Leptin reverses hyperglycemia and hyperphagia in insulin deficient diabetic rats by pituitary-independent central nervous system actions.

Alexandre A Da Silva,Jussara M Do Carmo,John E Hall,M Faadiel Essop

doi:10.1371/journal.pone.0184805

Abstract

The hypothalamic-pituitary-adrenal (HPA) axis has been postulated to play a major role in mediating the antidiabetic effects of leptin. We tested if the pituitary is essential for the chronic central nervous system mediated actions of leptin on metabolic and cardiovascular function in insulin-dependent diabetic and non-diabetic rats. Male 12-week-old hypophysectomized Sprague-Dawley rats (Hypo, n = 5) were instrumented with telemetry probes for determination of mean arterial pressure (MAP) and heart rate (HR) 24-hrs/day and an intracerebroventricular (ICV) cannula was placed into the brain lateral ventricle for continuous leptin infusion. In additional groups of Hypo and control rats (n = 5/group), diabetes was induced by single injection of streptozotocin (50 mg/kg, IP). Hypo rats were lighter, had lower MAP and HR (83±4 and 317±2 vs 105±4 mmHg and 339±4 bpm), with similar caloric intake per kilogram of body weight and fasting plasma glucose levels (84±4 vs 80±4 mg/dl) compared to controls. Chronic ICV leptin infusion (7 days, 0.62 μg/hr) in non-diabetic rats reduced caloric intake and body weight (-10%) in Hypo and control rats and markedly increased HR in control rats (~25 bpm) while causing only modest HR increases in Hypo rats (8 bpm). In diabetic Hypo and control rats, leptin infusion reduced caloric intake, body weight and glucose levels (323±74 to 99±20 and 374±27 to 108±10 mg/dl), respectively; however, the effects of leptin on HR were abolished in Hypo rats. These results indicate that hypophysectomy attenuates leptin’s effect on HR regulation without altering leptin’s ability to suppress appetite or normalize glucose levels in diabetes.

Highlights

Leptin, a peptide hormone produced by adipose tissue in proportion to the amount of body fat mass, acts in the central nervous system (CNS) to reduce appetite while increasing energy expenditure, sympathetic nerve activity (SNA), and blood pressure (BP) [1,2,3]
Despite similar caloric intake when corrected by body weight (Fig 1A) and baseline blood glucose levels (Fig 1B), non-diabetic hypophysectomized rats had reduced body weight (215±4 vs. 415 ±6 g), plasma leptin levels (4.0±0.3 vs. 1.8±0.2 ng/ml), and plasma insulin levels (Fig 1C) compared to control rats
Age-matched rats were used in these experiments and the difference in body weight was likely due to the absence of the pituitary gland leading to markedly reductions of growth hormones and smaller weight gain in hypophysectomized group

Summary

Introduction

A peptide hormone produced by adipose tissue in proportion to the amount of body fat mass, acts in the central nervous system (CNS) to reduce appetite while increasing energy expenditure, sympathetic nerve activity (SNA), and blood pressure (BP) [1,2,3].

Methods

Results

Conclusion