Expression of Human α2-Adrenergic Receptors in Adipose Tissue of β3-Adrenergic Receptor-deficient Mice Promotes Diet-induced Obesity

Philippe Valet,Danica Grujic,Jennifer Wade,Moriko Ito,M Cristina Zingaretti,Veronika Soloveva,Susan R Ross,Reed A Graves,Saverio Cinti,Max Lafontan,Bradford B Lowell

doi:10.1074/jbc.m005210200

Abstract

Catecholamines play an important role in controlling white adipose tissue function and development. beta- and alpha 2-adrenergic receptors (ARs) couple positively and negatively, respectively, to adenylyl cyclase and are co-expressed in human adipocytes. Previous studies have demonstrated increased adipocyte alpha 2/beta-AR balance in obesity, and it has been proposed that increased alpha 2-ARs in adipose tissue with or without decreased beta-ARs may contribute mechanistically to the development of increased fat mass. To critically test this hypothesis, adipocyte alpha 2/beta-AR balance was genetically manipulated in mice. Human alpha 2A-ARs were transgenically expressed in the adipose tissue of mice that were either homozygous (-/-) or heterozygous (+/-) for a disrupted beta 3-AR allele. Mice expressing alpha 2-ARs in fat, in the absence of beta 3-ARs (beta 3-AR -/- background), developed high fat diet-induced obesity. Strikingly, this effect was due entirely to adipocyte hyperplasia and required the presence of alpha2-ARs, the absence of beta 3-ARs, and a high fat diet. Of note, obese alpha 2-transgenic beta 3 -/- mice failed to develop insulin resistance, which may reflect the fact that expanded fat mass was due to adipocyte hyperplasia and not adipocyte hypertrophy. In summary, we have demonstrated that increased alpha 2/beta-AR balance in adipocytes promotes obesity by stimulating adipocyte hyperplasia. This study also demonstrates one way in which two genes (alpha 2 and beta 3-AR) and diet interact to influence fat mass.

Highlights

Catecholamines play an important role in controlling white adipose tissue function and development. ␤- and ␣2-adrenergic receptors (ARs) couple positively and negatively, respectively, to adenylyl cyclase and are coexpressed in human adipocytes
We hypothesized that the absence of an effect of ␣2ARs on fat stores was due to the presence of abundant ␤3-ARs, which along with ␤1- and ␤2-ARs override the inhibitory actions of transgenically expressed ␣2-ARs
It is important to note that the number of ␤1/␤2-ARs (91.6 Ϯ 4.0 fmol/mg of protein; n ϭ 5) observed in adipocytes of ␣2-trans, ␤3 Ϫ/Ϫ mice was not different from that found in adipocytes of ␤3 Ϫ/Ϫ mice (102.7 Ϯ 7.5 fmol/mg of protein; n ϭ 3) and was within the range of ␤-AR binding sites typically observed in human fat cells [23]

Summary

Introduction

Catecholamines play an important role in controlling white adipose tissue function and development. ␤- and ␣2-adrenergic receptors (ARs) couple positively and negatively, respectively, to adenylyl cyclase and are coexpressed in human adipocytes. Previous studies have demonstrated increased adipocyte ␣2/␤-AR balance in obesity, and it has been proposed that increased ␣2-ARs in adipose tissue with or without decreased ␤-ARs may contribute mechanistically to the development of increased fat mass. To critically test this hypothesis, adipocyte ␣2/␤-AR balance was genetically manipulated in mice. Human ␣2A-ARs were transgenically expressed in the adipose tissue of mice that were either homozygous (؊/؊) or heterozygous (؉/؊) for a disrupted ␤3-AR allele. Mice with increased ␣2/␤-AR balance developed diet-induced obesity secondary to adipocyte hyperplasia These results strongly suggest that ␣2/␤-AR balance plays an important role in regulating fat mass

Methods

Results

Conclusion