Lack of adipocyte IP3R1 reduces diet-induced obesity and greatly improves whole-body glucose homeostasis

Abstract

The normal function of skeletal muscle and adipose tissue ensures whole-body glucose homeostasis. Ca ²⁺ release channel inositol 1,4,5-trisphosphate receptor 1 (IP3R1) plays a vital role in regulating diet-induced obesity and disorders, but its functions in peripheral tissue regulating glucose homeostasis remain unexplored. In this study, mice with Ip3r1 specific knockout in skeletal muscle or adipocytes were used for investigating the mediatory role of IP3R1 on whole-body glucose homeostasis under normal or high-fat diet. We reported that IP3R1 expression levels were increased in the white adipose tissue and skeletal muscle of diet-induced obese mice. Ip3r1 knockout in skeletal muscle improved glucose tolerance and insulin sensitivity of mice on a normal chow diet, but worsened insulin resistance in diet-induced obese mice. These changes were associated with the reduced muscle weight and compromised Akt signaling activation. Importantly, Ip3r1 deletion in adipocytes protected mice from diet-induced obesity and glucose intolerance, mainly due to the enhanced lipolysis and AMPK signaling pathway in the visceral fat. In conclusion, our study demonstrates that IP3R1 in skeletal muscle and adipocytes exerts divergent effects on systemic glucose homeostasis, and characterizes adipocyte IP3R1 as a promising target for treating obesity and type 2 diabetes.