Metabolic Consequences of Skeletal Muscle- and Liver-specific BBSome Deficiency

The BBSome is a protein complex composed of eight Bardet-Biedl syndrome (BBS) proteins including BBS1. Humans and mice lacking a functional BBSome display obesity and type 2 diabetes, highlighting the importance of this protein complex for metabolic regulation. However, the contribution of the BBSome in insulin-sensitive tissues such as skeletal muscle and liver to metabolic regulation is ill-defined. Here, we show that disruption of the BBSome through gene deletion in the skeletal muscle had no effect on body weight or glucose handling, but improved insulin sensitivity of female mice without changing insulin receptor signaling. Interestingly, when fed an obesogenic diet, male mice lacking the gene in skeletal muscle exhibited heightened insulin sensitivity despite the comparable weight gain and glucose tolerance relative to controls. On the other hand, normal chow-fed mice missing the gene in hepatocytes displayed increased body weight, as well as impaired glucose handling and insulin sensitivity. This was associated with attenuated insulin signaling in liver and hepatocytes, but not skeletal muscle and white adipose tissue. Moreover, hepatocytes lacking the gene displayed significant reduction in plasma membrane insulin receptor levels due to the mitochondrial dysfunction evoked by loss of the BBSome. Together, these findings demonstrate that myocyte BBSome is minimally involved in metabolic regulation, whereas the hepatic BBSome plays a critical role in the control of energy homeostasis and insulin sensitivity through its requirement for insulin receptor trafficking. The ongoing epidemic of obesity and associated illnesses highlights the need to understand the biological processes that regulate energy balance. Here, we identified an important role for a protein complex called BBSome in the control of hepatic function. We show that the liver BBSome is necessary to maintain body weight and blood glucose levels due to its requirements to generate energy and detect insulin, a hormone that is essential for metabolic regulation.