抄録
Background: Hypothalamus coordinates whole-body energy and glucose homeostasis. In particular, hypothalamic orexin system plays a major role in the daily regulation of inter-organ networks for energy/glucose metabolism. Orexin deficiency causes age-related development of insulin resistance in mice. However, functional significance of the orexin system under the conditions of obesity remains unclear. Therefore, we investigated whether orexin prevents metabolic disorders under the diet-induced obese conditions.
Methods: Male and female orexin knockout (ORXKO) mice, ovariectomized (OVX) ORXKO mice, and their wild-type (WT) controls were fed a high fat diet (HFD) for 16-24 weeks. Beta-estradiol (E2) and orexin A were intracerebroventricularly (ICV) injected to HFD-fed OVX mice and type 2 diabetic db/db mice, respectively. Glucose tolerance test, metabolic cage analysis, and biochemical analyses were performed.
Results: On HFD, male ORXKO mice showed severe obesity mainly due to reduced locomotor activity and severely impaired glucose tolerance, when compared to WT controls. In the liver of HFD-fed ORXKO males, tissue weight and the levels of markers for chronic inflammation and fibrosis (e.g., Tnf-alpha and Tgf-beta mRNAs) were remarkably increased. In females, HFD feeding had negligible or solely minor/mild impacts on these metabolic parameters in WT and OVX-WT mice. In contrast, the levels of proinflammatory markers were markedly increased in the white adipose tissues of HFD-fed ORXKO females, and the levels were further increased by ovariectomy (i.e., in OVX-ORXKO mice). Sirius-red staining of the liver sections demonstrated obvious hepatic fibrosis in OVX-ORXKO mice. ICV injection of E2 improved glucose tolerance in OVX-WT but not OVX-ORXKO mice. ICV injection of orexin A reduced the levels of proinflammatory markers in white adipose tissues in db/db mice. These results indicate that orexin plays fundamental roles in preventing obesity-related disorders, including non-alcoholic fatty liver disease in both sexes, and that orexin enhances the metabolic functions of estrogen especially in females.
Conclusion: Pharmacological intervention targeting the orexin system is a valuable therapeutic approach to prevent metabolic disorders in obesity and type 2 diabetes.
