Regulation of Adipocyte Formation by GLP-1/GLP-1R Signaling*

Background: Nutrient intake directly affects adipose tissue function and growth. Results: The gut peptide GLP-1 controls adipogenesis via its receptor through regulation of cell proliferation and apoptosis. Conclusion: GLP-1 is a signaling molecule from the intestine relating nutritional status to the adipose tissue. Significance: GLP-1 is used in treatment of type 2 diabetes, and regulation of adipose tissue mass might be one influencing factor. Increased nutrient intake leads to excessive adipose tissue accumulation, obesity, and the development of associated metabolic disorders. How the intestine signals to adipose tissue to adapt to increased nutrient intake, however, is still not completely understood. We show here, that the gut peptide GLP-1 or its long-lasting analog liraglutide, function as intestinally derived signals to induce adipocyte formation, both in vitro and in vivo. GLP-1 and liraglutide activate the GLP-1R, thereby promoting pre-adipocyte proliferation and inhibition of apoptosis. This is achieved at least partly through activation of ERK, PKC, and AKT signaling pathways. In contrast, loss of GLP-1R expression causes reduction in adipogenesis, through induction of apoptosis in pre-adipocytes, by inhibition of the above mentioned pathways. Because GLP-1 and liraglutide are used for the treatment of type 2 diabetes, these findings implicate GLP-1 as a regulator of adipogenesis, which could be an alternate pathway leading to improved lipid homeostasis and controlled downstream insulin signaling.

[1]  D. Gašperíková,et al.  Adipogenesis and insulin sensitivity in obesity are regulated by retinoid-related orphan receptor gamma , 2011, EMBO molecular medicine.

[2]  R. Krishnapuram,et al.  PPARgamma-independent increase in glucose uptake and adiponectin abundance in fat cells. , 2011, Endocrinology.

[3]  H. Grill,et al.  Comparative Effects of the Long‐Acting GLP‐1 Receptor Ligands, Liraglutide and Exendin‐4, on Food Intake and Body Weight Suppression in Rats , 2011, Obesity.

[4]  B. Meissburger,et al.  Tissue inhibitor of matrix metalloproteinase 1 (TIMP1) controls adipogenesis in obesity in mice and in humans , 2011, Diabetologia.

[5]  E. Arner,et al.  Regional impact of adipose tissue morphology on the metabolic profile in morbid obesity , 2010, Diabetologia.

[6]  P. von der Weid,et al.  Review article: lymphatic system and associated adipose tissue in the development of inflammatory bowel disease , 2010, Alimentary pharmacology & therapeutics.

[7]  M. Mattson,et al.  Enhancing the GLP‐1 receptor signaling pathway leads to proliferation and neuroprotection in human neuroblastoma cells , 2010, Journal of neurochemistry.

[8]  M. Tschöp,et al.  The intestinal lymph fistula model--a novel approach to study ghrelin secretion. , 2010, American journal of physiology. Gastrointestinal and liver physiology.

[9]  E. Blázquez,et al.  Signaling and biological effects of glucagon-like peptide 1 on the differentiation of mesenchymal stem cells from human bone marrow. , 2010, American journal of physiology. Endocrinology and metabolism.

[10]  G. Willars,et al.  Role of the signal peptide in the synthesis and processing of the glucagon‐like peptide‐1 receptor , 2010, British journal of pharmacology.

[11]  J. Bockaert,et al.  GLP-1 Mediates Antiapoptotic Effect by Phosphorylating Bad through a β-Arrestin 1-mediated ERK1/2 Activation in Pancreatic β-Cells , 2009, The Journal of Biological Chemistry.

[12]  D. Drucker,et al.  Incretin-based therapies for type 2 diabetes mellitus , 2009, Nature Reviews Endocrinology.

[13]  Junghyo Jo,et al.  Hypertrophy and/or Hyperplasia: Dynamics of Adipose Tissue Growth , 2009, PLoS Comput. Biol..

[14]  Masato Kasuga,et al.  [Obesity and insulin resistance]. , 2009, Nihon rinsho. Japanese journal of clinical medicine.

[15]  R. Henkelman,et al.  GLP-1R Agonist Liraglutide Activates Cytoprotective Pathways and Improves Outcomes After Experimental Myocardial Infarction in Mice , 2009, Diabetes.

[16]  G. Karsenty,et al.  Reciprocal regulation of bone and energy metabolism. , 2008, Journal of musculoskeletal & neuronal interactions.

[17]  G. Bray,et al.  Pathogenic potential of adipose tissue and metabolic consequences of adipocyte hypertrophy and increased visceral adiposity , 2008, Expert review of cardiovascular therapy.

[18]  J. Buteau.  GLP-1 receptor signaling: effects on pancreatic beta-cell proliferation and survival. , 2008, Diabetes & metabolism.

[19]  J. Holst.  The physiology of glucagon-like peptide 1. , 2007, Physiological reviews.

[20]  E. Ferrannini,et al.  Effects of the long-acting human glucagon-like peptide-1 analog liraglutide on beta-cell function in normal living conditions. , 2007, Diabetes care.

[21]  Tanya Hansotia,et al.  Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure. , 2007, The Journal of clinical investigation.

[22]  B. Hemmings,et al.  PKBα is required for adipose differentiation of mouse embryonic fibroblasts , 2006, Journal of Cell Science.

[23]  B. Friedrichsen,et al.  Stimulation of pancreatic β-cell replication by incretins involves transcriptional induction of cyclin D1 via multiple signalling pathways , 2006 .

[24]  D. Drucker.  The biology of incretin hormones. , 2006, Cell metabolism.

[25]  A. Körner,et al.  Obesity in childhood and adolescence: a review in the interface between adipocyte physiology and clinical challenges. , 2005, Hormones.

[26]  Guillermo Oliver,et al.  Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult-onset obesity , 2005, Nature Genetics.

[27]  Hiroshi Sakaue,et al.  The Molecular Scaffold Kinase Suppressor of Ras 1 (KSR1) Regulates Adipogenesis , 2005, Molecular and Cellular Biology.

[28]  P. Scherer,et al.  Adipose tissue, inflammation, and cardiovascular disease. , 2005, Circulation research.

[29]  N. Blume,et al.  The long-acting glucagon-like peptide-1 analogue, liraglutide, inhibits beta-cell apoptosis in vitro. , 2005, Biochemical and biophysical research communications.

[30]  T. Kadowaki,et al.  Adiponectin and adiponectin receptors. , 2005, Endocrine reviews.

[31]  Jie Chen,et al.  regulation of peroxisome proliferator-activated receptor-gamma activity by mammalian target of rapamycin and amino acids in adipogenesis. , 2004, Diabetes.

[32]  Christian Wolfrum,et al.  Role of Foxa-2 in adipocyte metabolism and differentiation. , 2003, The Journal of clinical investigation.

[33]  J. Egan,et al.  GLP‐1 receptor agonists are growth and differentiation factors for pancreatic islet beta cells , 2003, Diabetes/metabolism research and reviews.

[34]  Patricia Ducy,et al.  Leptin Regulates Bone Formation via the Sympathetic Nervous System , 2002, Cell.

[35]  J. Holst,et al.  Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes: a parallel-group study , 2002, The Lancet.

[36]  Roy J Martin,et al.  The biology of white adipocyte proliferation , 2001, Obesity reviews : an official journal of the International Association for the Study of Obesity.

[37]  J. Holst,et al.  Impaired incretin response after a mixed meal is associated with insulin resistance in nondiabetic men. , 2001, Diabetes care.

[38]  S. Toubro,et al.  The role of postprandial releases of insulin and incretin hormones in meal-induced satiety—effect of obesity and weight reduction , 2001, International Journal of Obesity.

[39]  L. B. Knudsen,et al.  Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration. , 2000, Journal of medicinal chemistry.

[40]  Yihong Wang,et al.  Novel signal transduction and peptide specificity of glucagon‐like peptide receptor in 3T3‐L1 adipocytes , 1997, Journal of cellular physiology.

[41]  Y. Giudicelli,et al.  Zeta PKC in rat preadipocytes: modulation by insulin and serum mitogenic factors and possible role in adipogenesis. , 1995, Biochemical and biophysical research communications.

[42]  J. Egan,et al.  Glucagon-like peptide-1(7-36) amide (GLP-1) enhances insulin-stimulated glucose metabolism in 3T3-L1 adipocytes: one of several potential extrapancreatic sites of GLP-1 action. , 1994, Endocrinology.

[43]  M. Clemens,et al.  The role of protein kinase C isoenzymes in the regulation of cell proliferation and differentiation. , 1992, Journal of cell science.

[44]  B. Thorens.  Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[45]  Y. Cheung,et al.  Feasibility of sentinel lymph node biopsy in multifocal/multicentric breast cancer. , 2009, Chang Gung medical journal.

[46]  Fuqiang Li,et al.  Different roles of protein kinase C-βI and -δ in the regulation of adipocyte differentiation , 2006 .

[47]  F. Bost,et al.  The role of MAPKs in adipocyte differentiation and obesity. , 2005, Biochimie.

[48]  R. Carroll,et al.  Morphodensitometric analysis of protein kinase C beta(II) expression in rat colon: modulation by diet and relation to in situ cell proliferation and apoptosis. , 2000, Carcinogenesis.

[49]  N. Kaplan.  Obesity in hypertension: effects on prognosis and treatment. , 1998, Journal of hypertension. Supplement : official journal of the International Society of Hypertension.

[50]  S. Mandrup,et al.  Adipocyte differentiation and leptin expression. , 1997, Annual review of cell and developmental biology.

[51]  O. MacDougald,et al.  Regulation of adipocyte development. , 1994, Annual review of nutrition.