| First Author | Lee YS | Year | 2019 |
| Journal | Sci Adv | Volume | 5 |
| Issue | 7 | Pages | eaaw4176 |
| PubMed ID | 31281892 | Mgi Jnum | J:287565 |
| Mgi Id | MGI:6415849 | Doi | 10.1126/sciadv.aaw4176 |
| Citation | Lee YS, et al. (2019) Hepatocyte-specific HIF-1alpha ablation improves obesity-induced glucose intolerance by reducing first-pass GLP-1 degradation. Sci Adv 5(7):eaaw4176 |
| abstractText | 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, we found that liver HIF-1alpha expression was increased mainly by soluble factors released from obese adipocytes, leading to decreased incretin effects. Deletion of hepatocyte HIF-1alpha protected obesity-induced glucose intolerance without changes in body weight, liver steatosis, or insulin resistance. 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. Hepatocyte HIF-1alpha KO blocked these changes induced by obesity. Deletion of hepatocyte HIF-2alpha 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. |
