Impaired Glucose Homeostasis in Mice Lacking the α1b-Adrenergic Receptor Subtype

Rémy Burcelin,Marc Uldry,Marc Foretz,Christophe Perrin,Anabela Dacosta,Monique Nenniger-Tosato,Josiane Seydoux,Susanna Cotecchia,Bernard Thorens

doi:10.1074/jbc.m307788200

Abstract

To assess the role of the alpha1b-adrenergic receptor (AR) in glucose homeostasis, we investigated glucose metabolism in knockout mice deficient of this receptor subtype (alpha1b-AR-/-). Mutant mice had normal blood glucose and insulin levels, but elevated leptin concentrations in the fed state. During the transition to fasting, glucose and insulin blood concentrations remained markedly elevated for at least 6 h and returned to control levels after 24 h whereas leptin levels remained high at all times. Hyperinsulinemia in the post-absorptive phase was normalized by atropine or methylatropine indicating an elevated parasympathetic activity on the pancreatic beta cells, which was associated with increased levels of hypothalamic NPY mRNA. Euglycemic clamps at both low and high insulin infusion rates revealed whole body insulin resistance with reduced muscle glycogen synthesis and impaired suppression of endogenous glucose production at the low insulin infusion rate. The liver glycogen stores were 2-fold higher in the fed state in the alpha1b-AR-/- compared with control mice, but were mobilized at the same rate during the fed to fast transition or following glucagon injections. Finally, high fat feeding for one month increased glucose intolerance and body weight in the alpha1b-AR-/-, but not in control mice. Altogether, our results indicate that in the absence of the alpha1b-AR the expression of hypotalamic NPY and the parasympathetic nervous activity are both increased resulting in hyperinsulinemia and insulin resistance as well as favoring obesity and glucose intolerance development during high fat feeding.

Highlights

To assess the role of the ␣1b-adrenergic receptor (AR) in glucose homeostasis, we investigated glucose metabolism in knockout mice deficient of this receptor subtype (␣1b-AR؊/؊)
Blood glucose levels were similar in control and ␣1b-ARϪ/Ϫ mice (Fig. 1A), they remained significantly higher in the ␣1bARϪ/Ϫ mice during the first six hours of fasting but eventually returned to the level of the control mice after 24 h of fasting
The high leptin levels in mutant mice could in part be explained by an elevated total body fat content, which was increased by ϳ60% (5.33 Ϯ 0.76 g versus 3.34 Ϯ 0.40 g in mutant and control mice, respectively), even though body weights were similar (34.5 Ϯ 1.0 g versus 34.0 Ϯ 1.3 g for mutant and control mice, respectively)

Summary

Introduction

To assess the role of the ␣1b-adrenergic receptor (AR) in glucose homeostasis, we investigated glucose metabolism in knockout mice deficient of this receptor subtype (␣1b-AR؊/؊). The ␣1b-AR has been mapped to different brain regions, including several hypothalamic nuclei, in particular the arcuate nucleus, the paraventricular and lateral hypothalamic nuclei as well as in the brain stem (in the nucleus of the tractus solitarius) (2) These brain structures control several important homeostatic functions such as insulin and glucagon secretion, glucose utilization or production, energy expenditure, and food intake. In addition to their sensitivity to catecholamines (14), these central regions, in particular the arcuate nucleus and the nucleus of the tractus solitarius, are regulated by peripheral signals such as insulin, leptin, and glucose levels (15–18).

Methods

Results

Conclusion