| First Author | Onodera T | Year | 2023 |
| Journal | Mol Metab | Volume | 78 |
| Pages | 101821 | PubMed ID | 37806486 |
| Mgi Jnum | J:341479 | Mgi Id | MGI:7539627 |
| Doi | 10.1016/j.molmet.2023.101821 | Citation | Onodera T, et al. (2023) Protective roles of adiponectin and molecular signatures of HNF4alpha and PPARalpha as downstream targets of adiponectin in pancreatic beta cells. Mol Metab :101821 |
| abstractText | 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 beta 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 PPARalpha and HNF4alpha as additional down-regulated transcription factors during a prolonged metabolic challenge. To elucidate the function of beta cell-specific PPARalpha and HNF4alpha expression, we developed doxycycline inducible pancreatic beta cell-specific PPARalpha (beta-PPARalpha) and HNF4alpha (beta-HNF4alpha) overexpression mice. beta-PPARalpha mice exhibited improved protection from lipotoxicity and elevated beta-oxidative damage in the islets, but also displayed lowered phospholipid levels and impaired glucose-stimulated insulin secretion. beta-HNF4alpha mice showed a more severe phenotype when compared to beta-PPARalpha 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 beta-PPARalpha and beta-HNF4alpha. Given that beta-HNF4alpha potently induces PPARalpha expression, we define a novel adiponectin-HNF4alpha-PPARalpha 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. |
