Weight loss after AT1-blockade is correlated to a downregulation of orexigenic peptides in the hypothalamus

W. Raasch; A. Markert; C. Wittmershaus; P. Dominiak; O. Jöhren

doi:10.1055/s-2006-932869

Experimental and Clinical Endocrinology & Diabetes, Table of Contents

Weight loss after AT1-blockade is correlated to a downregulation of orexigenic peptides in the hypothalamus

W Raasch ¹, A Markert ¹, C Wittmershaus ¹, P Dominiak ¹, O Jöhren ¹

¹Institute of Pharmacology, University Clinic Schleswig Holstein, Campus Lübeck, Lübeck, Germany

Abstract

Objectives: Angiotensin II has been reported to lower bodyweight, an effect, that is attributed to peripheral mechanisms e.g. lipolysis, reduction of body fat and thermogenesis as well as an increase in sympathetic activity. In contrast, it has recently been demonstrated, that weight loss was even observed after treating rats with AT₁-blockers. Thus, the aim of our study was to investigate, whether weight loss might be associated with a regulation of orexigenic peptides (orexin; NPY; MCH: melanin concentrating hormone; AgRP: agouti-related protein) or anorexigenic peptides (POMC: pro-opiomelanocortin; CRH: corticotropin-releasing hormone; CART: cocaine- and amphetamine-regulated transcript) in the hypothalamus.

Methods: Spontaneously hypertensive rats were treated for a period of 4 weeks with candesartan (CAND; 0, 2, 6 or 16mg/kg). mRNA levels of peptides were determined by real time PCR.

Results: Efficacy of treatment was verified by a dose-dependent antihypertensive effect (21%, 30% and 51%, respectively). Only after 16mg CAND, bodyweight and body mass index were lessened (each 6%), which was paralleled by a decrease in food intake (18%). Plasma glucose and insulin were unaffected. After 16mg CAND, hypothalamic mRNA levels of MCH (51%) and orexin (62%), but not of NPY and AgRP, were reduced. Less CAND was not effective. None of the anorexigenic peptides (POMC, CRH or CART) were influenced by CAND at each dose. Plasma leptin tends to be reduced after 16mg CAND, showing a) a negative correlation between gain in bodyweight and plasma leptin and b) a positive correlation between leptin in plasma and fat.

Conclusions: We conclude, that weight loss and decrease in food intake after an effective AT₁-receptor blockade have mainly to be attributed to a down regulation of orexigenic peptides in the hypothalamus. The fact, that plasma leptin is rather decreased than increased indicates, that modulation of leptin occurs secondary as a result of the reduction in body weight and body fat and seems not to be the underlying mechanism.