To dissect the mechanisms involved in the metabolic disorders associated with BBS, we assessed the development of obesity in multiple BBS mouse models developed in our laboratory. We found that BBS mice are hyperphagic, have low motor activity, and elevated circulating levels of leptin. The effect of exogenous leptin on body weight and food intake is attenuated in BBS mice, suggesting that leptin resistance contributes to hyperleptinemia and obesity in these mice. Although all BBS mouse models were resistant to the anorectic effects of leptin, the sensitivity of renal SNA to leptin was maintained in Bbs4–/– and Bbs6–/– mice, but not in Bbs2–/– mice. Consequently, Bbs4–/– and Bbs6–/– mice had higher baseline renal SNA and arterial pressure. Furthermore, we found that BBS mice have a decreased hypothalamic expression of proopiomelanocortin, which suggests that BBS genes play an important role in maintaining leptin sensitivity in proopiomelanocortin neurons. This work was the first to demonstrate a role for BBS proteins in leptin signaling. In subsequent work, we studied the mechanism of leptin resistance in BBS mice by normalizing their body weights and circulating leptin levels by calorie-restriction. Despite attaining normal serum leptin levels, direct central administration of leptin fails to reduce food intake or activate hypothalamic leptin receptor (LepR) signaling (e.g. STAT3). These data demonstrate that BBS mice are leptin resistant. We also demonstrate that BBS proteins are required for LepR signaling in the hypothalamus. Of note, we found that the BBS1 protein physically interacts with the LepR and that loss of BBS proteins perturbs LepR trafficking. Our data indicate that BBS proteins mediate LepR trafficking and signaling. These findings represent a novel mechanism for leptin resistance and obesity. In subsequent work, we identify a potential pharmacologic treatment for BBS associated obesity.

This work was published in J Clin Invest 118(4):1458-1467.