Insulin Signaling in Adipocytes Controls Systemic Insulin Sensitivity through the 5-LO-LTB4 Axis

Abstract

Although adipocytes are major targets of insulin, the influence of impaired insulin action in adipocytes on metabolic homeostasis has been unclear. To provide insight into the role of insulin action in adipocytes, we generated mice that lack 3'-phosphoinositide-dependent kinase1 (PDK1) specifically in adipocytes (A-PDK1KO mice). These mice manifest impairment of metabolic actions of insulin in adipose tissue and a reduction in adipose tissue mass. The mice developed insulin resistance, glucose intolerance, and hepatic steatosis, all of which were markedly attenuated by additional ablation of FoxO1 specifically in adipocytes without an effect on adipose tissue mass, indicating that the PDK1-FoxO1 axis in adipocytes plays an important role in systemic metabolic homeostasis through a mechanism independent of the regulation of adipose tissue mass. Neither circulating levels of adiponectin and leptin nor inflammation in adipose tissue differed between A-PDK1KO mice and adipocyte-specific PDK1/FoxO1 deficient mice (A-PDK1/FoxO1KO mice), indicating that those factors did not account for the difference in metabolic phenotypes of the two genotypes of mice. Microarray and lipidomics analyses revealed that leukotriene B4 (LTB4) levels in plasma and in adipose tissues as well as the expression of 5-lipoxygenase (5-LO), a rate limiting enzyme for LTB4 production, in adipose tissues were increased and normalized in A-PDK1KO and A-PDK1/FoxO1KO mice, respectively. Administration of a 5-LO inhibitor reduced plasma levels of LTB4 and ameliorated insulin resistance and glucose intolerance in A-PDK1KO mice. Furthermore, insulin was found to inhibit LTB4 production through downregulation of 5-LO expression via the PDK1-FoxO1 pathway in isolated adipocytes. These results thus indicate that insulin signaling via the PDK1-FoxO1 pathway negatively regulates the production of LTB4 through the suppression of 5-LO in adipocytes and thereby maintains systemic insulin sensitivity. Disclosure T. Hosooka: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. W. Ogawa: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Abbott.