Elimination of glucagon-like peptide 1R signaling does not modify weight gain and islet adaptation in mice with combined disruption of leptin and GLP-1 action.

Leptin and glucagon-like peptide 1 (GLP-1) exhibit opposing actions in the endocrine pancreas. GLP-1 stimulates insulin biosynthesis, secretion, and islet growth, whereas leptin inhibits glucose-dependent insulin secretion and insulin gene transcription. In contrast, GLP-1 and leptin actions overlap in the central nervous system, where leptin has been shown to activate GLP-1 circuits that inhibit food intake. To determine the physiological importance of GLP-1 receptor (GLP-1R)-leptin interactions, we studied islet function and feeding behavior in ob/ob:GLP-1R(-/-) mice. Although GLP-1R actions are thought to be essential for glucose-dependent insulin secretion, the levels of fasting glucose, glycemic excursion after glucose loading, glucose-stimulated insulin, and pancreatic insulin RNA content were similar in ob/ob:GLP-1R(+/+) versus ob/ob:GLP-1R(-/-) mice. Despite evidence linking GLP-1R signaling to the regulation of islet neogenesis and proliferation, ob/ob:GLP-1R(-/-) mice exhibited significantly increased islet numbers and area and an increase in the number of large islets compared with GLP-1R(+/+) or (-/-) mice (P < -0.01 to 0.05). Similarly, growth rates and both shortand long-term control of food intake were comparable in ob/ob:GLP-1R(+/+) versus ob/ob:GLP-1R4(-/-) mice. Furthermore, leptin produced a similar inhibition of food intake in GLP-1R(-/-), ob/ob:GLP-1R(+/+), and ob/ob:GLP1R4(-/-) mice. These findings illustrate that although leptin and GLP-1 actions overlap in the brain and endocrine pancreas, disruption of GLP-1 signaling does not modify the response to leptin or the phenotype of leptin deficiency in the ob/ob mouse, as assessed by long-term control of body weight or the adaptive beta-cell response to insulin resistance in vivo.

[1]  Jie Zhou,et al.  Glucagon-Like Peptide-1 Regulates the Beta Cell Transcription Factor, PDX-1, in Insulinoma Cells. , 1999, Endocrinology.

[2]  J. Egan,et al.  Glucagon-like peptide-1 regulates the beta cell transcription factor, PDX-1, in insulinoma cells. , 1999, Endocrinology.

[3]  K. Mounzih,et al.  Leptin treatment rescues the sterility of genetically obese ob/ob males. , 1997, Endocrinology.

[4]  S. Woods,et al.  Central infusion of glucagon-like peptide-1-(7–36) amide (GLP-1) receptor antagonist attenuates lithium chloride-induced c-Fos induction in rat brainstem , 1998, Brain Research.

[5]  S. Bonner-Weir,et al.  Insulinotropic glucagon-like peptide 1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas. , 2000, Diabetes.

[6]  S. Bloom,et al.  Leptin interacts with glucagon‐like peptide‐1 neurons to reduce food intake and body weight in rodents , 1997, FEBS letters.

[7]  P. Dubuc.  The development of obesity, hyperinsulinemia, and hyperglycemia in ob/ob mice. , 1976, Metabolism: clinical and experimental.

[8]  J. Holst,et al.  Inhibition of the activity of dipeptidyl-peptidase IV as a treatment for type 2 diabetes. , 1998, Diabetes.

[9]  D. Smith,et al.  A role for glucagon-like peptide-1 in the central regulation of feeding , 1996, Nature.

[10]  A. Astrup,et al.  Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. , 1998, The Journal of clinical investigation.

[11]  Jie Zhou,et al.  Glucagon-like peptide 1 and exendin-4 convert pancreatic AR42J cells into glucagon- and insulin-producing cells. , 1999, Diabetes.

[12]  F. Chehab,et al.  Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin , 1996, Nature Genetics.

[13]  S. Woods,et al.  University of Groningen Central infusion of GLP-1, but not leptin, produces conditioned taste aversions in rats , 2002 .

[14]  J. Habener,et al.  The adipoinsular axis: effects of leptin on pancreatic β-cells , 2000 .

[15]  J. Holst,et al.  Both Subcutaneously and Intravenously Administered Glucagon-Like Peptide I Are Rapidly Degraded From the NH2-Terminus in Type II Diabetic Patients and in Healthy Subjects , 1995, Diabetes.

[16]  C. Ricordi,et al.  Journal of Clinical Endocrinology and Metabolism Printed in U.S.A. Copyright © 1999 by The Endocrine Society Leptin Suppression of Insulin Secretion and Gene Expression in Human Pancreatic Islets: Implications for the Development of Adipogenic Diabetes Me , 2022 .

[17]  T. Mizuno,et al.  Of Mice and MEN What Transgenic Models Tell Us about Hypothalamic Control of Energy Balance , 2000, Neuron.

[18]  J. Flier,et al.  Clinical review 94: What's in a name? In search of leptin's physiologic role. , 1998, The Journal of clinical endocrinology and metabolism.

[19]  S. Woods,et al.  Insulin and leptin: dual adiposity signals to the brain for the regulation of food intake and body weight , 1999, Brain Research.

[20]  D. Drucker,et al.  Proglucagon gene expression is regulated by a cyclic AMP-dependent pathway in rat intestine. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[21]  B. Göke,et al.  Exendin(9-39)amide is an antagonist of glucagon-like peptide-1(7-36)amide in humans. , 1998, The Journal of clinical investigation.

[22]  S. Bloom,et al.  Glucagon-like peptide 1 has a physiological role in the control of postprandial glucose in humans: studies with the antagonist exendin 9-39. , 1999, Diabetes.

[23]  K. Moar,et al.  Association of leptin receptor (OB-Rb), NPY and GLP-1 gene expression in the ovine and murine brainstem , 1998, Regulatory Peptides.

[24]  J. Habener,et al.  Leptin Suppression of Insulin Secretion by the Activation of ATP-Sensitive K+ Channels in Pancreatic β-Cells , 1997, Diabetes.

[25]  D O'Shea,et al.  Repeated intracerebroventricular administration of glucagon-like peptide-1-(7-36) amide or exendin-(9-39) alters body weight in the rat. , 1999, Endocrinology.

[26]  D. Drucker,et al.  Effects of aging and a high fat diet on body weight and glucose tolerance in glucagon-like peptide-1 receptor -/- mice. , 1998, Endocrinology.

[27]  S. Bloom,et al.  Effect of leptin on hypothalamic GLP-1 peptide and brain-stem pre-proglucagon mRNA. , 2000, Biochemical and biophysical research communications.

[28]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[29]  J. Habener,et al.  Leptin inhibits insulin gene transcription and reverses hyperinsulinemia in leptin-deficient ob/ob mice. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[30]  D. Drucker,et al.  Inhibition of pancreatic proglucagon gene expression in mice bearing subcutaneous endocrine tumors. , 1994, The American journal of physiology.

[31]  S. Woods,et al.  Targeted gene disruption in endocrine research--the case of glucagon-like peptide-1 and neuroendocrine function. , 2000, Endocrinology.

[32]  M. Prentki,et al.  Glucagon-like peptide-1 promotes DNA synthesis, activates phosphatidylinositol 3-kinase and increases transcription factor pancreatic and duodenal homeobox gene 1 (PDX-1) DNA binding activity in beta (INS-1)-cells , 1999, Diabetologia.

[33]  S. Woods,et al.  The Role of CNS Glucagon-Like Peptide-1 (7-36) Amide Receptors in Mediating the Visceral Illness Effects of Lithium Chloride , 2000, The Journal of Neuroscience.

[34]  D. Drucker,et al.  Essential requirement for Pax6 in control of enteroendocrine proglucagon gene transcription. , 1999, Molecular endocrinology.

[35]  M. Prentki,et al.  Glucose and glucoincretin peptides synergize to induce c‐fos, c‐jun, junB, zif‐268, and nur‐77 gene expression in pancreatic β(INS‐1) cells , 1998, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[36]  A. Joyner,et al.  Glucose intolerance but normal satiety in mice with a null mutation in the glucagon–like peptide 1 receptor gene , 1996, Nature Medicine.

[37]  D. Drucker,et al.  Identification of glucagon-like peptide 1 (GLP-1) actions essential for glucose homeostasis in mice with disruption of GLP-1 receptor signaling. , 1998, Diabetes.

[38]  S. Bonner-Weir,et al.  Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. , 1999, Diabetes.

[39]  S. Woods,et al.  Intraventricular GLP-1 reduces short- but not long-term food intake or body weight in lean and obese rats , 1998, Brain Research.

[40]  D. Drucker,et al.  Leptin Sensitivity in Nonobese Glucagon-Like Peptide I Receptor −/− Mice , 1997, Diabetes.

[41]  D. Smith,et al.  Glucagon-like peptide-1 is a physiological incretin in rat. , 1995, The Journal of clinical investigation.

[42]  V. Emilsson,et al.  Expression of the Functional Leptin Receptor mRNA in Pancreatic Islets and Direct Inhibitory Action of Leptin on Insulin Secretion , 1997, Diabetes.

[43]  W. Chung,et al.  The Molecular Genetics of Rodent Single Gene Obesities* , 1997, The Journal of Biological Chemistry.

[44]  J. Bue-Valleskey,et al.  The role of neuropeptide Y in the antiobesity action of the obese gene product , 1995, Nature.

[45]  D. Drucker,et al.  Altered cAMP and Ca2+ signaling in mouse pancreatic islets with glucagon-like peptide-1 receptor null phenotype. , 1999, Diabetes.

[46]  R. Palmiter,et al.  Attenuation of the Obesity Syndrome of ob/ob Mice by the Loss of Neuropeptide Y , 1996, Science.

[47]  Clifford B. Saper,et al.  Unraveling the central nervous system pathways underlying responses to leptin , 1998, Nature Neuroscience.

[48]  D. Smith,et al.  Leptin rapidly suppresses insulin release from insulinoma cells, rat and human islets and, in vivo, in mice. , 1997, The Journal of clinical investigation.

[49]  L. Recant,et al.  Functional abnormalities of islets of Langerhans of obese hyperglycemic mouse. , 1977, The American journal of physiology.

[50]  R. Palmiter,et al.  Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y , 1996, Nature.

[51]  C. Saper,et al.  Chemical characterization of leptin‐activated neurons in the rat brain , 2000, The Journal of comparative neurology.

[52]  M. Pelleymounter,et al.  Effects of the obese gene product on body weight regulation in ob/ob mice. , 1995, Science.

[53]  J. Habener,et al.  The glucagon-like peptides. , 1999, Endocrine reviews.

[54]  J. Holst,et al.  Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans , 1997 .