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.