Adipose tissue‐specific disruption of the BBSome cause insulin resistance

Abstract

The BBSome is a protein complex composed of 8 Bardet‐Biedl syndrome (BBS) proteins including BBS1. Patients carrying mutations in any of the BBS genes display several features including obesity and type 2 diabetes mellitus. We previously demonstrated that the BBSome is required for membrane localization of the insulin receptor. We also showed that mice lacking several Bbs genes developed obesity associated with increased blood glucose, impaired glucose clearance and insulin resistance. However, the role and contribution of Bbs genes in insulin‐sensitive tissues such as adipose tissue for the development of obesity and diabetes remains unclear. To address this, we used a new conditional knockout mouse where exon 3 of the Bbs1 gene is floxed (Bbs1flox). Cre‐mediated recombination causes a frame shift resulting in a premature stop. We assessed whether deletion of the Bbs1 gene in adipocytes (by breeding Bbs1flox mice with AdiponectinCre mice) affects glucose homeostasis. Interestingly, no obesity phenotype was observed in both male and female AdipoCre/Bbs1flox mice fed either normal chow or high fat diet (45%), suggesting that development of obesity in BBS is not due to defects in adipose tissue. White fat adipose (WAT) cell size was similar between AdipoCre/Bbs1flox mice and control animals. However, mRNA and protein expression of PPARg was significantly decreased in WAT of AdipoCre/Bbs1flox mice compared to control animals (48%± 5% for mRNA and 47%± 14% for protein, respectively). In addition, fat acid synthetase (FAS) mRNA was reduced in WAT of AdipoCre/Bbs1flox mice relative to controls (34%± 10% vs control. Insulin‐induced activation of AKT was significantly decreased in the WAT, but not in the liver and skeletal muscle of AdipoCre/Bbs1flox mice versus control animals. Finally, fasting glucose level was similar between AdipoCre/Bbs1flox mice and control animals, and glucose tolerance test revealed no difference between AdipoCre/Bbs1flox mice and controls. However, insulin tolerance test uncovered impaired insulin‐induced glucose clearance in AdipoCre/Bbs1flox mice. These findings demonstrate the importance of the adipocyte BBSome for insulin sensitivity and glucose homeostasis.