Oral Metformin Treatment Counteracts Adipoinsular Axis Dysfunction in Hypothalamic Obese Rats.

Daniel Castrogiovanni,Eduardo Spinedi,Andrés Giovambattista,Guillermina Zuburía,Luisina Ongaro

doi:10.1155/2015/284042

Abstract

Rats neonatally treated with monosodium L-glutamate (MSG) are deeply dysfunctional in adulthood. We explored the effect of an oral low dose of metformin treatment in male MSG rats on adipoinsular axis and visceral adipose tissue (VAT) dysfunctions, in both basal (nonfasting) and endotoxemia conditions. MSG rats, treated or not treated with metformin (30 days prior to experimentation), and control litter-mates (CTR) were studied at 90 days of age. Peripheral concentrations of glucose, lipids, and hormones were determined in basal and post-lipopolysaccharide (LPS) treatment conditions. Food intake and body weight (BW) were recorded and VAT mass and leptin mRNA levels were evaluated. Data indicated that MSG rats were lighter and displayed hypercorticosteronemia, hypophagia, adipoinsular axis hyperactivity, and enhanced VAT mass associated with an increased leptin gene expression. Interestingly, metformin-treated MSG rats corrected BW catch-up and counteracted VAT (mass and leptin mRNA level) and adipoinsular axis (basal and post-LPS) dysfunctions. Thus metformin treatment in MSG rats is able to correct several VAT and metabolic-endocrine dysfunctions. Our study suggests that a low-dose metformintherapy is effective to correct, at least in part, adipoinsular axis dysfunction in hypertrophic obese phenotypes, such as that of the human Cushing syndrome.

Highlights

Neonatal monosodium L-glutamate (MSG) administration induces morphological, behavioral, and neuroendocrine abnormalities such as growth disturbances, self-mutilation, hyperadiposity, and hypogonadism [1,2,3,4]
Our study indicates that MSG-induced neonatal hypothalamic damage resulted in the alteration of endocrine-metabolic function at the adult age and, importantly, that this multidysfunction can be improved by the treatment with a very low dose of metformin
It should be stressed that several dysfunctions in the adult male MSG rat, a phenotype of hypothalamic obesity, have been extensively revisited [1,2,3,4,5,6,7,8,9,10,11,12,13], only few studies have been focused on the metabolic improvement induced by metformin treatment in these animals

Summary

Introduction

Neonatal monosodium L-glutamate (MSG) administration induces morphological, behavioral, and neuroendocrine abnormalities such as growth disturbances, self-mutilation, hyperadiposity, and hypogonadism [1,2,3,4]. A conspicuous effect of MSG-induced hypothalamic damage is an overall enhanced response of median eminence (ME) neuron terminals [10,11,12]. Acute inflammatory stress affects anterior pituitary hormone secretion by mechanisms involving different hypothalamic neuronal systems [17,18,19,20,21], already altered in the MSG animal model [4,5,6]. The ARC is a pivotal structure involved in the regulation of energy storage and expenditure [22], and both adipose tissue leptin secretion and hypothalamic leptin signaling system play key roles in maintaining homeostasis [22]. MSG rats are partly refractory to leptin inhibition of food intake and body weight gain [25], and overall leptin resistance seems to be directly dependent on enhanced glucocorticoid production [13, 26]

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Results

Conclusion