Protective roles of adiponectin and molecular signatures of HNF4 and PPAR as downstream targets of adiponectin in pancreatic cells

The disease progression of the metabolic syndrome is associated with prolonged hyperlipidemia and insulin resistance, eventually giving rise to impaired insulin secretion, often concomitant with hypoadiponectinemia. As an adipose tissue derived hormone, adiponectin is beneficial for insulin secretion and b cell health and differentiation. However, the down-stream pathway of adiponectin in the pancreatic islets has not been studied extensively. Here, along with the overall reduction of endocrine pancreatic function in islets from adiponectin KO mice, we examine PPARa and HNF4a as additional down-regulated transcription factors during a prolonged metabolic challenge. To elucidate the function of b cell specific PPARa and HNF4a expression, we developed doxycycline inducible pancreatic b cell-specific PPARa (b-PPARa) and HNF4a (b-HNF4a) overexpression mice. b-PPARa mice exhibited improved protection from lipotoxicity, but elevated b-oxidative damage in the islets, and also displayed lowered phospholipid levels and impaired glucose-stimulated insulin secretion. b-HNF4a mice showed a more severe phenotype when compared to b-PPARa mice, characterized by lower body weight, small islet mass and impaired insulin secretion. RNA-sequencing of the islets of these models highlights overlapping yet unique roles of b-PPARa and b-HNF4a. Given that b-HNF4a potently induces PPARa expression, we define a novel adiponectin-HNF4a-PPARa cascade. We further analyzed downstream genes consistently regulated by this axis. Among them, the islet amyloid polypeptide (IAPP) gene is an important target and accumulates in adiponectin KO mice. We propose a new mechanism of IAPP aggregation in type 2 diabetes through reduced adiponectin action.(c) 2023 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).