Peptide-YY 3-36/Glucagon-Like Peptide-1 Combination Treatment of Obese-Diabetic Mice Improves Insulin Sensitivity associated with Recovered Pancreatic ß-Cell Function and Synergistic Activation of Discrete Hypothalamic and Brainstem Neuronal Circuitries

Mol Metab. 2021 Nov 12;101392. doi: 10.1016/j.molmet.2021.101392. Online ahead of print.

Abstract

Objective: Obesity-linked type 2 diabetes (T2D) is a worldwide health concern and many novel approaches are being considered for its treatment and subsequent prevention of serious comorbidities. Co-administration of glucagon like peptide 1 (Fc-GLP-1) and peptide YY3-36 (Fc-PYY3-36) renders a synergistic decrease in energy intake in obese men. However, mechanistic details of the synergy between these peptide agonists and their effects on metabolic homeostasis remain relatively scarce.

Methods: In this study, we utilized long-acting analogues of GLP-1 and PYY3-36 (via Fc-peptide conjugation) to better characterize the synergistic pharmacological benefits of their co-administration on body weight and glycaemic regulation in obese and diabetic mouse models. Hyperinsulinemic-euglycemic clamps were used to measure weight-independent effects of Fc-PYY3-36 + Fc-GLP-1 on insulin action. Fluorescent light sheet microscopy analysis of whole brain was performed to assess activation of brain regions.

Results: Co-administration of long-acting Fc-IgG/peptide conjugates of Fc-GLP-1 and Fc-PYY3-36 (specific for PYY receptor-2 (Y2R)) resulted in profound weight loss, restored glucose homeostasis, and recovered endogenous β-cell function in two mouse models of obese T2D. Hyperinsulinemic-euglycemic clamps in C57BLKS/J db/db and diet-induced obese Y2R-deficient (Y2RKO) mice indicated Y2R is required for a weight-independent improvement in peripheral insulin sensitivity and enhanced hepatic glycogenesis. Brain cFos staining demonstrated distinct temporal activation of regions of the hypothalamus and hindbrain following Fc-PYY3-36 + Fc-GLP-1R agonist administration.

Conclusions: These results reveal a therapeutic approach for obesity/T2D that improved insulin sensitivity and restored endogenous β-cell function. This data also highlights the potential association between the gut-brain axis in control of metabolic homeostasis.

Keywords: Glucagon-like peptide-1 (GLP-1); Peptide-YY(3-36) (PYY(3-36)); central nervous system; diabetes remission; glucose homeostasis; insulin sensitivity; β-cell function.