RAGE displays sex-specific differences in obesity-induced adipose tissue insulin resistance

The receptor for advanced glycation end products (RAGE) plays an important role in obesity-associated insulin sensitivity. We have also previously reported that RAGE deficiency improved insulin resistance in obesity-induced adipose tissue. The current study was aimed to elucidate the sex-specific mechanism of RAGE deficiency in adipose tissue metabolic regulation and systemic glucose homeostasis.

RAGE-deficient (RAGE^-/-) mice were fed a high-fat diet (HFD) and subjected to glucose and insulin tolerance tests. Subcutaneous adipose tissue (sAT) was collected, and macrophage polarization was assessed by quantitative real-time PCR. Immunoblotting was performed to evaluate the insulin signaling in adipose tissues.

Under HFD feeding conditions, body weight and adipocyte size of female RAGE deficient (RAGE^-/-) were markedly lower than that of male mice. Female RAGE^-/- mice showed significantly improved glucose and insulin tolerance compared to male RAGE^-/- mice, accompanied with increased M2 macrophages polarization. Expressions of genes involved in anti-oxidant and browning were up-regulated in adipose tissues of female RAGE^-/- mice. Moreover, insulin-induced AKT phosphorylation was significantly elevated in adipose tissue in female RAGE^-/- mice compared to male RAGE^-/- mice.

Our findings suggest that RAGE-mediated adipose tissue insulin resistance is sex-specific, which is associated with different expression of genes involved in anti-oxidant and browning and insulin-induced AKT phosphorylation.