GPR40 reduces food intake and body weight through GLP-1

Abstract

G protein-coupled receptor 40 (GPR40) partial agonists lower glucose through the potentiation of glucose-stimulated insulin secretion, which is believed to provide significant glucose lowering without the weight gain or hypoglycemic risk associated with exogenous insulin or glucose-independent insulin secretagogues. The class of small-molecule GPR40 modulators, known as AgoPAMs (agonist also capable of acting as positive allosteric modulators), differentiate from partial agonists, binding to a distinct site and functioning as full agonists to stimulate the secretion of both insulin and glucagon-like peptide-1 (GLP-1). Here we show that GPR40 AgoPAMs significantly increase active GLP-1 levels and reduce acute and chronic food intake and body weight in diet-induced obese (DIO) mice. These effects of AgoPAM treatment on food intake are novel and required both GPR40 and GLP-1 receptor signaling pathways, as demonstrated in GPR40 and GLP-1 receptor-null mice. Furthermore, weight loss associated with GPR40 AgoPAMs was accompanied by a significant reduction in gastric motility in these DIO mice. Chronic treatment with a GPR40 AgoPAM, in combination with a dipeptidyl peptidase IV inhibitor, synergistically decreased food intake and body weight in the mouse. The effect of GPR40 AgoPAMs on GLP-1 secretion was recapitulated in lean, healthy rhesus macaque demonstrating that the putative mechanism mediating weight loss translates to higher species. Together, our data indicate effects of AgoPAMs that go beyond glucose lowering previously observed with GPR40 partial agonist treatment with additional potential for weight loss.

GPR40 partial agonists and AgoPAMs: Differentiating effects on glucose and hormonal secretions in the rodent

“…Further, these hormonal effects are observed alongside greater glucose lowering suggesting a possible causal link between these two observations. The data we described in this manuscript and others [ 5 , 23 ] extend these initial reports of greater efficacy with GPR40 AgoPAMs beyond what was first observed acutely in mice and cells to the chronic setting in the diabetic GK rat. Furthermore, these studies used two structurally distinct AgoPAM compounds dosed at levels aimed to achieve comparable percent target engagement as the partial GPR40 agonists used.…”

Mechanisms to Elevate Endogenous GLP-1 Beyond Injectable GLP-1 Analogs and Metabolic Surgery

“…These experiments also revealed the significance of blocking SSTR5. While combinations of just the DPP4 inhibitor and the TGR5 or GPR40 agonist increased GLP-1 concentrations (31 and 28 pmol/L, respectively; similar to levels reported for the DPP4 inhibitor-GPR40 agonist combination [39]), the addition of the SSTR5 Figure 2-Determining the concentration of GLP-1 equivalents that maximize glucose lowering. A: Wild-type mice fasted overnight were subcutaneously injected with exenatide (0.01-30 nmol/kg), followed 1 h later by assessment of exenatide levels in plasma (limit of detection of 24 pmol/L is denoted by the dotted line).…”

The current state of GPCR‐based drug discovery to treat metabolic disease

“…Consistent with these results, the stimulatory effects of fatty acids on insulin secretion are lost in FFA1 receptor knockout mice (Lan et al ., ). Interestingly, a new report shows the ability of FFA1 receptor agonists or potentiators to increase GLP‐1 to levels sufficient for reducing food intake and body weight in obese rodents (Gorski et al ., ). Several FFA1 receptor agonists have entered clinical testing with mixed results.…”