A novel dual agonist of glucagon-like peptide-1 receptors and neuropeptide Y2 receptors attenuates fentanyl taking and seeking in male rats

Objective: To determine the effect of tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, on biomarkers of nonalcoholic steatohepatitis (NASH) and fibrosis in T2DM patients. Research Design and Methods: T2DM patients received either once weekly tirzepatide (1, 5, 10, or 15 mg), dulaglutide (1.5 mg), or placebo for 26 weeks. Changes from baseline in alanine aminotransferase (ALT), aspartate aminotransferase (AST), Keratin-18 (K-18), Procollagen III (Pro-C3), and adiponectin, were analyzed in a modified intent-to-treat population. Results: Significant (p<0.05) reductions from baseline in ALT (all groups), AST (all groups, except tirzepatide 10 mg), K-18 (tirzepatide 5, 10, 15 mg) and Pro-C3 (tirzepatide 15 mg) were observed at 26 weeks. Decreases with tirzepatide were significant compared with placebo for K-18 (10 mg) and Pro-C3 (15 mg), and with dulaglutide for ALT (10, 15 mg). Adiponectin significantly increased from baseline with tirzepatide compared with placebo (10 and 15 mg). Conclusions: In post-hoc analyses, higher tirzepatide doses significantly decreased NASH-related biomarkers and increased adiponectin in T2DM patients.

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Combined gastrin releasing peptide-29 and glucagon like peptide-1 reduce body weight more than each individual peptide in diet-induced obese male rats

Neuropeptides ◽

10.1016/j.npep.2017.11.009 ◽

2018 ◽

Vol 67 ◽

pp. 71-78 ◽

Cited By ~ 1

Author(s):

Thaer R. Mhalhal ◽

Martha C. Washington ◽

Kayla D. Newman ◽

John C. Heath ◽

Ayman I. Sayegh

Keyword(s):

Body Weight ◽

Male Rats ◽

Gastrin Releasing Peptide ◽

Reduce Body Weight ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Obese Male ◽

Individual Peptide

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Unraveling oxyntomodulin, GLP1's enigmatic brother

Journal of Endocrinology ◽

10.1530/joe-12-0368 ◽

2012 ◽

Vol 215 (3) ◽

pp. 335-346 ◽

Cited By ~ 77

Author(s):

Alessandro Pocai

Keyword(s):

Weight Loss ◽

Glycemic Control ◽

Glucose Tolerance ◽

Obese Mice ◽

Glucagon Receptor ◽

Glucose Levels ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Diabetes And Obesity ◽

Dual Agonist

Oxyntomodulin (OXM) is a peptide secreted from the L cells of the gut following nutrient ingestion. OXM is a dual agonist of the glucagon-like peptide-1 receptor (GLP1R) and the glucagon receptor (GCGR) combining the effects of GLP1 and glucagon to act as a potentially more effective treatment for obesity than GLP1R agonists. Injections of OXM in humans cause a significant reduction in weight and appetite, as well as an increase in energy expenditure. Activation of GCGR is classically associated with an elevation in glucose levels, which would be deleterious in patients with T2DM, but the antidiabetic properties of GLP1R agonism would be expected to counteract this effect. Indeed, OXM administration improved glucose tolerance in diet-induced obese mice. Thus, dual agonists of the GCGR and GLP1R represent a new therapeutic approach for diabetes and obesity with the potential for enhanced weight loss and improvement in glycemic control beyond those of GLP1R agonists.

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667-P: IBI362 (LY3305677), a Weekly-Dose Glucagon-Like Peptide-1/Glucagon Receptor Dual Agonist, in Subjects with Overweight or Obesity

Diabetes ◽

10.2337/db21-667-p ◽

2021 ◽

Vol 70 (Supplement 1) ◽

pp. 667-P

Author(s):

HONGWEI JIANG ◽

PEI AN ◽

HELENA DENG ◽

LI LI ◽

LIQI FENG ◽

...

Keyword(s):

Weekly Dose ◽

Glucagon Receptor ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Dual Agonist ◽

Overweight Or Obesity

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A novel glucagon-like peptide-1/glucagon receptor dual agonist exhibits weight-lowering and diabetes-protective effects

European Journal of Medicinal Chemistry ◽

10.1016/j.ejmech.2017.07.046 ◽

2017 ◽

Vol 138 ◽

pp. 1158-1169 ◽

Cited By ~ 23

Author(s):

Jie Zhou ◽

Xingguang Cai ◽

Xun Huang ◽

Yuxuan Dai ◽

Lidan Sun ◽

...

Keyword(s):

Protective Effects ◽

Glucagon Receptor ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Dual Agonist

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Hindbrain Oxytocin Receptors Contribute to the Effects of Circulating Oxytocin on Food Intake in Male Rats

Endocrinology ◽

10.1210/en.2014-1148 ◽

2014 ◽

Vol 155 (8) ◽

pp. 2845-2857 ◽

Cited By ~ 37

Author(s):

Jacqueline M. Ho ◽

Vishwanath T. Anekonda ◽

Benjamin W. Thompson ◽

Mingyan Zhu ◽

Robert W. Curry ◽

...

Keyword(s):

Food Intake ◽

Male Rats ◽

Predominant Role ◽

Catecholaminergic Neurons ◽

Downstream Target ◽

Oxytocin Receptors ◽

Electrophysiological Studies ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Catecholamine Neurons

Oxytocin (OT)-elicited hypophagia has been linked to neural activity in the nucleus of the solitary tract (NTS). Because plasma OT levels increase after a meal, we hypothesized that circulating OT acts at both peripheral and hindbrain OT receptors (OTRs) to limit food intake. To initially determine whether circulating OT inhibits food intake by acting at hindbrain OTRs, we pretreated rats with an OTR antagonist administered into the fourth ventricle (4V) followed by either central or systemic OT administration. Administration of the OTR antagonist into the 4V blocked anorexia induced by either 4V or ip injection of OT. However, blockade of peripheral OTRs also weakened the anorectic response to ip OT. Our data suggest a predominant role for hindbrain OTRs in the hypophagic response to peripheral OT administration. To elucidate central mechanisms of OT hypophagia, we tested whether OT activates NTS catecholaminergic neurons. OT (ip) increased the number of NTS cells expressing c-Fos, of which 10%–15% were catecholaminergic. Furthermore, electrophysiological studies in mice revealed that OT stimulated 47% (8 of 17) of NTS catecholamine neurons through a presynaptic mechanism. However, OT-elicited hypophagia did not appear to require activation of α1-adrenoceptors, and blockade of glucagon-like peptide-1 receptors similarly did not attenuate anorexia induced by OT. These findings demonstrate that OT elicits satiety through both central and peripheral OTRs and that although catecholamine neurons are a downstream target of OT signaling in the NTS, the hypophagic effect is mediated independently of α1-adrenoceptor signaling.

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