Expression of human α2-adrenergic receptors in adipose tissue of β3-adrenergic receptor-deficient mice promotes diet-induced obesity

Catecholamines play an important role in controlling white adipose tissue function and development. beta- and alpha2-adrenergic receptors (ARs) couple positively and negatively, respectively, to adenylyl cyclase and are coexpressed in human adipocytes. Previous studies have demonstrated increased adipocyte alpha2/beta -AR balance in obesity, and it has been proposed that increased alpha2-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 alpha2/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 beta3-AR allele. Mice expressing alpha2-ARs in fat, in the absence of beta3-ARs (beta3-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 beta3-ARs, and a high fat diet. Of note, obese alpha2-transgenic, beta3 (-/-) 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 alpha2/beta -AR balance in adipocytes promotes obesity by stimulating adipocyte hyperplasia. This study also demonstrates one way in which two genes (alpha2 and beta3-AR) and diet interact to influence fat mass.