Morbid obesity-1 (MO-1): Linkage, identification and characterization of a novel obesity gene

Obesity is a complex disease with a strong genetic component. It represents a serious global health problem with far-reaching socioeconomic implications. Although genes that contribute to its pathogenesis remain mostly unknown, efforts are currently underway to identify these genetic contributors. In this study, we identify and describe a large, multigenerational family with a novel autosomal recessive form of morbid obesity with comorbid features of diabetes, heart disease and hypertension. We link the disease trait to chromosome 3q29 and identify a novel, highly conserved, mitochondrial protein, morbid obesity-1 (MO-1). Affected individuals harbor a homozygous nonsense mutation, R82X, which results in premature truncation and eventual degradation of the mutant protein. MO-1 expression is ubiquitous and is regulated in response to glucose and insulin. Furthermore, its expression is differentially regulated during adipogenesis. Altering expression of MO-1, whose sequence shows homology to PEPC and PEPCK, enzymes critical to glucose production, affects both intracellular glucose levels and cellular proliferation. Targeted inhibition results in delayed adipogenic differentiation and increased hepatic glucose uptake highlighting its effects on metabolic pathways relevant to the development of obesity. Finally, MO1-deficient cells produce increased levels of H2O 2 and exhibit increased activation of the Akt-mediated PI3-kinase pathway. Taken together, these results demonstrate that MO-1 is an evolutionarily conserved biologically active protein that is able to affect obesity-relevant phenotypes possibly through ROS-mediated activation of the Akt-mediated PI3-kinase pathway representing a novel link to the pathogenesis of obesity.