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Publication

Peptide-YY3-36/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.

Authors	Boland BB, Laker RC, O'Brien S, Sitaula S, Sermadiras I, Nielsen JC, Barkholt P, Roostalu U, Hecksher-Sørensen J, Sejthen SR, Thorbek DD, Suckow A, Burmeister N, Oldham S, Will S, Howard VG, Gill BM, Newton P, Naylor J, Hornigold DC, Austin J, Lantier L, McGuinness OP, Trevaskis JL, Grimsby JS, Rhodes CJ
Submitted By	Submitted Externally on 1/10/2022
Status	Published
Journal	Molecular metabolism
Year	2021
Date Published	11/1/2021
Volume : Pages	55 : 101392
PubMed Reference	34781035
Abstract	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 (GLP-1) and peptide YY3-36 (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., 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., 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 ß-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., These results reveal a therapeutic approach for obesity/T2D that improved insulin sensitivity and restored endogenous ß-cell function. These data also highlight the potential association between the gut-brain axis in control of metabolic homeostasis.

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