Hypothalamic Orexin Is Essential for Estrogenic Action on Glucose and Energy Metabolism in Diet-Induced Obese Mice

Abstract

Decreased estrogen is a crucial pathogenic factor for type 2 diabetes in postmenopausal women; however, the precise mechanism remains unknown. Orexin is a major hypothalamic neuropeptides regulating energy/glucose metabolism, and its anti-obese effect is more evident in females. We therefore investigated whether estrogen prevents obesity and glucose intolerance through interaction with the orexin system. Ovariectomized (OVX) mice and female orexin knockout (OXKO) mice were prepared to examine the impact of estrogen and orexin deficiency, respectively. When maintained on 60% high fat diet (HFD) for 16-24 weeks, body weight gain, adipose tissue inflammation, and hepatic triglyceride contents were markedly increased in OXKO, compared to wild type (WT) mice. Ovariectomy did not significantly affect the body weight in WT and OXKO mice after prolonged HFD feeding. Importantly, the levels of proinflammatory markers (e.g., TNFα mRNA) in the white adipose tissues were increased mildly in sham-operated OXKO (Sham-OXKO) mice and remarkably in OVX-OXKO mice. The rank order of the severity was OVX-OXKO>Sham-OXKO>OVX-WT>Sham-WT. Moreover, Sirius-Red staining to evaluate the fatty liver disease (i.e., NAFLD/NASH) demonstrated mild and severe fibrosis in the liver of Sham-OXKO and OVX-OXKO mice, respectively, whereas there was no abnormality in OVX-WT and Sham-WT mice. In glucose tolerance test, 1) metabolic activity was greater in Sham-WT than OVX-WT mice, whereas no difference was observed between Sham-OXKO and OVX-OXKO mice on HFD, 2) intracerebroventricular injection of estrogen improved glucose tolerance in OVX-WT but not OVX-OXKO mice on HFD, suggesting that estrogen prevents glucose intolerance on HFD in an orexin-dependent manner. Taken together, orexin may play a fundamental role in the anti-obese and antidiabetic effects of estrogen. Therefore, orexin appears to be a novel therapeutic target to prevent metabolic disorders in postmenopausal women. Disclosure K. Kon: None. H. Tsuneki: None. S. Takata: None. T. Maeda: None. T. Wada: Research Support; Self; Sanwa Kagaku Kenkyusho Co., Ltd.. T. Sasaoka: None.