A GLP-1R/GCGR dual agonist exhibits differential effects on metabolic control versus a single GLP-1R agonist by activation of BAT and browning in diet-induced obese mice

Abstract

[Question]: Brown adipose tissue (BAT), a specialized fat that dissipates energy to produce heat, plays an important role in the regulation of energy balance. We designed a pharmacological intervention protocol with a GLP-1R agonist and GLP-1R/ GCGR dual agonist to investigate their effects in preventing diet-induced obesity in m ice by enhancing BAT activation, browning and insulin signaling in differentiated brown adipocytes (BA). [Methods]: 8 week-old male C57Bl/6 mice were fed chow or high fat diet (HFD) for 10 weeks. HFD-fed mice were subsequently injected (s.c. every 2 days) vehicle or a GLP-1R agonist (10 nmol/kg) or G49, a GLP-1R/GCGR dual agonist (4.4 mg/kg). Parameters assessing obesity, glucose homeostasis, b-cell function, BAT activation and browning were analyzed following treatment for 3-6 weeks. lnsulin signaling was assayed in differentiated BA. [Results]: Following 3 weeks of treatment, body weight loss was greater in m ice injected G49 compared to those injected GLP-1R agonist. PET analysis revealed cold-induced activation of BAT by both drug treatments, but the effect was higher in G49-treated group. These differential effects were maintained following 6 weeks of treatment, at which time adiposity and macrophage inftltration of eWAT were reduced and UCP1 immunostaining in BAT and iWAT was increased. Also, the effects of G49 in inducing mRNA levels of BAT activation markers and browning in iWAT and eWAT were higher in m ice injected G49. A stronger decrease in plasma glucose and insulin was detected in G49-treated animals versus those receiving GLP-1 R agonist in parallel with improvement of islet morphology. The higher efftcacy of G49 was tested in differentiated BA by its effect in counteracting the impairment in insulin signaling induced by pro-inflammatory cytokines. [Conclusions]: Our results strongly suggest a novel role of an oxyntomodulin-like dual acting GLP-1R/GCGR agonist in reducing obesity and improve insulin sensitivity by increasing energy expenditure due to its effects in BAT and beta-cell function.