Research, Gedeon Richter Plc., Budapest, Hungary
- Richter Department, Semmelweis University, Budapest, Hungary
| | - István Hernádi
- Grastyán E. Translational Research Centre, University of Pécs, Pécs, Hungary.
- Department of Neurobiology, Institute of Biology, Faculty of Sciences, University of Pécs, Pécs, Hungary.
- Institute of Physiology, Medical School, University of Pécs, Pécs, Hungary.
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Xuan Y, Ding TT, Mao XL, Pang S, He R, Qin L, Yuan JZ. Liraglutide alleviates high-fat diet-induced kidney injury in mice by regulating the CaMKKβ/AMPK pathway. Ren Fail 2024; 46:2351473. [PMID: 38915241 PMCID: PMC11207906 DOI: 10.1080/0886022x.2024.2351473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 04/30/2024] [Indexed: 06/26/2024] Open
Abstract
OBJECTIVE Liraglutide, a glucagon-like peptide-1 receptor agonist, has been shown to regulate blood sugar and control body weight, but its ability to treat obesity-related nephropathy has been poorly studied. Therefore, this study was designed to observe the characteristics and potential mechanism of liraglutide against obesity-related kidney disease. METHODS Thirty-six C57BL/6J male mice were randomly divided into six groups (n = 6 per group). Obesity-related nephropathy was induced in mice by continuous feeding of high-fat diet (HFD) for 12 weeks. After 12 weeks, liraglutide (0.6 mg/kg) and AMP-activated protein kinase (AMPK) agonists bortezomib (200 μg/kg) were injected for 12 weeks, respectively. Enzyme-linked immunosorbent assay was employed to detect the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, blood urea nitrogen, creatinine in serum, as well as urinary protein in urine. Besides, hematoxylin-eosin staining and periodic acid-Schiff staining were used to observe the pathological changes of kidney tissue; immunohistochemistry, western blot, and real-time quantitative PCR to assess the calmodulin-dependent protein kinase kinase beta (CaMKKβ)/AMPK signaling pathway activation. RESULTS Liraglutide significantly reduced serum lipid loading, improved kidney function, and relieved kidney histopathological damage and glycogen deposition in the mouse model of obesity-related kidney disease induced by HFD. In addition, liraglutide also significantly inhibited the CaMKKβ/AMPK signaling pathway in kidney tissue of HFD-induced mice. However, bortezomib partially reversed the therapeutic effect of liraglutide on HDF-induced nephropathy in mice. CONCLUSIONS Liraglutide has a therapeutic effect on obesity-related kidney disease, and such an effect may be achieved by inhibiting the CaMKKβ/AMPK signaling pathway in kidney tissue.
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Affiliation(s)
- Yingli Xuan
- Department of Nephrology, School of Medicine, Baoshan Branch of Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Ting-ting Ding
- Department of Nephrology, School of Medicine, Baoshan Branch of Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xiao-lei Mao
- Department of Nephrology, School of Medicine, Baoshan Branch of Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Shiqing Pang
- Department of Nephrology, School of Medicine, Baoshan Branch of Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Ruibin He
- Department of Nephrology, School of Medicine, Baoshan Branch of Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Li Qin
- Department of Nephrology, School of Medicine, Baoshan Branch of Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Jiang zi Yuan
- Department of Nephrology, School of Medicine, Baoshan Branch of Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
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Alcaino C, Reimann F, Gribble FM. Incretin hormones and obesity. J Physiol 2024:10.1113/JP286293. [PMID: 39576749 PMCID: PMC7617301 DOI: 10.1113/jp286293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Accepted: 10/31/2024] [Indexed: 11/24/2024] Open
Abstract
The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) play critical roles in co-ordinating postprandial metabolism, including modulation of insulin secretion and food intake. They are secreted from enteroendocrine cells in the intestinal epithelium following food ingestion, and act at multiple target sites including pancreatic islets and the brain. With the recent development of agonists targeting GLP-1 and GIP receptors for the treatment of type 2 diabetes and obesity, and the ongoing development of new incretin-based drugs with improved efficacy, there is great interest in understanding the physiology and pharmacology of these hormones.
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Affiliation(s)
- Constanza Alcaino
- Institute of Metabolic Science Metabolic Research Laboratories, University of Cambridge, Addenbrooke’s Hospital, CambridgeCB2 0QQ, UK
| | - Frank Reimann
- Institute of Metabolic Science Metabolic Research Laboratories, University of Cambridge, Addenbrooke’s Hospital, CambridgeCB2 0QQ, UK
| | - Fiona M Gribble
- Institute of Metabolic Science Metabolic Research Laboratories, University of Cambridge, Addenbrooke’s Hospital, CambridgeCB2 0QQ, UK
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Lian K, Zhang K, Kan C, Hou N, Han F, Sun X, Qiu H, Guo Z. Emerging therapeutic landscape: Incretin agonists in chronic kidney disease management. Life Sci 2024; 351:122801. [PMID: 38862060 DOI: 10.1016/j.lfs.2024.122801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 05/09/2024] [Accepted: 06/04/2024] [Indexed: 06/13/2024]
Abstract
The increasing incidence of chronic kidney disease (CKD) poses a significant public health concern, prompting heightened attention to its treatment. Incretins, including glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide, are intestinal peptides released after nutrient intake, known for their hypoglycemic effects in diabetes management. Recent advancements highlight the promising outcomes of GLP-1 receptor agonists in reducing CKD risk factors and improving renal outcomes. The multifaceted functions of GLP-1, such as its anti-obesity, anti-hypertensive, anti-hyperglycemic, anti-lipid, anti-inflammatory, and endothelial function protective properties, contribute to its potential as a therapeutic agent for CKD. Although experiments suggest the potential benefits of incretin in CKD, a comprehensive understanding of its specific mechanisms is still lacking. This review aims to provide a detailed examination of current evidence and potential future directions, emphasizing the promising yet evolving landscape of incretin agonists in the context of CKD.
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Affiliation(s)
- Kexin Lian
- Department of Nephropathy, Affiliated Hospital of Shandong Second Medical University, Weifang, China; Department of Endocrinology and Metabolism, Clinical Research Center, Affiliated Hospital of Shandong Second Medical University, Weifang, China
| | - Kexin Zhang
- Department of Endocrinology and Metabolism, Clinical Research Center, Affiliated Hospital of Shandong Second Medical University, Weifang, China
| | - Chengxia Kan
- Department of Endocrinology and Metabolism, Clinical Research Center, Affiliated Hospital of Shandong Second Medical University, Weifang, China
| | - Ningning Hou
- Department of Endocrinology and Metabolism, Clinical Research Center, Affiliated Hospital of Shandong Second Medical University, Weifang, China
| | - Fang Han
- Department of Pathology, Affiliated Hospital of Shandong Second Medical University, Weifang, China
| | - Xiaodong Sun
- Department of Endocrinology and Metabolism, Clinical Research Center, Affiliated Hospital of Shandong Second Medical University, Weifang, China
| | - Hongyan Qiu
- Department of Endocrinology and Metabolism, Clinical Research Center, Affiliated Hospital of Shandong Second Medical University, Weifang, China.
| | - Zhentao Guo
- Department of Nephropathy, Affiliated Hospital of Shandong Second Medical University, Weifang, China.
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Jin FX, Wang Y, Li MN, Li RJ, Guo JT. Intestinal glucagon-like peptide-1: A new player associated with impaired counterregulatory responses to hypoglycaemia in type 1 diabetic mice. World J Diabetes 2024; 15:1764-1777. [PMID: 39192849 PMCID: PMC11346100 DOI: 10.4239/wjd.v15.i8.1764] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 06/03/2024] [Accepted: 07/05/2024] [Indexed: 07/25/2024] Open
Abstract
BACKGROUND Impaired hypoglycaemic counterregulation has emerged as a critical concern for diabetic patients who may be hesitant to medically lower their blood glucose levels due to the fear of potential hypoglycaemic reactions. However, the patho-genesis of hypoglycaemic counterregulation is still unclear. Glucagon-like peptide-1 (GLP-1) and its analogues have been used as adjunctive therapies for type 1 diabetes mellitus (T1DM). The role of GLP-1 in counterregulatory dys-function during hypoglycaemia in patients with T1DM has not been reported. AIM To explore the impact of intestinal GLP-1 on impaired hypoglycaemic counterregulation in type 1 diabetic mice. METHODS T1DM was induced in C57BL/6J mice using streptozotocin, followed by intraperitoneal insulin injections to create T1DM models with either a single episode of hypoglycaemia or recurrent episodes of hypoglycaemia (DH5). Immunofluorescence, Western blot, and enzyme-linked immunosorbent assay were employed to evaluate the influence of intestinal GLP-1 on the sympathetic-adrenal reflex and glucagon (GCG) secretion. The GLP-1 receptor agonist GLP-1(7-36) or the antagonist exendin (9-39) were infused into the terminal ileum or injected intraperitoneally to further investigate the role of intestinal GLP-1 in hypoglycaemic counterregulation in the model mice. RESULTS The expression levels of intestinal GLP-1 and its receptor (GLP-1R) were significantly increased in DH5 mice. Consecutive instances of excess of intestinal GLP-1 weakens the sympathetic-adrenal reflex, leading to dysfunction of adrenal counterregulation during hypoglycaemia. DH5 mice showed increased pancreatic δ-cell mass, cAMP levels in δ cells, and plasma somatostatin concentrations, while cAMP levels in pancreatic α cells and plasma GCG levels decreased. Furthermore, GLP-1R expression in islet cells and plasma active GLP-1 levels were significantly increased in the DH5 group. Further experiments involving terminal ileal infusion and intraperitoneal injection in the model mice demonstrated that intestinal GLP-1 during recurrent hypoglycaemia hindered the secretion of the counterregulatory hormone GCG via the endocrine pathway. CONCLUSION Excessive intestinal GLP-1 is strongly associated with impaired counterregulatory responses to hypoglycaemia, leading to reduced appetite and compromised secretion of adrenaline, noradrenaline, and GCG during hypo-glycaemia.
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Affiliation(s)
- Fang-Xin Jin
- Department of Histology and Embryology, Key Laboratory of Universities in Shandong Province, Shandong Second Medical University, Weifang 261053, Shandong Province, China
| | - Yan Wang
- Department of Histology and Embryology, Key Laboratory of Universities in Shandong Province, Shandong Second Medical University, Weifang 261053, Shandong Province, China
| | - Min-Ne Li
- Department of Histology and Embryology, Key Laboratory of Universities in Shandong Province, Shandong Second Medical University, Weifang 261053, Shandong Province, China
| | - Ru-Jiang Li
- Department of Histology and Embryology, Key Laboratory of Universities in Shandong Province, Shandong Second Medical University, Weifang 261053, Shandong Province, China
| | - Jun-Tang Guo
- Department of Pathological Physiology, Shandong Second Medical University, Weifang 261053, Shandong Province, China
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10
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Herman RJ, Schmidt HD. Targeting GLP-1 receptors to reduce nicotine use disorder: Preclinical and clinical evidence. Physiol Behav 2024; 281:114565. [PMID: 38663460 PMCID: PMC11128349 DOI: 10.1016/j.physbeh.2024.114565] [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: 01/31/2024] [Revised: 04/18/2024] [Accepted: 04/22/2024] [Indexed: 04/30/2024]
Abstract
Nicotine use disorder (NUD) remains a leading cause of preventable death in the U.S. Unfortunately, current FDA-approved pharmacotherapies for smoking cessation have limited efficacy and are associated with high rates of relapse. One major barrier to long-term smoking abstinence is body weight gain during withdrawal. Nicotine withdrawal-induced body weight gain can also lead to development of chronic disease states like obesity and type II diabetes mellitus. Therefore, it is critical to identify novel pharmacotherapies for NUD that decrease relapse and nicotine withdrawal symptoms including body weight gain. Recent studies demonstrate that glucagon-like peptide-1 receptor (GLP-1R) agonists attenuate voluntary nicotine taking and seeking and prevent withdrawal-induced hyperphagia and body weight gain. Emerging evidence also suggests that GLP-1R agonists improve cognitive deficits, as well as depressive- and anxiety-like behaviors, which contribute to smoking relapse during withdrawal. While further studies are necessary to fully characterize the effects of GLP-1R agonists on NUD and understand the mechanisms by which GLP-1R agonists decrease nicotine withdrawal-mediated behaviors, the current literature supports GLP-1R-based approaches to treating NUD.
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Affiliation(s)
- Rae J Herman
- Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Heath D Schmidt
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, United States; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
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Yu WL, Liao YN, Yang TH, Yang CW, Kao TI, Lee PW, Hsu CY, Huang JL, Huang YT, Chen HY. Laser Acupuncture versus Liraglutide in Treatment of Obesity: A Multi-Institutional Retrospective Cohort Study. Healthcare (Basel) 2024; 12:1279. [PMID: 38998814 PMCID: PMC11241425 DOI: 10.3390/healthcare12131279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 06/15/2024] [Accepted: 06/16/2024] [Indexed: 07/14/2024] Open
Abstract
BACKGROUND Obesity is a global concern, driving the search for alternative treatments beyond lifestyle changes and medications. Laser acupuncture (LA) shows promise in obesity management, yet few studies compare it with FDA-approved medications. This study aimed to assess and compare LA's impact with liraglutide on weight reduction in obese individuals. METHODS Data from the Chang Gung Research Database (CGRD) (2013-2018) were analyzed. Primary outcomes included changes in body weight and BMI within 180 days, with secondary outcomes measuring the proportion achieving 5%, 10%, and 15% weight loss. Adverse events were also assessed. RESULTS Of 745 subjects (173 LA users, 572 liraglutide users), LA users lost more weight by day 180 (5.82 ± 4.39 vs. 2.38 ± 5.75 kg; p < 0.001) and had a greater BMI reduction (-2.27 ± 1.73 vs. -0.93 ± 2.25 kg/m2; p < 0.001). More LA users achieved 5% and 10% weight loss compared to liraglutide users (64.2% vs. 22.7%, 26.6% vs. 4.2%; all p < 0.001). After balancing baseline differences, LA's benefits remained significant. No adverse events were reported with LA. CONCLUSIONS LA may offer superior weight reduction compared to liraglutide. Future studies should explore LA alone or in combination with liraglutide for obesity management.
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Affiliation(s)
- Wen-Lin Yu
- Division of Chinese Internal Medicine, Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (W.-L.Y.); (Y.-N.L.); (T.-H.Y.); (C.-W.Y.)
| | - Yu-Ning Liao
- Division of Chinese Internal Medicine, Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (W.-L.Y.); (Y.-N.L.); (T.-H.Y.); (C.-W.Y.)
| | - Tsung-Hsien Yang
- Division of Chinese Internal Medicine, Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (W.-L.Y.); (Y.-N.L.); (T.-H.Y.); (C.-W.Y.)
| | - Ching-Wei Yang
- Division of Chinese Internal Medicine, Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (W.-L.Y.); (Y.-N.L.); (T.-H.Y.); (C.-W.Y.)
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Ting-I Kao
- Division of Chinese Internal Medicine, Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (W.-L.Y.); (Y.-N.L.); (T.-H.Y.); (C.-W.Y.)
| | - Pai-Wei Lee
- Center for Big Data Analytics and Statistics, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan 333, Taiwan; (P.-W.L.); (C.-Y.H.); (J.-L.H.)
| | - Chiu-Yi Hsu
- Center for Big Data Analytics and Statistics, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan 333, Taiwan; (P.-W.L.); (C.-Y.H.); (J.-L.H.)
| | - Jhen-Ling Huang
- Center for Big Data Analytics and Statistics, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan 333, Taiwan; (P.-W.L.); (C.-Y.H.); (J.-L.H.)
| | - Yu-Tung Huang
- Center for Big Data Analytics and Statistics, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan 333, Taiwan; (P.-W.L.); (C.-Y.H.); (J.-L.H.)
| | - Hsing-Yu Chen
- Division of Chinese Internal Medicine, Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (W.-L.Y.); (Y.-N.L.); (T.-H.Y.); (C.-W.Y.)
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
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12
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McMorrow HE, Lorch CM, Hayes NW, Fleps SW, Frydman JA, Xia JL, Samms RJ, Beutler LR. Incretin hormones and pharmacomimetics rapidly inhibit AgRP neuron activity to suppress appetite. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.18.585583. [PMID: 38562891 PMCID: PMC10983981 DOI: 10.1101/2024.03.18.585583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Analogs of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) have become mainstays of obesity and diabetes management. However, both the physiologic role of incretin hormones in the control of appetite and the pharmacologic mechanisms by which incretin-mimetic drugs suppress caloric intake remain incompletely understood. Hunger-promoting AgRP-expressing neurons are an important hypothalamic population that regulates food intake. Therefore, we set out to determine how incretins analogs affect their activity in vivo. Using fiber photometry, we observed that both GIP receptor (GIPR) and GLP-1 receptor (GLP-1R) agonism acutely inhibit AgRP neuron activity in fasted mice and reduce the response of AgRP neurons to food. Moreover, optogenetic stimulation of AgRP neurons partially attenuated incretin-induced feeding suppression, suggesting that AgRP neuron inhibition is necessary for the full appetite-suppressing effects of incretin-based therapeutics. Finally, we found that GIP but not GLP-1 is necessary for nutrient-mediated AgRP neuron inhibition, representing a novel physiologic role for GIP in maintaining energy balance. Taken together, these findings reveal neural mechanisms underlying the efficacy of incretin-mimetic obesity therapies. Understanding these drugs' mechanisms of action is crucial for the development of next-generation obesity pharmacotherapies with an improved therapeutic profile.
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Affiliation(s)
- Hayley E McMorrow
- Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University, Chicago, IL 60611, USA
- Interdepartmental Neuroscience Graduate Program, Northwestern University, Chicago, IL, USA
| | - Carolyn M Lorch
- Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University, Chicago, IL 60611, USA
- Driskill Graduate Program in Life Sciences, Northwestern University, Chicago, IL, USA
| | - Nikolas W Hayes
- Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University, Chicago, IL 60611, USA
- Interdepartmental Neuroscience Graduate Program, Northwestern University, Chicago, IL, USA
| | - Stefan W Fleps
- Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University, Chicago, IL 60611, USA
- Department of Neuroscience, Northwestern University, Chicago, IL, USA
| | - Joshua A Frydman
- Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Jessica L Xia
- Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Ricardo J Samms
- Diabetes, Obesity and Complications Therapeutic Area, Eli Lilly, Indianapolis, IN, USA
| | - Lisa R Beutler
- Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University, Chicago, IL 60611, USA
- Lead contact
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13
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Gugliucci A. The chylomicron saga: time to focus on postprandial metabolism. Front Endocrinol (Lausanne) 2024; 14:1322869. [PMID: 38303975 PMCID: PMC10830840 DOI: 10.3389/fendo.2023.1322869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 12/28/2023] [Indexed: 02/03/2024] Open
Abstract
Since statins have had such tremendous therapeutic success over the last three decades, the field of atherosclerosis has become somewhat LDL-centric, dismissing the relevance of triglycerides (TG), particularly chylomicrons, in atherogenesis. Nonetheless, 50% of patients who take statins are at risk of developing atherosclerotic cardiovascular disease (ASCVD) and are unable to achieve their goal LDL-C levels. This residual risk is mediated, in part by triglyceride rich lipoproteins (TRL) and their remnants. Following his seminal investigation on the subject, Zilversmit proposed that atherosclerosis is a postprandial event in 1979 (1-4). In essence, the concept suggests that remnant cholesterol-rich chylomicron (CM) and very-low density lipoprotein (VLDL) particles play a role in atherogenesis. Given the foregoing, this narrative review addresses the most recent improvements in our understanding of postprandial dyslipidemia. The primary metabolic pathways of chylomicrons are discussed, emphasizing the critical physiological role of lipoprotein lipase and apoCIII, the importance of these particles' fluxes in the postprandial period, their catabolic rate, the complexities of testing postprandial metabolism, and the role of angiopoietin-like proteins in the partition of CM during the fed cycle. The narrative is rounded out by the dysregulation of postprandial lipid metabolism in insulin resistance states and consequent CVD risk, the clinical evaluation of postprandial dyslipidemia, current research limits, and potential future study directions.
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Affiliation(s)
- Alejandro Gugliucci
- Glycation, Oxidation and Disease Laboratory, Department of Research, Touro University California, Vallejo, CA, United States
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14
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Wu S, Jia W, He H, Yin J, Xu H, He C, Zhang Q, Peng Y, Cheng R. A New Dietary Fiber Can Enhance Satiety and Reduce Postprandial Blood Glucose in Healthy Adults: A Randomized Cross-Over Trial. Nutrients 2023; 15:4569. [PMID: 37960222 PMCID: PMC10648557 DOI: 10.3390/nu15214569] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 10/23/2023] [Accepted: 10/26/2023] [Indexed: 11/15/2023] Open
Abstract
BACKGROUND Dietary fiber plays a potential role in regulating energy intake and stabilizing postprandial blood glucose levels. Soluble dietary fiber has become an important entry point for nutritional research on the regulation of satiety. METHODS this was a double-blind, randomized cross-over trial enrolling 12 healthy subjects to compare the effects of RPG (R+PolyGly) dietary fiber products (bread, powder, and capsule) and pectin administered with a standard meal on satiety, blood glucose, and serum insulin level. RESULTS Adding 3.8% RPG dietary fiber to bread significantly increased the volume, water content, hardness, and chewiness of bread compared to 3.8% pectin bread and white bread and significantly improved the sensory quality of bread. RPG bread had better appetite suppression effects at some time points than the other two groups and the best postprandial blood glucose lowering effects among the three groups. Administration of RPG capsules containing 5.6 g of RPG dietary fiber with meals improved satiety and reduced hunger compared to 6 g of RPG powder and 6 g of pectin, which had the greatest effect on suppressing appetite and reducing prospective food consumption. The peak level of serum glucagon-like peptide-1 (GLP-1) in the RPG capsule group (578.17 ± 19.93 pg/mL) was significantly higher than that in other groups at 0 min and 30 min after eating. RPG powder had the best effect in reducing postprandial blood glucose and increasing serum insulin levels; the total area under the curve (AUC) of serum insulin with RPG powder was higher than other groups (5960 ± 252.46 μU min/mL). CONCLUSION RPG dietary fiber products can improve the sensory properties of food, reduce postprandial blood glucose, and enhance satiety, especially in capsule and powder forms. Further research on the physiological effects of RPG dietary fiber is required to facilitate its use as a functional ingredient in food products.
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Affiliation(s)
- Simou Wu
- Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China; (S.W.); (W.J.)
| | - Wen Jia
- Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China; (S.W.); (W.J.)
| | - Huimin He
- Recovery Plus USA, New York, NY 10019, USA; (H.H.); (J.Y.); (H.X.); (C.H.)
| | - Jun Yin
- Recovery Plus USA, New York, NY 10019, USA; (H.H.); (J.Y.); (H.X.); (C.H.)
| | - Huilin Xu
- Recovery Plus USA, New York, NY 10019, USA; (H.H.); (J.Y.); (H.X.); (C.H.)
| | - Chengyuan He
- Recovery Plus USA, New York, NY 10019, USA; (H.H.); (J.Y.); (H.X.); (C.H.)
| | - Qinqiu Zhang
- Sichuan Key Laboratory of Fruit and Vegetable Postharvest Physiology, College of Food Science, Sichuan Agricultural University, Ya’an 625014, China; (Q.Z.); (Y.P.)
| | - Yue Peng
- Sichuan Key Laboratory of Fruit and Vegetable Postharvest Physiology, College of Food Science, Sichuan Agricultural University, Ya’an 625014, China; (Q.Z.); (Y.P.)
| | - Ruyue Cheng
- Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China; (S.W.); (W.J.)
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15
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Jiang W, Li W, Cheng J, Li W, Cheng F. Efficacy and safety of liraglutide in patients with type 2 diabetes mellitus and severe obstructive sleep apnea. Sleep Breath 2023; 27:1687-1694. [PMID: 36542275 PMCID: PMC10539428 DOI: 10.1007/s11325-022-02768-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Revised: 12/08/2022] [Accepted: 12/12/2022] [Indexed: 12/24/2022]
Abstract
OBJECTIVES To observe the efficacy and side effects of liraglutide in the treatment of type 2 diabetes mellitus (T2DM) patients with severe obstructive sleep apnea (OSA). METHODS The study conducted in an outpatient setting was a two-center, prospective randomized controlled study. T2DM patients with severe OSA were randomized to the control group (continuous positive airway pressure [CPAP] and drug treatment without liraglutide) or the liraglutide group (CPAP and drug treatment including liraglutide). Demographic and clinical characteristics, sleep-disordered breathing indices, cardiac function indices, and side effects were evaluated and compared between the two groups before and after 3 months. RESULTS Of 90 patients, 45 were randomized to the intervention arm (with liraglutide) and 45 to the control arm (without liraglutide). One patient in the liraglutide group dropped out of the study on day 8 after enrollment due to obvious gastrointestinal symptoms. No significant differences were found between the two groups in baseline demographics, clinical characteristics, cardiac function indicators, or sleep disorder respiratory indices (P > 0.05). After 3 months, the body mass index (BMI), apnea hypopnea index (AHI), and mean systolic blood pressure in the liraglutide treatment group were significantly lower than those in the control group (P < 0.05). The minimum oxygen saturation was significantly higher in the liraglutide group compared with that in the control group after 3 months of follow-up (P < 0.05). No difference was found between the two groups in the summary of side effects (P > 0.05). CONCLUSIONS Liraglutide combined with CPAP can effectively reduce BMI, lower mean systolic blood pressure, and improve AHI scores and hypoxia in T2DM patients with severe OSA. Liraglutide did not increase side effects.
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Affiliation(s)
- Wenlong Jiang
- Department of Cardiovascular, Shenzhen Yantian District People's Hospital, Shenzhen, China
| | - Weiguo Li
- Department of Cardiovascular, Longyan First Hospital Affiliated to Fujian Medical University, Longyan, Fujian, China
| | - Jing Cheng
- Department of Cardiovascular, Shenzhen Yantian District People's Hospital, Shenzhen, China
| | - Wen Li
- Department of Cardiovascular, Shenzhen Yantian District People's Hospital, Shenzhen, China
| | - Fangzhou Cheng
- Department of Cardiovascular, Shenzhen Yantian District People's Hospital, Shenzhen, China.
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16
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Xing C, Huang X, Wang D, Yu D, Hou S, Cui H, Song L. Roles of bile acids signaling in neuromodulation under physiological and pathological conditions. Cell Biosci 2023; 13:106. [PMID: 37308953 PMCID: PMC10258966 DOI: 10.1186/s13578-023-01053-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 05/13/2023] [Indexed: 06/14/2023] Open
Abstract
Bile acids (BA) are important physiological molecules not only mediating nutrients absorption and metabolism in peripheral tissues, but exerting neuromodulation effect in the central nerve system (CNS). The catabolism of cholesterol to BA occurs predominantly in the liver by the classical and alternative pathways, or in the brain initiated by the neuronal-specific enzyme CYP46A1 mediated pathway. Circulating BA could cross the blood brain barrier (BBB) and reach the CNS through passive diffusion or BA transporters. Brain BA might trigger direct signal through activating membrane and nucleus receptors or affecting activation of neurotransmitter receptors. Peripheral BA may also provide the indirect signal to the CNS via farnesoid X receptor (FXR) dependent fibroblast growth factor 15/19 (FGF15/19) pathway or takeda G protein coupled receptor 5 (TGR5) dependent glucagon-like peptide-1 (GLP-1) pathway. Under pathological conditions, alterations in BA metabolites have been discovered as potential pathogenic contributors in multiple neurological disorders. Attractively, hydrophilic ursodeoxycholic acid (UDCA), especially tauroursodeoxycholic acid (TUDCA) can exert neuroprotective roles by attenuating neuroinflammation, apoptosis, oxidative or endoplasmic reticulum stress, which provides promising therapeutic effects for treatment of neurological diseases. This review summarizes recent findings highlighting the metabolism, crosstalk between brain and periphery, and neurological functions of BA to elucidate the important role of BA signaling in the brain under both physiological and pathological conditions.
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Affiliation(s)
- Chen Xing
- Beijing Institute of Basic Medical Sciences, Taiping Road #27, Beijing, 100850, China.
| | - Xin Huang
- Beijing Institute of Basic Medical Sciences, Taiping Road #27, Beijing, 100850, China
| | - Dongxue Wang
- Beijing Institute of Basic Medical Sciences, Taiping Road #27, Beijing, 100850, China
- College of Pharmacy, Jiamusi University, Jiamusi, 154007, China
| | - Dengjun Yu
- Beijing Institute of Basic Medical Sciences, Taiping Road #27, Beijing, 100850, China
- College of Pharmacy, Jiamusi University, Jiamusi, 154007, China
| | - Shaojun Hou
- Beijing Institute of Basic Medical Sciences, Taiping Road #27, Beijing, 100850, China
- Anhui Medical University, Heifei, 230032, China
| | - Haoran Cui
- Beijing Institute of Basic Medical Sciences, Taiping Road #27, Beijing, 100850, China
| | - Lung Song
- Beijing Institute of Basic Medical Sciences, Taiping Road #27, Beijing, 100850, China.
- Anhui Medical University, Heifei, 230032, China.
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17
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Failor M, Bohler M, Cao C, Gilbert E, Cline M. Elucidating the central anorexigenic mechanism of glucagon-like peptide 1 in Japanese quail (Coturnix japonica). Gen Comp Endocrinol 2023; 339:114292. [PMID: 37088166 DOI: 10.1016/j.ygcen.2023.114292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 04/04/2023] [Accepted: 04/19/2023] [Indexed: 04/25/2023]
Abstract
Glucagon-like peptide 1 (GLP-1) elicits a potent reduction in food intake, although the central mechanism mediating this appetite-suppressive effect is not fully understood in all species. To begin to elucidate the molecular mechanisms in quail, we administered GLP-1 via intracerebroventricular (ICV) injection to 7-day-old Japanese quail(Coturnix japonica) and determined effects on food and water intake, behavior, and brain nucleus activation. We observed a reduction in food and water intake, with the lowest effective dose being 0.01 nmol. Quail injected with GLP-1 displayed fewer steps, feeding pecks, exploratory pecks, and jumps, while time spent sitting increased. We quantified c-Fos immunoreactivity at 60 minutes post-injection in hypothalamic and brainstem nuclei that mediate food intake and determined that the hypothalamic paraventricular nucleus (PVN), and nucleus of the solitary tract and area postrema of the brainstem were activated in response to GLP-1.In conclusion, these results suggest that GLP-1 induces anorexigenic effects that are likely mediated at the level of the PVN and brainstem.
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Affiliation(s)
- Madison Failor
- Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
| | - Mark Bohler
- Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
| | - Chang Cao
- Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
| | - Elizabeth Gilbert
- Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
| | - Mark Cline
- Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.
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18
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Brakey DJ, Schatz KC, Paul MJ, Daniels D. The role of glucagon-like peptide-1 (GLP-1) in fluid and food intakes in vasopressin-deficient Brattleboro rats. Physiol Behav 2023; 262:114093. [PMID: 36706972 PMCID: PMC9974868 DOI: 10.1016/j.physbeh.2023.114093] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/17/2023] [Accepted: 01/20/2023] [Indexed: 01/26/2023]
Abstract
Eating and drinking co-occur and many of the same mechanisms that control one are involved in the control of the other, making it difficult to isolate specific mechanisms for the control of fluid intake. Glucagon-like peptide-1 (GLP-1) is a peptide that seems to be involved in the endogenous control of both ingestive behaviors, but we lack a thorough understanding of how and where GLP-1 is acting to control fluid intake. Vasopressin-deficient Brattleboro rats are a model of hereditary hypothalamic diabetes insipidus that have been used extensively for the study of vasopressin actions in behavior and physiology. Here, we propose that these rats, that eat normally but drink excessively, provide a useful model to dissociate central controls of food and fluid intakes. As an initial step toward establishing this model for these purposes, we focused on GLP-1. Similar to the effect observed after treatment with a GLP-1 receptor (GLP-1R) agonist, the intake difference between wildtype and Brattleboro rats was largely a function in the number of licking bursts, indicating differences in post-ingestive feedback (e.g., satiation). When given central injections of a GLP-1R agonist, the effect on feeding was comparable between wildtype and Brattleboro rats, but the effect of drug on fluid intake was markedly exaggerated in Brattleboro rats. Additionally, Brattleboro rats did not respond to GLP-1R antagonism, whereas wildtype rats did. Taken together, these results suggest that Brattleboro rats exhibit a selective disruption to GLP-1's control of water intake. Overall, these experiments provide foundational studies of the ingestive behavior of Brattleboro rats and demonstrate the potential to use these rats to disentangle the effects of GLP-1 on food and fluid intakes.
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Affiliation(s)
- Destiny J Brakey
- Department of Biological Sciences, State University of New York at Buffalo, Buffalo, NY, USA; Department of Psychology, State University of New York at Buffalo, Buffalo, NY, USA
| | - Kelcie C Schatz
- Department of Psychology, State University of New York at Buffalo, Buffalo, NY, USA
| | - Matthew J Paul
- Department of Psychology, State University of New York at Buffalo, Buffalo, NY, USA
| | - Derek Daniels
- Department of Biological Sciences, State University of New York at Buffalo, Buffalo, NY, USA; Department of Psychology, State University of New York at Buffalo, Buffalo, NY, USA; Center for Ingestive Behavior Research, State University of New York at Buffalo, Buffalo, NY, USA.
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19
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Jiao R, Lin C, Bai S, Cai X, Hu S, Lv F, Yang W, Zhu X, Ji L. The correlations between steady-state concentration, duration of action and molecular weight of GLP-1RAs and their efficacy and gastrointestinal side effects in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Expert Opin Pharmacother 2023; 24:511-521. [PMID: 36799287 DOI: 10.1080/14656566.2023.2181693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/18/2023]
Abstract
BACKGROUND To assess the influence of steady-state concentration, duration of action and molecular weight of glucagon-like peptide-1 receptor (GLP-1RA) on efficacy and gastrointestinal (GI) side effects in patients with type 2 diabetes mellitus (T2DM). METHODS PubMed, EMBASE, the Cochrane Center Register of Controlled Trials for Studies and Clinicaltrial.gov were searched from inception to April 2022. Randomized controlled trials (RCTs) comparing GLP-1RA versus non-GLP-1RA agents in patients with T2DM were included. Sensitivity analyses on steady-state concentration, duration of action and molecular weight of GLP-1RA were conducted. RESULTS 113 RCTs were included. Greater HbA1c reduction between GLP-1RA users versus non-GLP-1RA users was observed in the high-steady-state-concentration stratum and long-acting stratum compared with the low-steady-state-concentration stratum (Psubgroup difference = 0.0004) and short-acting stratum (Psubgroup difference<0.0001). The risk of GI adverse events in GLP-1RA users versus non-GLP-1RA users was decreased in the high-steady-state-concentration stratum, long-acting stratum and heavy-molecular-weight stratum compared with low-steady-state-concentration stratum (Psubgroup difference<0.0001), short-acting stratum (Psubgroup difference = 0.002) and light-molecular-weight stratum (Psubgroup difference = 0.0008). CONCLUSION GLP-1RA with high steady-state concentration and long duration of action showed better hypoglycemic effect. GLP-1RA with high steady-state concentration, long duration of action and heavy molecular weight was associated with lower risk of GI adverse events.
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Affiliation(s)
- Ruoyang Jiao
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, Hebei, China
| | - Chu Lin
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, Hebei, China
| | - Shuzhen Bai
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, Hebei, China
| | - Xiaoling Cai
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, Hebei, China
| | - Suiyuan Hu
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, Hebei, China
| | - Fang Lv
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, Hebei, China
| | - Wenjia Yang
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, Hebei, China
| | - Xingyun Zhu
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, Hebei, China
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, Hebei, China
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20
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Effect of Weight Regain on Body Composition and Metabolic Biomarkers After Sleeve Gastrectomy: a Cross-Sectional Study from a Hospital Database. Obes Surg 2023; 33:268-278. [PMID: 36462120 PMCID: PMC9834094 DOI: 10.1007/s11695-022-06384-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 11/17/2022] [Accepted: 11/27/2022] [Indexed: 12/04/2022]
Abstract
INTRODUCTION Weight regain (WR) is described in approximately 30% of patient's post-bariatric surgery. It is related to the progression or recurrence of associated medical problems and decline in health-related quality of life. This study aimed to test the return of body composition and metabolic biomarkers to pre-operative levels when WR occurs. METHODS In this cross-sectional study conducted in 2021, patients were randomly selected from the hospital's electronic databases between 2001 and 2020. Patient demographic data, comorbidities, body compositions, and metabolic biomarkers were collected. Three groups were defined: groups A (WR), B (weight loss), and C (control group; patients with obesity who had not yet undergone bariatric surgery). RESULTS A total of 88 patients were enrolled in this study and matched with the control group. The body mass index in group A was 43.8 ± 6.9 kg/m2; group B was 28.6 ± 4.2; group C was 43.9 ± 7.1. Body muscle mass, body fat mass, and visceral fat significantly differed between groups A and B (p < 0.001) but not between groups A and C (p = 0.8). There was a significant difference in leptin, ghrelin, postprandial glucagon-like peptide-1, insulin, and fibroblast growth factor-21 (but not retinol-binding protein-4) between groups A and B. Most metabolic biomarkers in group A returned to the pre-operative values as in group C. CONCLUSION WR had a direct negative effect on body composition and metabolic biomarkers, whereby the values returned to pre-operative levels. Early detection of WR and possible additional therapy are necessary to prevent associated medical problems.
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Kong H, Yu L, Li C, Ban X, Gu Z, Li Z. Short-Clustered Maltodextrin Activates Ileal Glucose-Sensing and Induces Glucagon-like Peptide 1 Secretion to Ameliorate Glucose Homeostasis in Type 2 Diabetic Mice. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:12604-12619. [PMID: 36125960 DOI: 10.1021/acs.jafc.2c04978] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Reconstructing molecular structure is an effective approach to attenuating glycemic response to starch. Previously, we rearranged α-1,4 and α-1,6-glycosidic bonds in starch molecules to produce short-clustered maltodextrin (SCMD). The present study revealed that SCMD slowly released glucose until the distal ileum. The activated ileal glucose-sensing enabled SCMD to be a potent inducer for glucagon-like peptide-1 (GLP-1). Furthermore, SCMD was found feasible to serve as the dominant dietary carbohydrate to rescue mice from diabetes. Interestingly, a mixture of normal maltodextrin and resistant dextrin (MD+RD), although it caused an attenuated glycemic response similar to that of SCMD, failed to ameliorate glucose homeostasis because it hardly induced GLP-1 secretion. The serum GLP-1 levels seen in MD+RD-fed mice (5.25 ± 1.51 pmol/L) were significantly lower than those seen in SCMD-fed mice (8.25 ± 2.01 pmol/L, p < 0.05). Further investigation revealed that the beneficial effects of SCMD could be abolished by a GLP-1 receptor (GLP-1R) antagonist. These results identify GLP-1R signaling as a critical contributor to SCMD-exerted health benefits and highlight the role of ileal glucose-sensing in designing dietary carbohydrates.
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Affiliation(s)
- Haocun Kong
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Luxi Yu
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Caiming Li
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- Collaborative Innovation Center for Food Safety and Quality Control, Jiangnan University, Wuxi 214122, China
| | - Xiaofeng Ban
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- Collaborative Innovation Center for Food Safety and Quality Control, Jiangnan University, Wuxi 214122, China
| | - Zhengbiao Gu
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- Collaborative Innovation Center for Food Safety and Quality Control, Jiangnan University, Wuxi 214122, China
| | - Zhaofeng Li
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- Collaborative Innovation Center for Food Safety and Quality Control, Jiangnan University, Wuxi 214122, China
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22
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Blonde GD, Fletcher FH, Tang T, Newsome R, Spector AC. A new apparatus to analyze meal-related ingestive behaviors in rats fed a complex multi-food diet. Physiol Behav 2022; 252:113824. [PMID: 35472328 PMCID: PMC10544710 DOI: 10.1016/j.physbeh.2022.113824] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 04/21/2022] [Accepted: 04/22/2022] [Indexed: 10/18/2022]
Abstract
The measurement of the size and timing of meals provides critical insight into the processes underlying food intake. While most work has been conducted with a single food or fluid, the availability of food choices can also influence eating and interact with these processes. The 5-Item Food Choice Monitor (FCM), a device that continuously measures eating and drinking behaviors of rats provided up to 5 foods and 2 fluids simultaneously, was designed to allow study of food choices simultaneously with meal patterns. To validate this device, adult male and female (n = 8 each) Sprague-Dawley rats were housed in the FCM. Food and fluid intake were measured continuously (22-h/day) while rats were presented water and powdered chow. Then a cafeteria diet of 5 foods varying in macronutrient content, texture, and flavors were offered along with water. Lastly, the 5 foods were offered along with 0.3 M sucrose and water. Analyses were conducted to find optimal criteria for parceling ingestive behavior into meals, and then meal patterns were quantified. Total intake, as assessed by FCM software, was in good concordance with that measured by an independent scale. A minimum meal size of 1 kcal and a meal termination criterion of 15-min accounted for >90% of total intake and produced meal dynamics that were in register with the literature. Use of the cafeteria diet allowed comparisons between meal patterns with a single food versus a multi-food diet, as well as analyses of macronutrient-related food choices across subsets of meals. The FCM proved to accurately measure food intake over a 22-h period and was able to detect differences and similarities in the meal patterns of rats as a function of sex and food choice availability. Combined with any number of experimental manipulations, the FCM holds great promise in the investigation of the physiological and neural controls of ingestive behavior in a dietary environment that allows food choices, more closely emulating human eating conditions.
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Affiliation(s)
- Ginger D Blonde
- Department of Psychology and Program in Neuroscience, Florida State University, 1107 W. Call St., Tallahassee, FL, 32306-4301 USA
| | - Fred H Fletcher
- Department of Psychology and Program in Neuroscience, Florida State University, 1107 W. Call St., Tallahassee, FL, 32306-4301 USA
| | - Te Tang
- Department of Psychology and Program in Neuroscience, Florida State University, 1107 W. Call St., Tallahassee, FL, 32306-4301 USA
| | - Ryan Newsome
- Department of Psychology and Program in Neuroscience, Florida State University, 1107 W. Call St., Tallahassee, FL, 32306-4301 USA
| | - Alan C Spector
- Department of Psychology and Program in Neuroscience, Florida State University, 1107 W. Call St., Tallahassee, FL, 32306-4301 USA.
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23
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Aly E, Sánchez‐Moya T, Darwish AA, Ros‐Berruezo G, López‐Nicolás R. In vitro digestion effect on CCK and GLP‐1 release and antioxidant capacity of some plant‐based milk substitutes. J Food Sci 2022; 87:1999-2008. [DOI: 10.1111/1750-3841.16140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 03/11/2022] [Accepted: 03/16/2022] [Indexed: 11/29/2022]
Affiliation(s)
- Esmat Aly
- Dairy Research Department, Food Technology Research Institute Agricultural Research Center Giza Egypt
- Department of Food Science and Nutrition, Faculty of Veterinary Science, Regional Campus of International Excellence Campus Mare Nostrum University of Murcia Murcia Spain
| | - Teresa Sánchez‐Moya
- Department of Food Science and Nutrition, Faculty of Veterinary Science, Regional Campus of International Excellence Campus Mare Nostrum University of Murcia Murcia Spain
| | - Aliaa A. Darwish
- Dairy Research Department, Food Technology Research Institute Agricultural Research Center Giza Egypt
- Department of Food Science and Nutrition, Faculty of Veterinary Science, Regional Campus of International Excellence Campus Mare Nostrum University of Murcia Murcia Spain
| | - Gaspar Ros‐Berruezo
- Department of Food Science and Nutrition, Faculty of Veterinary Science, Regional Campus of International Excellence Campus Mare Nostrum University of Murcia Murcia Spain
| | - Rubén López‐Nicolás
- Department of Food Science and Nutrition, Faculty of Veterinary Science, Regional Campus of International Excellence Campus Mare Nostrum University of Murcia Murcia Spain
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24
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Watts AG, Kanoski SE, Sanchez-Watts G, Langhans W. The physiological control of eating: signals, neurons, and networks. Physiol Rev 2022; 102:689-813. [PMID: 34486393 PMCID: PMC8759974 DOI: 10.1152/physrev.00028.2020] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 08/30/2021] [Indexed: 02/07/2023] Open
Abstract
During the past 30 yr, investigating the physiology of eating behaviors has generated a truly vast literature. This is fueled in part by a dramatic increase in obesity and its comorbidities that has coincided with an ever increasing sophistication of genetically based manipulations. These techniques have produced results with a remarkable degree of cell specificity, particularly at the cell signaling level, and have played a lead role in advancing the field. However, putting these findings into a brain-wide context that connects physiological signals and neurons to behavior and somatic physiology requires a thorough consideration of neuronal connections: a field that has also seen an extraordinary technological revolution. Our goal is to present a comprehensive and balanced assessment of how physiological signals associated with energy homeostasis interact at many brain levels to control eating behaviors. A major theme is that these signals engage sets of interacting neural networks throughout the brain that are defined by specific neural connections. We begin by discussing some fundamental concepts, including ones that still engender vigorous debate, that provide the necessary frameworks for understanding how the brain controls meal initiation and termination. These include key word definitions, ATP availability as the pivotal regulated variable in energy homeostasis, neuropeptide signaling, homeostatic and hedonic eating, and meal structure. Within this context, we discuss network models of how key regions in the endbrain (or telencephalon), hypothalamus, hindbrain, medulla, vagus nerve, and spinal cord work together with the gastrointestinal tract to enable the complex motor events that permit animals to eat in diverse situations.
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Affiliation(s)
- Alan G Watts
- The Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California
| | - Scott E Kanoski
- The Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California
| | - Graciela Sanchez-Watts
- The Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California
| | - Wolfgang Langhans
- Physiology and Behavior Laboratory, Eidgenössische Technische Hochschule-Zürich, Schwerzenbach, Switzerland
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25
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Cifuentes L, Acosta A. Homeostatic regulation of food intake. Clin Res Hepatol Gastroenterol 2022; 46:101794. [PMID: 34481092 PMCID: PMC9721532 DOI: 10.1016/j.clinre.2021.101794] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023]
Abstract
Food intake and energy expenditure are key regulators of body weight. To regulate food intake, the brain must integrate physiological signals and hedonic cues. The brain plays an essential role in modulating the appropriate responses to the continuous update of the body energy-status by the peripheral signals and the neuronal pathways that generate the gut-brain axis. This regulation encompasses various steps involved in food consumption, include satiation, satiety, and hunger. It is important to have a comprehensive understanding of the mechanisms that regulate food consumption as well as to standardize the vocabulary for the steps involved. This review discusses the current knowledge of the regulation and the contribution peripheral and central signals at each step of the cycle to control appetite. We also highlight how food intake has been measured. The increasingly complex understanding of regulation and action mechanisms intervening in the gut-brain axis offers ambitious targets for new strategies to control appetite.
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26
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Silencing gut CCK cells alters gut reaction to sugar. Nat Neurosci 2022; 25:136-138. [PMID: 35027762 DOI: 10.1038/s41593-021-00998-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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27
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Abstract
The enteroendocrine system coordinates the physiological response to food intake by regulating rates of digestion, nutrient absorption, insulin secretion, satiation and satiety. Gut hormones with important anorexigenic and/or insulinotropic roles include glucagon-like peptide 1 (GLP-1), peptide YY (PYY3-36), cholecystokinin (CCK) and glucose-dependent insulinotropic peptide (GIP). High BMI or obesogenic diets do not markedly disrupt this enteroendocrine system, which represents a critical target for inducing weight loss and treating co-morbidities in individuals with obesity.
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28
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Saraiva JFK, Franco D. Oral GLP-1 analogue: perspectives and impact on atherosclerosis in type 2 diabetic patients. Cardiovasc Diabetol 2021; 20:235. [PMID: 34911560 PMCID: PMC8675489 DOI: 10.1186/s12933-021-01417-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 11/07/2021] [Indexed: 01/02/2023] Open
Abstract
Cardiovascular events related to atherosclerosis are responsible for high morbidity and mortality among patients with type 2 diabetes. Improvement in care, especially in early stages, is crucial. Oral semaglutide, a glucagon-like peptide 1 analogue, controls blood glucose and results in significant body weight loss in patients with type 2 diabetes. Beyond these well-known effects, an interesting aspect of this drug is its antiatherogenic activity, which should be further explored in clinical practice. This paper reviews the evidence related to oral semaglutide decreasing cardiovascular risk in patients with type 2 diabetes, focusing on the drug's antiatherosclerotic properties. The glucagon-like peptide 1 analogue restores endothelial dysfunction, induces vasodilatation, and reduces plasma lipids. Oral semaglutide showed cardiovascular safety profile, with significant reduced risk of death from cardiovascular events. Based on current data, clinicians should consider oral semaglutide for type 2 diabetes management.
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Affiliation(s)
- José Francisco Kerr Saraiva
- Faculdade de Medicina do Centro de Ciências da Vida - Pontifícia, Universidade Católica de Campinas, Av John Boyd Dunlop, s/n - Jd. Ipaussurama, Campinas, SP, CEP: 13060-904, Brazil
| | - Denise Franco
- CPCLIN/DASA Centro de Pesquisas Clínicas, Av Angelica, 2162 - Consolação, São Paulo, SP, CEP: 01228-200, Brazil.
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29
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Luo J, Zhang H, Lu J, Ma C, Chen T. Antidiabetic effect of an engineered bacterium Lactobacillus plantarum-pMG36e -GLP-1 in monkey model. Synth Syst Biotechnol 2021; 6:272-282. [PMID: 34584995 PMCID: PMC8455315 DOI: 10.1016/j.synbio.2021.09.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 08/12/2021] [Accepted: 09/13/2021] [Indexed: 12/20/2022] Open
Abstract
Glucagon-like peptide-1 (GLP-1) reduces postprandial hyperglycaemia, but its short half-life inhibits clinical application. The aim of the current study was to evaluate the treatment efforts of an engineered strain, Lactobacillus plantarum-pMG36e-GLP-1 (L. plantarum-pMG36e-GLP-1), that continuously expresses GLP-1 in spontaneous type 2 diabetes mellitus (T2DM) monkeys. After 7 weeks of oral supplementation with L. plantarum-pMG36e-GLP-1, the fasting blood glucose (FPG) of monkeys was significantly (p < 0.05) reduced to a normal level and only a small amount of weight was lost. The results of metagenomic sequencing showed that L. plantarum-pMG36e-GLP-1 caused a substantial (p < 0.05) reduction in the intestinal pathogen Prevotella and marked enhancement of butyrate-producing Alistipes genera. According to the functional analysis using Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathways, 19 metabolism-related pathways were significantly enriched in T2DM monkeys after treatment with L. plantarum-pMG36e-GLP-1. LC-MS faecal metabolomics analysis found 41 significant differential metabolites (11 higher and 30 lower) in monkeys after treatment pathways linked to the metabolism of cofactors and vitamins were the most relevant. The present study suggests that L. plantarum-pMG36e-GLP-1 had an impact on the gut microbial composition and faecal metabolomic profile in spontaneous T2DM monkeys and may be a novel candidate for diabetes treatment.
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Affiliation(s)
- Jie Luo
- School of Public Health and Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, 330031, China
| | - Hongfei Zhang
- Institute of Life Sciences, Nanchang University, Nanchang, 330031, China
| | - Jiachen Lu
- School of Queen Mary, Nanchang University, Nanchang, 330031, China
| | - ChaoLin Ma
- Institute of Life Sciences, Nanchang University, Nanchang, 330031, China
| | - Tingtao Chen
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, The First Affiliated Hospital, Nanchang University, 1299 Xuefu Road, Honggu District, Nanchang, 330031, PR China
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30
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Blonde GD, Price RK, le Roux CW, Spector AC. Meal Patterns and Food Choices of Female Rats Fed a Cafeteria-Style Diet Are Altered by Gastric Bypass Surgery. Nutrients 2021; 13:3856. [PMID: 34836110 PMCID: PMC8623594 DOI: 10.3390/nu13113856] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/21/2021] [Accepted: 10/26/2021] [Indexed: 12/28/2022] Open
Abstract
After Roux-en-Y gastric bypass surgery (RYGB), rats tend to reduce consumption of high-sugar and/or high-fat foods over time. Here, we sought to investigate the behavioral mechanisms underlying these intake outcomes. Adult female rats were provided a cafeteria diet comprised of five palatable foodstuffs varying in sugar and fat content and intake was monitored continuously. Rats were then assigned to either RYGB, or one of two control (CTL) groups: sham surgery or a nonsurgical control group receiving the same prophylactic iron treatments as RYGB rats. Post-sur-gically, all rats consumed a large first meal of the cafeteria diet. After the first meal, RYGB rats reduced intake primarily by decreasing the meal sizes relative to CTL rats, ate meals more slowly, and displayed altered nycthemeral timing of intake yielding more daytime meals and fewer nighttime meals. Collectively, these meal patterns indicate that despite being motivated to consume a cafeteria diet after RYGB, rats rapidly learn to modify eating behaviors to consume foods more slowly across the entire day. RYGB rats also altered food preferences, but more slowly than the changes in meal patterns, and ate proportionally more energy from complex carbohydrates and protein and proportionally less fat. Overall, the pattern of results suggests that after RYGB rats quickly learn to adjust their size, eating rate, and distribution of meals without altering meal number and to shift their macronutrient intake away from fat; these changes appear to be more related to postingestive events than to a fundamental decline in the palatability of food choices.
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Affiliation(s)
- Ginger D. Blonde
- Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee, FL 32306, USA;
| | - Ruth K. Price
- Nutrition Innovation Centre for Food and Health (NICHE), School of Biomedical Sciences, Ulster University, Coleraine BT52 1SA, UK;
| | - Carel W. le Roux
- Diabetes Complications Research Centre, Conway Institute, School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland;
| | - Alan C. Spector
- Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee, FL 32306, USA;
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Eliaschewitz FG, Canani LH. Advances in GLP-1 treatment: focus on oral semaglutide. Diabetol Metab Syndr 2021; 13:99. [PMID: 34526121 PMCID: PMC8442336 DOI: 10.1186/s13098-021-00713-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/23/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND There is currently a large arsenal of antidiabetic drugs available to treat type 2 diabetes (T2D). However, this is a serious chronic disease that affects millions of adults worldwide and is responsible for severe complications, comorbidities, and low quality of life when uncontrolled due mainly to delays in initiating treatment or inadequate therapy. This review article aims to clarify the therapeutic role of the oral formulation of the glucagon-like peptide 1 receptor agonist (GLP-1 RA) semaglutide in treating typical T2D patients. The discussion focused on metabolic, glycemic, and weight alteration effects and the safety of the therapy with this drug. MAIN TEXT Therapy with glucagon-like peptide 1 receptor agonist (GLP-1 RA) promotes strategic changes in the pathophysiological pathway of T2D and improves the secretion of glucagon and insulin, which results in a reduction in blood glucose levels and the promotion of weight loss. Until recently, the only route for semaglutide administration was parenteral. However, an oral formulation of GLP-1 RA was recently developed and approved by the Brazilian Health Regulatory Agency (ANVISA) and the Food and Drug Administration (FDA) based on the Peptide Innovation for Early Diabetes Treatment (PIONEER) program results. A sequence of 10 clinical studies compared oral semaglutide with placebo or active standard-of-care medications (empagliflozin 25 mg, sitagliptin 100 mg, or liraglutide 1.8 mg) in different T2D populations. CONCLUSIONS Oral semaglutide effectively reduces glycated hemoglobin (HbA1c) levels and body weight in a broad spectrum of patients with T2D and shows cardiovascular safety. Oral semaglutide broadens therapy options and facilitates the adoption of earlier GLP-1 RA treatment once T2D patients present low rates of treatment discontinuation. The main adverse events reported were related to the gastrointestinal tract, common to GLP-1 RA class drugs.
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Affiliation(s)
- Freddy G Eliaschewitz
- CPClin/DASA Clinical Research Center, Avenida Angélica, 2162, São Paulo, CEP 01228-200, Brazil.
| | - Luis Henrique Canani
- Endocrinology Division of Hospital de Clínicas de Porto Alegre and Department of Internal Medicine, Medical School of Federal, University of Rio Grande Do Sul, Porto Alegre, Brazil
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Kabahizi A, Wallace B, Lieu L, Chau D, Dong Y, Hwang ES, Williams KW. Glucagon-like peptide-1 (GLP-1) signalling in the brain: From neural circuits and metabolism to therapeutics. Br J Pharmacol 2021; 179:600-624. [PMID: 34519026 PMCID: PMC8820188 DOI: 10.1111/bph.15682] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 08/23/2021] [Accepted: 08/27/2021] [Indexed: 12/18/2022] Open
Abstract
Glucagon‐like‐peptide‐1 (GLP‐1) derived from gut enteroendocrine cells and a discrete population of neurons in the caudal medulla acts through humoral and neural pathways to regulate satiety, gastric motility and pancreatic endocrine function. These physiological attributes contribute to GLP‐1 having a potent therapeutic action in glycaemic regulation and chronic weight management. In this review, we provide an overview of the neural circuits targeted by endogenous versus exogenous GLP‐1 and related drugs. We also highlight candidate subpopulations of neurons and cellular mechanisms responsible for the acute and chronic effects of GLP‐1 and GLP‐1 receptor agonists on energy balance and glucose metabolism. Finally, we present potential future directions to translate these findings towards the development of effective therapies for treatment of metabolic disease.
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Affiliation(s)
- Anita Kabahizi
- Department of Internal Medicine, Center for Hypothalamic Research, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
| | - Briana Wallace
- Department of Internal Medicine, Center for Hypothalamic Research, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
| | - Linh Lieu
- Department of Internal Medicine, Center for Hypothalamic Research, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
| | - Dominic Chau
- Department of Internal Medicine, Center for Hypothalamic Research, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
| | - Yanbin Dong
- Department of Internal Medicine, Center for Hypothalamic Research, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
| | - Eun-Sang Hwang
- Department of Internal Medicine, Center for Hypothalamic Research, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
| | - Kevin W Williams
- Department of Internal Medicine, Center for Hypothalamic Research, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
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An Exceedingly Rare Case of Liraglutide-Induced Liver Injury. Case Rep Gastrointest Med 2021; 2021:6306149. [PMID: 34471551 PMCID: PMC8405313 DOI: 10.1155/2021/6306149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 08/12/2021] [Indexed: 11/24/2022] Open
Abstract
Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist used for the treatment of type 2 diabetes mellitus. We are reporting the second case of liraglutide-induced liver injury, with complete resolution of liver injury after discontinuation of the drug.
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Smith KR, Moran TH. Gastrointestinal peptides in eating-related disorders. Physiol Behav 2021; 238:113456. [PMID: 33989649 PMCID: PMC8462672 DOI: 10.1016/j.physbeh.2021.113456] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 04/19/2021] [Accepted: 05/04/2021] [Indexed: 12/13/2022]
Abstract
Food intake is tightly controlled by homeostatic signals sensitive to metabolic need for the regulation of body weight. This review focuses on the peripherally-secreted gastrointestinal peptides (i.e., ghrelin, cholecystokinin, glucagon-like peptide 1, and peptide tyrosine tyrosine) that contribute to the control of appetite and discusses how these peptides or the signals arising from their release are disrupted in eating-related disorders across the weight spectrum, namely anorexia nervosa, bulimia nervosa, and obesity, and whether they are normalized following weight restoration or weight loss treatment. Further, the role of gut peptides in the pathogenesis and treatment response in human weight conditions as identified by rodent models are discussed. Lastly, we review the incretin- and hormone-based pharmacotherapies available for the treatment of obesity and eating-related disorders.
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Affiliation(s)
- Kimberly R Smith
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
| | - Timothy H Moran
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States
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35
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Shang P, Baker M, Banks S, Hong SI, Choi DS. Emerging Nondopaminergic Medications for Parkinson's Disease: Focusing on A2A Receptor Antagonists and GLP1 Receptor Agonists. J Mov Disord 2021; 14:193-203. [PMID: 34399565 PMCID: PMC8490190 DOI: 10.14802/jmd.21035] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 05/21/2021] [Accepted: 06/10/2021] [Indexed: 12/16/2022] Open
Abstract
Parkinson's disease (PD) is a severe neurodegenerative disease characterized by classic motor features associated with the loss of dopaminergic neurons and appearance of Lewy bodies in the substantia nigra. Due to the complexity of PD, a definitive diagnosis in the early stages and effective management of symptoms in later stages are difficult to achieve in clinical practice. Previous research has shown that colocalization of A2A receptors (A2AR) and dopamine D2 receptors (D2R) may induce an antagonistic interaction between adenosine and dopamine. Clinical trials have found that the A2AR antagonist istradefylline decreases dyskinesia in PD and could be used as an adjuvant to levodopa treatment. Meanwhile, the incretin hormone glucagon-like peptide 1 (GLP1) mainly facilitates glucose homeostasis and insulin signaling. Preclinical experiments and clinical trials of GLP1 receptor (GLP1R) agonists show that they may be effective in alleviating neuroinflammation and sustaining cellular functions in the central nervous system of patients with PD. In this review, we summarize up-to-date findings on the usefulness of A2AR antagonists and GLP1R agonists in PD management. We explain the molecular mechanisms of these medications and their interactions with other neurotransmitter receptors. Furthermore, we discuss the efficacy and limitations of A2AR antagonists and GLP1R agonists in clinical practice.
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Affiliation(s)
- Pei Shang
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, College of Medicine, Rochester, MN, USA
| | - Matthew Baker
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, College of Medicine, Rochester, MN, USA
| | - Samantha Banks
- Department of Neurology, Mayo Clinic, College of Medicine, Rochester, MN, USA
| | - Sa-Ik Hong
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, College of Medicine, Rochester, MN, USA
| | - Doo-Sup Choi
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, College of Medicine, Rochester, MN, USA
- Department of Psychiatry and Psychology, Mayo Clinic, College of Medicine, Rochester, MN, USA
- Department of Neuroscience Program, Mayo Clinic, College of Medicine, Rochester, MN, USA
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Trapp S, Brierley DI. Brain GLP-1 and the regulation of food intake: GLP-1 action in the brain and its implications for GLP-1 receptor agonists in obesity treatment. Br J Pharmacol 2021; 179:557-570. [PMID: 34323288 PMCID: PMC8820179 DOI: 10.1111/bph.15638] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 06/22/2021] [Accepted: 07/03/2021] [Indexed: 12/19/2022] Open
Abstract
This review considers the similarities and differences between the physiological systems regulated by gut-derived and neuronally produced glucagon-like peptide 1 (GLP-1). It addresses the questions of whether peripheral and central GLP-1 sources constitute separate, linked or redundant systems and whether the brain GLP-1 system consists of disparate sections or is a homogenous entity. This review also explores the implications of the answers to these questions for the use of GLP-1 receptor agonists as anti-obesity drugs.
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Affiliation(s)
- Stefan Trapp
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK
| | - Daniel I Brierley
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK
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37
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Brierley DI, de Lartigue G. Reappraising the role of the vagus nerve in GLP-1-mediated regulation of eating. Br J Pharmacol 2021; 179:584-599. [PMID: 34185884 PMCID: PMC8714868 DOI: 10.1111/bph.15603] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 06/03/2021] [Accepted: 06/16/2021] [Indexed: 12/19/2022] Open
Abstract
Here, we provide a focused review of the evidence for the roles of the vagus nerve in mediating the regulatory effects of peripherally and centrally produced GLP-1 on eating behaviour and energy balance. We particularly focus on recent studies which have used selective genetic, viral, and transcriptomic approaches to provide important insights into the anatomical and functional organisation of GLP-1-mediated gut-brain signalling pathways. A number of these studies have challenged canonical ideas of how GLP-1 acts in the periphery and the brain to regulate eating behaviour, with important implications for the development of pharmacological treatments for obesity.
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Affiliation(s)
- Daniel I Brierley
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK
| | - Guillaume de Lartigue
- Center for Integrative Cardiovascular and Metabolic Disease, University of Florida, Gainesville, Florida, USA
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Nahmias A, Stahel P, Tian L, Xiao C, Lewis GF. GLP-1 (Glucagon-Like Peptide-1) Is Physiologically Relevant for Chylomicron Secretion Beyond Its Known Pharmacological Role. Arterioscler Thromb Vasc Biol 2021; 41:1893-1900. [PMID: 33951941 DOI: 10.1161/atvbaha.121.316311] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
[Figure: see text].
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Affiliation(s)
- Avital Nahmias
- Division of Endocrinology, Department of Medicine and Banting and Best Diabetes Centre, University of Toronto, Ontario, Canada (A.N., P.S., L.T., G.F.L.)
| | - Priska Stahel
- Division of Endocrinology, Department of Medicine and Banting and Best Diabetes Centre, University of Toronto, Ontario, Canada (A.N., P.S., L.T., G.F.L.)
| | - Lili Tian
- Division of Endocrinology, Department of Medicine and Banting and Best Diabetes Centre, University of Toronto, Ontario, Canada (A.N., P.S., L.T., G.F.L.)
| | - Changting Xiao
- Department of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Canada (C.X.)
| | - Gary F Lewis
- Division of Endocrinology, Department of Medicine and Banting and Best Diabetes Centre, University of Toronto, Ontario, Canada (A.N., P.S., L.T., G.F.L.)
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39
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Williams DL. The diverse effects of brain glucagon-like peptide 1 receptors on ingestive behaviour. Br J Pharmacol 2021; 179:571-583. [PMID: 33990944 DOI: 10.1111/bph.15535] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 04/12/2021] [Accepted: 05/07/2021] [Indexed: 12/31/2022] Open
Abstract
Glucagon-like peptide 1 (GLP-1) is well known as a gut hormone and also acts as a neuropeptide, produced in a discrete population of caudal brainstem neurons that project widely throughout the brain. GLP-1 receptors are expressed in many brain areas of relevance to energy balance, and stimulation of these receptors at many of these sites potently suppresses food intake. This review surveys the current evidence for effects mediated by GLP-1 receptors on feeding behaviour at a wide array of brain sites and discusses behavioural and neurophysiological mechanisms for the effects identified thus far. Taken together, it is clear that GLP-1 receptor activity in the brain can influence feeding by diverse means, including mediation of gastrointestinal satiation and/or satiety signalling, suppression of motivation for food reward, induction of nausea and mediation of restraint stress-induced hypophagia, but many questions about the organization of this system remain.
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Affiliation(s)
- Diana L Williams
- Department of Psychology, Program in Neuroscience, Florida State University, Tallahassee, Florida, USA
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40
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Imai J, Katagiri H. Regulation of systemic metabolism by the autonomic nervous system consisting of afferent and efferent innervation. Int Immunol 2021; 34:67-79. [PMID: 33982088 DOI: 10.1093/intimm/dxab023] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 05/10/2021] [Indexed: 12/18/2022] Open
Abstract
Autonomic nerves, sympathetic and parasympathetic, innervate organs and modulate their functions. It has become evident that afferent and efferent signals of the autonomic nervous system play important roles in regulating systemic metabolism, thereby maintaining homeostasis at the whole-body level. Vagal afferent nerves receive signals, such as nutrients and hormones, from the peripheral organs/tissues including the gastrointestinal tract and adipose tissue then transmit these signals to the hypothalamus, thereby regulating feeding behavior. In addition to roles in controlling appetite, areas in the hypothalamus serves as regulatory centers of both sympathetic and parasympathetic efferent fibers. These efferent innervations regulate the functions of peripheral organs/tissues, such as pancreatic islets, adipose tissues and the liver, which play roles in metabolic regulation. Furthermore, recent evidence has unraveled the metabolic regulatory systems governed by autonomic nerve circuits. In these systems, afferent nerves transmit metabolic information from peripheral organs to the central nervous system (CNS) and the CNS thereby regulates the organ functions through the efferent fibers of autonomic nerves. Thus, the autonomic nervous system regulates the homeostasis of systemic metabolism, and both afferent and efferent fibers play critical roles in its regulation. In addition, several lines of evidence demonstrate the roles of the autonomic nervous system in regulating and dysregulating the immune system. This review introduces variety of neuron-mediated inter-organ cross-talk systems and organizes the current knowledge of autonomic control/coordination of systemic metabolism, focusing especially on a liver-brain-pancreatic β-cell autonomic nerve circuit, as well as highlighting the potential importance of connections with the neuronal and immune systems.
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Affiliation(s)
- Junta Imai
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, Japan
| | - Hideki Katagiri
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, Japan
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Vana V, Lærke MK, Kleberg K, Mroz PA, Lindberg BL, Ekberg JH, Rehfeld JF, Schwartz TW, Hansen HS. Post-oral fat-induced satiation is mediated by endogenous CCK and GLP-1 in a fat self-administration mouse model. Physiol Behav 2021; 234:113315. [DOI: 10.1016/j.physbeh.2021.113315] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 01/06/2021] [Accepted: 01/07/2021] [Indexed: 12/12/2022]
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Gastric Sensory and Motor Functions and Energy Intake in Health and Obesity-Therapeutic Implications. Nutrients 2021; 13:nu13041158. [PMID: 33915747 PMCID: PMC8065811 DOI: 10.3390/nu13041158] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 03/18/2021] [Accepted: 03/26/2021] [Indexed: 01/19/2023] Open
Abstract
Sensory and motor functions of the stomach, including gastric emptying and accommodation, have significant effects on energy consumption and appetite. Obesity is characterized by energy imbalance; altered gastric functions, such as rapid gastric emptying and large fasting gastric volume in obesity, may result in increased food intake prior to reaching usual fullness and increased appetite. Thus, many different interventions for obesity, including different diets, anti-obesity medications, bariatric endoscopy, and surgery, alter gastric functions and gastrointestinal motility. In this review, we focus on the role of the gastric and intestinal functions in food intake, pathophysiology of obesity, and obesity management.
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Alruwaili H, Dehestani B, le Roux CW. Clinical Impact of Liraglutide as a Treatment of Obesity. Clin Pharmacol 2021; 13:53-60. [PMID: 33732030 PMCID: PMC7958997 DOI: 10.2147/cpaa.s276085] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Accepted: 03/01/2021] [Indexed: 12/19/2022] Open
Abstract
Obesity is defined as a chronic, complex, relapsing disease characterized by excessive adipose tissue. Obesity impacts an individual's health by increasing complications such as prediabetes, type 2 diabetes mellitus (T2DM), hypertension, dyslipidemia, metabolic syndrome, cardiovascular disease, nonalcoholic fatty liver disease (NAFLD), cancers (eg endometrial), and obstructive sleep apnea (OSA). With the increase of obesity prevalence and its negative influences on individuals' quality of life, there is a great need for therapy with a purpose to produce sustainable weight loss of more than 10% in order to improve or even reverse the progress of obesity related complications. The GLP-1 analogue, liraglutide reduce food consumption, promote weight reduction and improve metabolic functions. The primary mechanism of GLP-1 effect on food intake, metabolism, and weight reduction is mainly due to its actions on peripheral (vagal) and central pathways and activation of hindbrain and hypothalamus. The average weight reduction induced by liraglutide was significant and the weight loss was maintained as long as the patients on therapy. Liraglutide has advantages on weight loss maintenance and promoting cardiovascular disease (CVD) risk reduction, by decreasing systolic blood pressure and glycemic index. In this review, we aim to explain the mechanism of action of Liraglutide, its pharmacokinetic properties, its clinical impact on obesity and its safety and tolerability.
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Affiliation(s)
- Heshma Alruwaili
- Diabetes Complications Research Centre, Conway Institute, University College Dublin, Dublin, Ireland
| | - Babak Dehestani
- Diabetes Complications Research Centre, Conway Institute, University College Dublin, Dublin, Ireland
| | - Carel W le Roux
- Diabetes Complications Research Centre, Conway Institute, University College Dublin, Dublin, Ireland
- Diabetes Research Group, School of Biomedical Sciences, Ulster University, Belfast, UK
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44
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Lu VB, Gribble FM, Reimann F. Nutrient-Induced Cellular Mechanisms of Gut Hormone Secretion. Nutrients 2021; 13:nu13030883. [PMID: 33803183 PMCID: PMC8000029 DOI: 10.3390/nu13030883] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 02/27/2021] [Accepted: 03/05/2021] [Indexed: 02/06/2023] Open
Abstract
The gastrointestinal tract can assess the nutrient composition of ingested food. The nutrient-sensing mechanisms in specialised epithelial cells lining the gastrointestinal tract, the enteroendocrine cells, trigger the release of gut hormones that provide important local and central feedback signals to regulate nutrient utilisation and feeding behaviour. The evidence for nutrient-stimulated secretion of two of the most studied gut hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), along with the known cellular mechanisms in enteroendocrine cells recruited by nutrients, will be the focus of this review. The mechanisms involved range from electrogenic transporters, ion channel modulation and nutrient-activated G-protein coupled receptors that converge on the release machinery controlling hormone secretion. Elucidation of these mechanisms will provide much needed insight into postprandial physiology and identify tractable dietary approaches to potentially manage nutrition and satiety by altering the secreted gut hormone profile.
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45
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Duca FA, Waise TMZ, Peppler WT, Lam TKT. The metabolic impact of small intestinal nutrient sensing. Nat Commun 2021; 12:903. [PMID: 33568676 PMCID: PMC7876101 DOI: 10.1038/s41467-021-21235-y] [Citation(s) in RCA: 98] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 01/19/2021] [Indexed: 12/12/2022] Open
Abstract
The gastrointestinal tract maintains energy and glucose homeostasis, in part through nutrient-sensing and subsequent signaling to the brain and other tissues. In this review, we highlight the role of small intestinal nutrient-sensing in metabolic homeostasis, and link high-fat feeding, obesity, and diabetes with perturbations in these gut-brain signaling pathways. We identify how lipids, carbohydrates, and proteins, initiate gut peptide release from the enteroendocrine cells through small intestinal sensing pathways, and how these peptides regulate food intake, glucose tolerance, and hepatic glucose production. Lastly, we highlight how the gut microbiota impact small intestinal nutrient-sensing in normal physiology, and in disease, pharmacological and surgical settings. Emerging evidence indicates that the molecular mechanisms of small intestinal nutrient sensing in metabolic homeostasis have physiological and pathological impact as well as therapeutic potential in obesity and diabetes. The gastrointestinal tract participates in maintaining metabolic homeostasis in part through nutrient-sensing and subsequent gut-brain signalling. Here the authors review the role of small intestinal nutrient-sensing in regulation of energy intake and systemic glucose metabolism, and link high-fat diet, obesity and diabetes with perturbations in these pathways.
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Affiliation(s)
- Frank A Duca
- BIO5 Institute, University of Arizona, Tucson, AZ, USA. .,School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ, USA.
| | - T M Zaved Waise
- Toronto General Hospital Research Institute, UHN, Toronto, Canada
| | - Willem T Peppler
- Toronto General Hospital Research Institute, UHN, Toronto, Canada
| | - Tony K T Lam
- Toronto General Hospital Research Institute, UHN, Toronto, Canada. .,Department of Physiology, University of Toronto, Toronto, Canada. .,Department of Medicine, University of Toronto, Toronto, Canada. .,Banting and Best Diabetes Centre, University of Toronto, Toronto, Canada.
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Taguchi T, Kodera Y, Oba K, Saito T, Nakagawa Y, Kawashima Y, Shichiri M. Suprabasin-derived bioactive peptides identified by plasma peptidomics. Sci Rep 2021; 11:1047. [PMID: 33441610 PMCID: PMC7806982 DOI: 10.1038/s41598-020-79353-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 11/08/2020] [Indexed: 01/29/2023] Open
Abstract
Identification of low-abundance, low-molecular-weight native peptides using non-tryptic plasma has long remained an unmet challenge, leaving potential bioactive/biomarker peptides undiscovered. We have succeeded in efficiently removing high-abundance plasma proteins to enrich and comprehensively identify low-molecular-weight native peptides using mass spectrometry. Native peptide sequences were chemically synthesized and subsequent functional analyses resulted in the discovery of three novel bioactive polypeptides derived from an epidermal differentiation marker protein, suprabasin. SBSN_HUMAN[279-295] potently suppressed food/water intake and induced locomotor activity when injected intraperitoneally, while SBSN_HUMAN[225-237] and SBSN_HUMAN[243-259] stimulated the expression of proinflammatory cytokines via activation of NF-κB signaling in vascular cells. SBSN_HUMAN[225-237] and SBSN_HUMAN[279-295] immunoreactivities were present in almost all human organs analyzed, while immunoreactive SBSN_HUMAN[243-259] was abundant in the liver and pancreas. Human macrophages expressed the three suprabasin-derived peptides. This study illustrates a new approach for discovering unknown bioactive peptides in plasma via the generation of peptide libraries using a novel peptidomic strategy.
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Affiliation(s)
- Tomomi Taguchi
- grid.410786.c0000 0000 9206 2938Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374 Japan
| | - Yoshio Kodera
- grid.410786.c0000 0000 9206 2938Department of Physics, Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373 Japan ,grid.410786.c0000 0000 9206 2938Center for Disease Proteomics, Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373 Japan
| | - Kazuhito Oba
- grid.410786.c0000 0000 9206 2938Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374 Japan
| | - Tatsuya Saito
- grid.410786.c0000 0000 9206 2938Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374 Japan ,grid.410786.c0000 0000 9206 2938Department of Physics, Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373 Japan
| | - Yuzuru Nakagawa
- grid.410786.c0000 0000 9206 2938Department of Physics, Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373 Japan
| | - Yusuke Kawashima
- grid.410786.c0000 0000 9206 2938Department of Physics, Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373 Japan
| | - Masayoshi Shichiri
- grid.410786.c0000 0000 9206 2938Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374 Japan
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Boer GA, Holst JJ. Incretin Hormones and Type 2 Diabetes-Mechanistic Insights and Therapeutic Approaches. BIOLOGY 2020; 9:biology9120473. [PMID: 33339298 PMCID: PMC7766765 DOI: 10.3390/biology9120473] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 12/09/2020] [Accepted: 12/10/2020] [Indexed: 02/06/2023]
Abstract
Simple Summary When we ingest a meal, our intestine secretes hormones that are released into the bloodstream. Amongst these hormones are the incretins hormones which stimulate the release of insulin from the pancreas which is essential for the regulation of in particular postprandial glucose concentrations. In patients with type 2 diabetes, the effect of the incretins is diminished. This is thought to contribute importantly to the pathophysiology of the disease. However, in pharmacological amounts, the incretins may still influence insulin secretion and metabolism. Much research has therefore been devoted to the development of incretin-based therapies for type 2 diabetes. These therapies include compounds that strongly resemble the incretins, hereby stimulating their effects as well as inhibitors of the enzymatic degradation of the hormones, thereby increasing the concentration of incretins in the blood. Both therapeutic approaches have been implemented successfully, but research is still ongoing aimed at the development of further optimized therapies. Abstract Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from the gut upon nutrient stimulation and regulate postprandial metabolism. These hormones are known as classical incretin hormones and are responsible for a major part of postprandial insulin release. The incretin effect is severely reduced in patients with type 2 diabetes, but it was discovered that administration of GLP-1 agonists was capable of normalizing glucose control in these patients. Over the last decades, much research has been focused on the development of incretin-based therapies for type 2 diabetes. These therapies include incretin receptor agonists and inhibitors of the incretin-degrading enzyme dipeptidyl peptidase-4. Especially the development of diverse GLP-1 receptor agonists has shown immense success, whereas studies of GIP monotherapy in patients with type 2 diabetes have consistently been disappointing. Interestingly, both GIP-GLP-1 co-agonists and GIP receptor antagonists administered in combination with GLP-1R agonists appear to be efficient with respect to both weight loss and control of diabetes, although the molecular mechanisms behind these effects remain unknown. This review describes our current knowledge of the two incretin hormones and the development of incretin-based therapies for treatment of type 2 diabetes.
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Affiliation(s)
- Geke Aline Boer
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark;
- NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark
| | - Jens Juul Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark;
- NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark
- Correspondence: ; Tel.: +45-2875-7518
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Diz-Chaves Y, Herrera-Pérez S, González-Matías LC, Lamas JA, Mallo F. Glucagon-Like Peptide-1 (GLP-1) in the Integration of Neural and Endocrine Responses to Stress. Nutrients 2020; 12:nu12113304. [PMID: 33126672 PMCID: PMC7692797 DOI: 10.3390/nu12113304] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 10/14/2020] [Accepted: 10/27/2020] [Indexed: 12/20/2022] Open
Abstract
Glucagon like-peptide 1 (GLP-1) within the brain is produced by a population of preproglucagon neurons located in the caudal nucleus of the solitary tract. These neurons project to the hypothalamus and another forebrain, hindbrain, and mesolimbic brain areas control the autonomic function, feeding, and the motivation to feed or regulate the stress response and the hypothalamic-pituitary-adrenal axis. GLP-1 receptor (GLP-1R) controls both food intake and feeding behavior (hunger-driven feeding, the hedonic value of food, and food motivation). The activation of GLP-1 receptors involves second messenger pathways and ionic events in the autonomic nervous system, which are very relevant to explain the essential central actions of GLP-1 as neuromodulator coordinating food intake in response to a physiological and stress-related stimulus to maintain homeostasis. Alterations in GLP-1 signaling associated with obesity or chronic stress induce the dysregulation of eating behavior. This review summarized the experimental shreds of evidence from studies using GLP-1R agonists to describe the neural and endocrine integration of stress responses and feeding behavior.
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Affiliation(s)
- Yolanda Diz-Chaves
- CINBIO, Universidade de Vigo, Grupo FB3A, Laboratorio de Endocrinología, 36310 Vigo, Spain;
- Correspondence: (Y.D.-C.); (F.M.); Tel.: +34-(986)-130226 (Y.D.-C.); +34-(986)-812393 (F.M.)
| | - Salvador Herrera-Pérez
- CINBIO, Universidade de Vigo, Grupo FB3B, Laboratorio de Neurociencia, 36310 Vigo, Spain; (S.H.-P.); (J.A.L.)
| | | | - José Antonio Lamas
- CINBIO, Universidade de Vigo, Grupo FB3B, Laboratorio de Neurociencia, 36310 Vigo, Spain; (S.H.-P.); (J.A.L.)
| | - Federico Mallo
- CINBIO, Universidade de Vigo, Grupo FB3A, Laboratorio de Endocrinología, 36310 Vigo, Spain;
- Correspondence: (Y.D.-C.); (F.M.); Tel.: +34-(986)-130226 (Y.D.-C.); +34-(986)-812393 (F.M.)
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Krieger JP. Intestinal glucagon-like peptide-1 effects on food intake: Physiological relevance and emerging mechanisms. Peptides 2020; 131:170342. [PMID: 32522585 DOI: 10.1016/j.peptides.2020.170342] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 05/01/2020] [Accepted: 06/03/2020] [Indexed: 02/06/2023]
Abstract
The gut-brain hormone glucagon-like peptide-1 (GLP-1) has received immense attention over the last couple of decades for its widespread metabolic effects. Notably, intestinal GLP-1 has been recognized as an endogenous satiation signal. Yet, the underlying mechanisms and the pathophysiological relevance of intestinal GLP-1 in obesity remain unclear. This review first recapitulates early findings indicating that intestinal GLP-1 is an endogenous satiation signal, whose eating effects are primarily mediated by vagal afferents. Second, on the basis of recent findings challenging a paracrine action of intestinal GLP-1, a new model for the mediation of GLP-1 effects on eating by two discrete vagal afferent subsets will be proposed. The central mechanisms processing the vagal anorexigenic signals need however to be further delineated. Finally, the idea that intestinal GLP-1 secretion and/or effects on eating are altered in obesity and play a pathophysiological role in the development of obesity will be discussed. In summary, despite the successful therapeutic use of GLP-1 receptor agonists as anti-obesity drugs, the eating effects of intestinal GLP-1 still remain to be elucidated. Specifically, the findings presented here call for a further evaluation of the vago-central neuronal substrates activated by intestinal GLP-1 and for further investigation of its pathophysiological role in obesity.
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Affiliation(s)
- Jean-Philippe Krieger
- Department of Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
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Grill HJ. A Role for GLP-1 in Treating Hyperphagia and Obesity. Endocrinology 2020; 161:bqaa093. [PMID: 32516384 PMCID: PMC7899438 DOI: 10.1210/endocr/bqaa093] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 06/02/2020] [Accepted: 06/04/2020] [Indexed: 02/06/2023]
Abstract
Obesity is a chronic recurring disease whose prevalence has almost tripled over the past 40 years. In individuals with obesity, there is significant increased risk of morbidity and mortality, along with decreased quality of life. Increased obesity prevalence results, at least partly, from the increased global food supply that provides ubiquitous access to tasty, energy-dense foods. These hedonic foods and the nonfood cues that through association become reward predictive cues activate brain appetitive control circuits that drive hyperphagia and weight gain by enhancing food-seeking, motivation, and reward. Behavioral therapy (diet and lifestyle modifications) is the recommended initial treatment for obesity, yet it often fails to achieve meaningful weight loss. Furthermore, those who lose weight regain it over time through biological regulation. The need to effectively treat the pathophysiology of obesity thus centers on biologically based approaches such as bariatric surgery and more recently developed drug therapies. This review highlights neurobiological aspects relevant to obesity causation and treatment by emphasizing the common aspects of the feeding-inhibitory effects of multiple signals. We focus on glucagon like peptide-1 receptor (GLP-1R) signaling as a promising obesity treatment target by discussing the activation of intestinal- and brain-derived GLP-1 and GLP-1R expressing central nervous system circuits resulting from normal eating, bariatric surgery, and GLP-1R agonist drug therapy. Given the increased availability of energy-dense foods and frequent encounters with cues that drive hyperphagia, this review also describes how bariatric surgery and GLP-1R agonist therapies influence food reward and the motivational drive to overeat.
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Affiliation(s)
- Harvey J Grill
- Institute of Diabetes, Obesity and Metabolism, Graduate Groups for Psychology and Neuroscience, University of Pennsylvania, Philadelphia, PA
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