Expression of human alpha 2-adrenergic receptors in adipose tissue of beta3-adrenergic receptor-deficient mice promotes diet-induced obesity

Catecholamines play an important role in controlling white adipose tissue f unction and development. beta- and alpha2-adrenergic receptors (ARs) couple positively and negatively, respectively, to adenylyl cyclase and are coexp ressed in human adipocytes. Previous studies have demonstrated increased ad ipocyte alpha2/beta -AR balance in obesity, and it has been proposed that i ncreased alpha2-ARs in adipose tissue with or without decreased beta -ARs m ay contribute mechanistically to the development of increased fat mass. To critically test this hypothesis, adipocyte alpha2/beta -AR balance was gene tically manipulated in mice. Human alpha 2A-ARs were transgenically express ed in the adipose tissue of mice that were either homozygous (-/-) or heter ozygous (+/-) for a disrupted beta3-AR allele. Mice expressing alpha2-ARs i n fat, in the absence of beta3-ARs (beta3-AR (-/-) background), developed h igh fat diet-induced obesity. Strikingly, this effect was due entirely to a dipocyte hyperplasia and required the presence of alpha2-ARs, the absence o f 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 h ypertrophy. In summary, we have demonstrated that increased alpha2/beta -AR balance in adipocytes promotes obesity by stimulating adipocyte hyperplasi a. This study also demonstrates one way in which two genes (alpha2 and beta 3-AR) and diet interact to influence fat mass.