Hepatocyte HIF‐1alpha mediates obesity‐induced decreased incretin effects

Abstract

The decrease in incretin effects is an important etiologic component of type 2 diabetes with unknown mechanisms. In an attempt to understand obesity‐induced changes in liver oxygen homeostasis and its metabolic consequence, we came across a novel finding that liver HIF‐1α expression was increased mainly by soluble factors released from obese adipocytes, leading to decreased incretin effects. In‐depth mouse metabolic phenotyping revealed that obesity increased first‐pass degradation of an incretin hormone GLP‐1 with increased liver DPP4 expression and decreased sinusoidal blood flow rate, reducing active GLP‐1 levels in peripheral circulation. Deletion of hepatocyte HIF‐1α KO blocked these changes induced by obesity: hepatocyte HIF‐1α KO mice were protected from obesity‐induced glucose intolerance without changes in body weight, liver steatosis, or insulin resistance. Deletion of hepatocyte HIF‐2α did not change liver DPP4 expression but improved hepatic steatosis. Our results identify a previously unknown pathway for obesity‐induced impaired beta cell glucose response (incretin effects) and the development of glucose intolerance through inter‐organ communications.