Long-term central infusion of adiponectin improves energy and glucose homeostasis by decreasing fat storage and suppressing hepatic gluconeogenesis without changing food intake.

摘要

Adiponectin is known to be an anti-diabetic adipocytokine. However, the action mechanism by which it produces this effect remains controversial. In the present study, we investigated the long-term central effect of adiponectin on energy homeostasis, peripheral insulin resistance, beta-cell function and mass in rats and aimed to determine the mechanism by which its effect was achieved. Intracerebroventricular infusion of adiponectin (50 ng/h) and artificial cerebrospinal fluid (CSF) was conducted by means of an osmotic pump for 4 weeks on nondiabetic rats and 90% pancreatectomised diabetic rats that were both fed 45% energy fat diets. After 4-weeks of treatment, i.c.v. adiponectin improved hypothalamic insulin/leptin signalling in nondiabetic and diabetic rats compared to i.c.v. CSF but it did not change the phosphorylation of AMP kinase (AMPK) in the hypothalamus. Adiponectin infusion decreased epididymal fats, representing visceral fat, by increasing energy expenditure and fat oxidation. During the euglycaemic hyperinsulinaemic clamp, i.c.v. adiponectin improved whole body insulin sensitivity and decreased hepatic glucose output in the hyperinsulinaemic state by attenuating hepatic insulin resistance. Central infusion of adiponectin did not modulate glucose-stimulated insulin secretion during the hyperglycaemic clamp compared to i.c.v. CSF infusion but it enhanced insulin sensitivity at a hyperglycaemic state. Although there were no changes in insulin secretion capacity, central adiponectin increased pancreatic beta-cell mass in nondiabetic and diabetic rats as a result of decreasing beta-cell death. In conclusion, long-term central infusion of adiponectin enhanced energy homeostasis by increasing energy expenditure via activating hypothalamic leptin and insulin signalling pathways but without potentiating AMPK signalling; it also improved glucose homeostasis by attenuating insulin resistance.