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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13293-022-00476-6.