OBESE (OB) GENE DEFECTS ARE RARE IN HUMAN OBESITY

Our knowledge of the role of the recently cloned ob-protein (leptin) i n the regulation of body fat stores is largely derived from experiment s performed in mice. Different mouse models exhibit abnormalities in o b-gene expression, with extreme overexpression in mice which lack bioa ctive ob-protein, have nonfunctional ob-receptors or hypothalamic lesi ons, and undetectable expression in mice with suggested defects in reg ulatory elements. The aim of this study is to examine if defects, corr esponding to those in mice, exist in human obesity. Adipose tissue was obtained from 94 adult obese subjects and from six children who had d eveloped obesity after surgery in the hypothalamic region. Total RNA w as isolated and ob-gene expression was examined by reverse transcripta se-polymerase chain reaction (RT-PCR) and Northern blot. The coding re gion of the ob-gene was sequenced in both directions in the 94 obese a dults. No mutations were detected in the coding region of the ob-gene and ob-gene expression was detectable in all subjects and none of the subjects had an extreme overexpression. There was no systematic increa se in ob-expression in obese children with hypothalamic disease compar ed to their healthy brothers and sisters. These results show that seve re abnormalities involving the ob-gene, analogous to those described i n mouse models, are rare in human obesity. We therefore conclude that the cloning and subsequent analysis of the ob-gene has not provided in formation that can, by itself, explain the genetic component in the de velopment of human obesity.