Central glucagon-like peptide 1 receptor-induced anorexia requires glucose metabolism-mediated suppression of AMPK and is impaired by central fructose

2013 ◽  
Vol 304 (7) ◽  
pp. E677-E685 ◽  
Author(s):  
Melissa A. Burmeister ◽  
Jennifer Ayala ◽  
Daniel J. Drucker ◽  
Julio E. Ayala
Keyword(s):  
Food Intake ◽  
Glucose Metabolism ◽  
Dependent Manner ◽  
Anorectic Effect ◽  
Dependent Inhibition ◽  
Glycolytic Inhibitor ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Amp Activated Protein Kinase ◽  
Mediated Reduction

Glucagon-like peptide-1 (GLP-1) suppresses food intake via activation of a central (i.e., brain) GLP-1 receptor (GLP-1R). Central AMP-activated protein kinase (AMPK) is a nutrient-sensitive regulator of food intake that is inhibited by anorectic signals. The anorectic effect elicited by hindbrain GLP-1R activation is attenuated by the AMPK stimulator AICAR. This suggests that central GLP-1R activation suppresses food intake via inhibition of central AMPK. The present studies examined the mechanism(s) by which central GLP-1R activation inhibits AMPK. Supporting previous findings, AICAR attenuated the anorectic effect elicited by intracerebroventricular (icv) administration of the GLP-1R agonist exendin-4 (Ex-4). We demonstrate that Ex-4 stimulates glycolysis and suppresses AMPK phosphorylation in a glucose-dependent manner in hypothalamic GT1-7 cells. This suggests that inhibition of AMPK and food intake by Ex-4 requires central glucose metabolism. Supporting this, the glycolytic inhibitor 2-deoxyglucose (2-DG) attenuated the anorectic effect of Ex-4. However, icv glucose did not enhance the suppression of food intake by Ex-4. AICAR had no effect on Ex-4-mediated reduction in locomotor activity. We also tested whether other carbohydrates affect the anorectic response to Ex-4. Intracerebroventricular pretreatment with the sucrose metabolite fructose, an AMPK activator, attenuated the anorectic effect of Ex-4. This potentially explains the increased food intake observed in sucrose-fed mice. In summary, we propose a model whereby activation of the central GLP-1R reduces food intake via glucose metabolism-dependent inhibition of central AMPK. We also suggest that fructose stimulates food intake by impairing central GLP-1R action. This has significant implications given the correlation between sugar consumption and obesity.

scholarly journals The glucagon-like peptide-1 receptor in the ventromedial hypothalamus reduces short-term food intake in male mice by regulating nutrient sensor activity

2017 ◽  
Vol 313 (6) ◽  
pp. E651-E662 ◽  
Author(s):  
Melissa A. Burmeister ◽  
Jacob D. Brown ◽  
Jennifer E. Ayala ◽  
Doris A. Stoffers ◽  
Darleen A. Sandoval ◽  
...  
Keyword(s):  
Food Intake ◽  
Mammalian Target Of Rapamycin ◽  
Chinese Hamster ◽  
Ventromedial Hypothalamus ◽  
Anorectic Effect ◽  
Inhibition Of Glycolysis ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Amp Activated Protein Kinase ◽  
Nutrient Homeostasis

Pharmacological activation of the glucagon-like peptide-1 receptor (GLP-1R) in the ventromedial hypothalamus (VMH) reduces food intake. Here, we assessed whether suppression of food intake by GLP-1R agonists (GLP-1RA) in this region is dependent on AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR). We found that pharmacological inhibition of glycolysis, and thus activation of AMPK, in the VMH attenuates the anorectic effect of the GLP-1R agonist exendin-4 (Ex4), indicating that glucose metabolism and inhibition of AMPK are both required for this effect. Furthermore, we found that Ex4-mediated anorexia in the VMH involved mTOR but not acetyl-CoA carboxylase, two downstream targets of AMPK. We support this by showing that Ex4 activates mTOR signaling in the VMH and Chinese hamster ovary (CHO)-K1 cells. In contrast to the clear acute pharmacological impact of the these receptors on food intake, knockdown of the VMH Glp1r conferred no changes in energy balance in either chow- or high-fat-diet-fed mice, and the acute anorectic and glucose tolerance effects of peripherally dosed GLP-1RA were preserved. These results show that the VMH GLP-1R regulates food intake by engaging key nutrient sensors but is dispensable for the effects of GLP-1RA on nutrient homeostasis.

scholarly journals The Glucagon-Like Peptide-1 Receptor Agonist Oxyntomodulin Enhances β-Cell Function but Does Not Inhibit Gastric Emptying in Mice

Endocrinology ◽  
2008 ◽  
Vol 149 (11) ◽  
pp. 5670-5678 ◽  
Author(s):  
Adriano Maida ◽  
Julie A. Lovshin ◽  
Laurie L. Baggio ◽  
Daniel J. Drucker
Keyword(s):  
Blood Glucose ◽  
Amino Acid ◽  
Gastric Emptying ◽  
Food Intake ◽  
Oral Glucose ◽  
Dependent Manner ◽  
Glucose Administration ◽  
Amino Acid Peptide ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

The proglucagon gene gives rise to multiple peptides that play diverse roles in the control of energy intake, gut motility, and nutrient disposal. Glucagon-like peptide-1 (GLP-1), a 30-amino-acid peptide regulates glucose homeostasis via control of insulin and glucagon secretion and by inhibition of gastric emptying and food intake. Oxyntomodulin (OXM) a 37-amino-acid peptide also derived from the proglucagon gene, binds to both the glucagon and GLP-1 receptor (GLP-1R); however, a separate OXM receptor has not yet been identified. Here we show that OXM, like other GLP-1R agonists, stimulates cAMP formation and lowers blood glucose after both oral and ip glucose administration, actions that require a functional GLP-1R. OXM also directly stimulates insulin secretion from murine islets and INS-1 cells in a glucose- and GLP-1R-dependent manner. Moreover, OXM ameliorates hyperglycemia and significantly reduces apoptosis in murine β-cells after streptozotocin administration and directly reduces apoptosis in thapsigargin-treated INS-1 cells. Unexpectedly, OXM, but not the GLP-1R agonist exendin-4, increased plasma levels of insulin after oral glucose administration. Moreover, OXM administered at doses that potently lower blood glucose had no effect on inhibition of gastric emptying but reduced food intake in WT mice. Taken together, these findings illustrate that although structurally distinct proglucagon-derived peptides such as GLP-1 and OXM engage the GLP-1R, OXM mimics some but not all of the actions of GLP-1R agonists in vivo. These findings may have implications for therapeutic efforts using OXM as a long-acting GLP-1R agonist for the treatment of metabolic disorders.

scholarly journals Potential Role of Hypothalamic and Plasma Ghrelin in the Feeding Behavior of Obese Type 2 Diabetic Rats with Intraventricular Glucagon-Like Peptide-1 Receptor Agonist Intervention

Obesity Facts ◽  
2020 ◽  
pp. 1-11
Author(s):  
Ke Lu ◽  
Xiaoyan Chen ◽  
Xuelian Deng ◽  
Juan Long ◽  
Jianhua Yan
Keyword(s):  
Food Intake ◽  
Receptor Agonist ◽  
Linear Regression Analysis ◽  
Diabetic Rats ◽  
Multivariate Linear Regression Analysis ◽  
Dependent Manner ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Type 2 Diabetic

<b><i>Objective:</i></b> To investigate the relationship of central and peripheral ghrelin during an exendin-4 (Ex-4) intervention to feeding in obese type 2 diabetic rodents. <b><i>Methods:</i></b> Animal models of diet-induced obesity (DIO) and type 2 diabetes were developed using male Sprague-Dawley rats fed with a high-fat diet and induced into DIO-streptozotocin diabetic rats. Ex-4 or the glucagon-like peptide-1 (GLP-1) receptor agonist exendin fragment-[9-39] (Ex-9) was intracerebroventricularly (ICV) administered. Multivariate linear regression analysis was performed to investigate potential predictors of food intake after Ex-4 administration. <b><i>Results:</i></b> ICV administration of Ex-4 significantly inhibited feeding and decreased weight, plasma active ghrelin, hypothalamic ghrelin, and gastric ghrelin levels. The changes in hypothalamic ghrelin and plasma ghrelin could predict the amount of 8-h average food intake. Central preadministration of Ex-9 followed by treatment with Ex-4 could inhibit the decrease in feeding at 0.5, 2, and 8 h. It could also inhibit the decrease in hypothalamic ghrelin at 0.5, 2, and 8 h, as well as in plasma and gastric ghrelin at 2 and 8 h. <b><i>Conclusions:</i></b> In a GLP-1 receptor-dependent manner, central and peripheral ghrelin play a vital role in the inhibition of feeding by Ex-4 administration. Hypothalamic ghrelin, but not plasma ghrelin, may be involved in central Ex-4 inhibition of feeding in the very early feeding period.

scholarly journals The Effects of Sleeve Gastrectomy on Glucose Metabolism and Glucagon-Like Peptide 1 in Goto-Kakizaki Rats

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Laiyuan Li ◽  
Xiaolin Wang ◽  
Liangliang Bai ◽  
Huichuan Yu ◽  
Zenghong Huang ◽  
...  
Keyword(s):  
Body Weight ◽  
Sleeve Gastrectomy ◽  
Blood Glucose ◽  
Food Intake ◽  
Glucose Metabolism ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Gk Rats ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Purpose. To investigate the effects of sleeve gastrectomy (SG) on glucose metabolism and changes in glucagon-like peptide 1 (GLP-1) in Goto-Kakizaki (GK) rats. Methods. GK rats were randomly assigned to one of three groups: SG, SG pair-fed plus sham surgery (PF-sham), and ad libitum-fed no surgery (control). Food intake, body weight, blood glucose, GLP-1 and insulin levels, and GLP-1 expression in the jejunum and ileum were compared. Results. The SG rats exhibited lower postoperative food intake, body weight, and fasting glucose than did the control rats (P<0.05). SG significantly improved glucose and insulin tolerance (P<0.05). Plasma GLP-1 levels were higher in SG rats than in control or PF-sham rats in the oral glucose tolerance test (OGTT) (P<0.05). Blood glucose levels expressed as a percentage of baseline were higher in SG rats than in control rats after exendin (9-39) administration (P<0.05). The levels of GLP-1 expression in the jejunum and ileum were higher in SG rats than in PF-sham and control rats (P<0.05). Conclusions. Improvement of glucose metabolism by SG was associated with increased GLP-1 secretion. SG contributes to an increase in plasma GLP-1 levels via increased GLP-1 expression in the mucosa of the jejunum and/or ileum.

scholarly journals Hindbrain glucagon-like peptide-1 neurons track intake volume and contribute to injection stress-induced hypophagia in meal-entrained rats

2016 ◽  
Vol 310 (10) ◽  
pp. R906-R916 ◽  
Author(s):  
Alison D. Kreisler ◽  
Linda Rinaman
Keyword(s):  
Food Intake ◽  
Potential Role ◽  
Liquid Diet ◽  
Neural Activation ◽  
Intracerebroventricular Injection ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Diet Intake ◽  
Published Research ◽  
Diet Type

Published research supports a role for central glucagon-like peptide 1 (GLP-1) signaling in suppressing food intake in rodent species. However, it is unclear whether GLP-1 neurons track food intake and contribute to satiety, and/or whether GLP-1 signaling contributes to stress-induced hypophagia. To examine whether GLP-1 neurons track intake volume, rats were trained to consume liquid diet (LD) for 1 h daily until baseline intake stabilized. On test day, schedule-fed rats consumed unrestricted or limited volumes of LD or unrestricted volumes of diluted (calorically matched to LD) or undiluted Ensure. Rats were perfused after the test meal, and brains processed for immunolocalization of cFos and GLP-1. The large majority of GLP-1 neurons expressed cFos in rats that consumed satiating volumes, regardless of diet type, with GLP-1 activation proportional to intake volume. Since GLP-1 signaling may limit intake only when such large proportions of GLP-1 neurons are activated, a second experiment examined the effect of central GLP-1 receptor (R) antagonism on 2 h intake in schedule-fed rats. Compared with baseline, intracerebroventricular vehicle (saline) suppressed Ensure intake by ∼11%. Conversely, intracerebroventricular injection of vehicle containing GLP-1R antagonist increased intake by ∼14% compared with baseline, partly due to larger second meals. We conclude that GLP-1 neural activation effectively tracks liquid diet intake, that intracerebroventricular injection suppresses intake, and that central GLP-1 signaling contributes to this hypophagic effect. GLP-1 signaling also may contribute to satiety after large volumes have been consumed, but this potential role is difficult to separate from a role in the hypophagic response to intracerebroventricular injection.

scholarly journals Exogenous glucagon-like peptide 1 reduces contractions in human colon circular muscle

2014 ◽  
Vol 221 (1) ◽  
pp. 29-37 ◽  
Author(s):  
Antonella Amato ◽  
Sara Baldassano ◽  
Rosa Liotta ◽  
Rosa Serio ◽  
Flavia Mulè
Keyword(s):  
Colonic Motility ◽  
Circular Muscle ◽  
Human Colon ◽  
Inhibitory Effect ◽  
Mechanical Activity ◽  
Organ Bath ◽  
Dependent Manner ◽  
Double Labeling ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide 1 (GLP1) is a naturally occurring peptide secreted by intestinal L-cells. Though its primary function is to serve as an incretin, GLP1 reduces gastrointestinal motility. However, only a handful of animal studies have specifically evaluated the influence of GLP1 on colonic motility. Consequently, the aims of this study were to investigate the effects induced by exogenous GLP1, to analyze the mechanism of action, and to verify the presence of GLP1 receptors (GLP1Rs) in human colon circular muscular strips. Organ bath technique, RT-PCR, western blotting, and immunofluorescence were used. In human colon, exogenous GLP1 reduced, in a concentration-dependent manner, the amplitude of the spontaneous contractions without affecting the frequency and the resting basal tone. This inhibitory effect was significantly reduced by exendin (9–39), a GLP1R antagonist, which per se significantly increased the spontaneous mechanical activity. Moreover, it was abolished by tetrodotoxin, a neural blocker, or Nω-nitro-l-arginine – a blocker of neuronal nitric oxide synthase (nNOS). The biomolecular analysis revealed a genic and protein expression of the GLP1R in the human colon. The double-labeling experiments with anti-neurofilament or anti-nNOS showed, for the first time, that immunoreactivity for the GLP1R was expressed in nitrergic neurons of the myenteric plexus. In conclusion, the results of this study suggest that GLP1R is expressed in the human colon and, once activated by exogenous GLP1, mediates an inhibitory effect on large intestine motility through NO neural release.

scholarly journals Glucagon-Like Peptide-1 Mediates the Protective Effect of the Dipeptidyl Peptidase IV Inhibitor on Renal Fibrosis via Reducing the Phenotypic Conversion of Renal Microvascular Cells in Monocrotaline-Treated Rats

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Jian Xu ◽  
Jingjing Wang ◽  
Yusheng Cheng ◽  
Xiang Li ◽  
Mengyu He ◽  
...  
Keyword(s):  
Protective Effect ◽  
Renal Fibrosis ◽  
Kidney Diseases ◽  
Dipeptidyl Peptidase ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Matrix Deposition ◽  
Renal Microcirculation ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Chronic kidney diseases are characterized by renal fibrosis with excessive matrix deposition, leading to a progressive loss of functional renal parenchyma and, eventually, renal failure. Renal microcirculation lesions, including the phenotypic conversion of vascular cells, contribute to renal fibrosis. Here, renal microcirculation lesions were established with monocrotaline (MCT, 60 mg/kg). Sitagliptin (40 mg/kg/d), a classical dipeptidyl peptidase-4 (DPP-4) inhibitor, attenuated the renal microcirculation lesions by inhibiting glomerular tuft hypertrophy, glomerular mesangial expansion, and microvascular thrombosis. These effects of sitagliptin were mediated by glucagon-like peptide-1 receptor (GLP-1R), since they were blocked by the GLP-1R antagonist exendin-3 (Ex-3, 40 ug/kg/d). The GLP-1R agonist liraglutide showed a similar renal protective effect in a dose-independent manner. In addition, sitagliptin, as well as liraglutide, alleviated the MCT-induced apoptosis of renal cells by increasing the expression of survival factor glucose-regulated protein 78 (GRP78), which was abolished by the GLP-1R antagonist Ex-3. Sitagliptin and liraglutide also effectively ameliorated the conversion of vascular smooth muscle cells (SMCs) from a synthetic phenotype to contractile phenotype. Moreover, sitagliptin and liraglutide inhibited endothelial-mesenchymal transition (EndMT) via downregulating transforming growth factor-β1 (TGF-β1). Collectively, these findings suggest that DPP-4 inhibition can reduce microcirculation lesion-induced renal fibrosis in a GLP-1-dependent manner.

scholarly journals The common hepatic branch of the vagus is not required to mediate the glycemic and food intake suppressive effects of glucagon-like-peptide-1

2011 ◽  
Vol 301 (5) ◽  
pp. R1479-R1485 ◽  
Author(s):  
Matthew R. Hayes ◽  
Scott E. Kanoski ◽  
Bart C. De Jonghe ◽  
Theresa M. Leichner ◽  
Amber L. Alhadeff ◽  
...  
Keyword(s):  
Food Intake ◽  
Vagal Afferents ◽  
Oral Glucose ◽  
Afferent Fibers ◽  
The Common ◽  
Vagal Afferent ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
And Control ◽  
Hepatic Branch

The incretin and food intake suppressive effects of intraperitoneally administered glucagon-like peptide-1 (GLP-1) involve activation of GLP-1 receptors (GLP-1R) expressed on vagal afferent fiber terminals. Central nervous system processing of GLP-1R-driven vagal afferents results in satiation signaling and enhanced insulin secretion from pancreatic-projecting vagal efferents. As the vast majority of endogenous GLP-1 is released from intestinal l-cells following ingestion, it stands to reason that paracrine GLP-1 signaling, activating adjacent GLP-1R expressed on vagal afferent fibers of gastrointestinal origin, contributes to glycemic and food intake control. However, systemic GLP-1R-mediated control of glycemia is currently attributed to endocrine action involving GLP-1R expressed in the hepatoportal bed on terminals of the common hepatic branch of the vagus (CHB). Here, we examine the hypothesis that activation of GLP-1R expressed on the CHB is not required for GLP-1's glycemic and intake suppressive effects, but rather paracrine signaling on non-CHB vagal afferents is required to mediate GLP-1's effects. Selective CHB ablation (CHBX), complete subdiaphragmatic vagal deafferentation (SDA), and surgical control rats received an oral glucose tolerance test (2.0 g glucose/kg) 10 min after an intraperitoneal injection of the GLP-1R antagonist, exendin-(9–39) (Ex-9; 0.5 mg/kg) or vehicle. CHBX and control rats showed comparable increases in blood glucose following blockade of GLP-1R by Ex-9, whereas SDA rats failed to show a GLP-1R-mediated incretin response. Furthermore, GLP-1(7–36) (0.5 mg/kg ip) produced a comparable suppression of 1-h 25% glucose intake in both CHBX and control rats, whereas intake suppression in SDA rats was blunted. These findings support the hypothesis that systemic GLP-1R mediation of glycemic control and food intake suppression involves paracrine-like signaling on GLP-1R expressed on vagal afferent fibers of gastrointestinal origin but does not require the CHB.

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