G protein–coupled receptor 21 deletion improves insulin sensitivity in diet-induced obese mice

Abstract

Obesity-induced inflammation is a key component of systemic insulin resistance, which is a hallmark of type 2 diabetes. A major driver of this inflammation/insulin resistance syndrome is the accumulation of proinflammatory macrophages in adipose tissue and liver. We found that the orphan GPCR Gpr21 was highly expressed in the hypothalamus and macrophages of mice and that whole-body KO of this receptor led to a robust improvement in glucose tolerance and systemic insulin sensitivity and a modest lean phenotype. The improvement in insulin sensitivity in the high-fat diet-fed (HFD-fed) Gpr21 KO mouse was traced to a marked reduction in tissue inflammation caused by decreased chemotaxis of Gpr21 KO macrophages into adipose tissue and liver. Furthermore, mice lacking macrophage expression of Gpr21 were protected from HFD-induced inflammation and displayed improved insulin sensitivity. Results of in vitro chemotaxis studies in human monocytes suggested that the defect in chemotaxis observed ex vivo and in vivo in mice is also translatable to humans. Cumulatively, our data indicate that GPR21 has a critical function in coordinating macrophage proinflammatory activity in the context of obesity-induced insulin resistance.

Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance

“…Mice were gavaged with 100 mg/kg Fex or corn oil vehicle daily for 3 weeks before hyperinsulinemic-euglycemic clamp studies. Clamp studies were performed as described 50 . Briefly, dual catheters (cat.…”

The role of dietary fat in obesity-induced insulin resistance

“…Blood glucose was measured at 0, 15, 30, 60, and 90 min after injection, and blood samples were taken at 0 and 10 min to measure glucose-stimulated insulin secretion. Hyperinsulinemic-euglycemic clamps were performed in the sixth week of iG feeding, as previously described (9,26), to quantitate the degree of systemic and tissue-specific insulin sensitivity. Briefly, dual catheters (MRE-025) were implanted in the right jugular vein, tunneled subcutaneously, and exteriorized at the back of the neck.…”

TGR5 reduces macrophage migration through mTOR-induced C/EBPβ differential translation

“…In line with these observations, several studies that target ATMs to attenuate the secretion of proinflammatory cytokines have shown beneficial effects with respect to insulin resistance (6,7). Over the last years, several G proteincoupled receptors (GPCRs) have emerged as critical regulators of ATM function (8)(9)(10)(11)(12)(13)(14), rendering them highly attractive as targets for drug development.…”