Bbs1 gene deletion from the leptin receptor‐containing neurons causes obesity (1126.10)

Abstract

Bardet‐Biedl syndrome (BBS) is a pleiotropic autosomal recessive disorder with several features including obesity. Systemic knock‐out mice lacking expression of Bbs2, Bbs4 and Bbs6, or Bbs1M390R knock‐in, recapitulated many BBS phenotypes including obesity. However, the role and contribution of Bbs genes in different tissues to obesity remains unclear. To address this, we generated a new conditional knockout mouse where exon 3 of the Bbs1 gene is floxed. Cre‐mediated recombination causes a frame shift resulting in a premature stop. We assessed whether deletion of the Bbs1 gene in the leptin receptor neurons (LRb) affects body weight. Importantly, Bbs1flox/LRbCre mice display an obesity phenotype as indicated by the increased body weight and fat mass measured by MRI. We found that the obesity phenotype in Bbs1flox/LRbCre mice is due to both an increase in food intake and reduction in energy expenditure as indicated by the decreased O2 consumption and heat production. These results indicate that hyperphagia and low metabolic rate explain the development of obesity in Bbs1flox/LRbCre mice. Finally, in HEK 293 cells, silencing Bbs1 or Bbs2 genes significantly decreased LRb, but not LRa or transferrin receptor, trafficking to the plasma membrane highlighting the important role of Bbs gene in the regulation of LRb signaling. These findings demonstrate that Bbs genes are critical for energy homeostasis.Grant Funding Source: NIH and AHA