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mTORC1 is Involved in the Regulation of Bardet‐Biedl Syndrome 1 (BBS1) Gene Expression

The high prevalence of obesity is associated with increased health risks such as cardiovascular disease and diabetes. A combination of genetic and environmental factors such as availability of nutrition‐rich food contributes to the epidemic of obesity. Recent studies from our group have demonstrated the importance of hypothalamic BBS genes and the BBSome for the regulation of energy homeostasis. We hypothesized that regulation of BBS genes in the hypothalamus may be altered in diet‐induced obese mice. To test this, we investigated the expression of different BBS genes in the hypothalamus of mice fed with normal diet (ND) or 60% high fat diet (HFD) for 36 weeks. Expression of Bbs1 gene, but not Bbs2, Bbs4, Bbs5, Bbs6, Bbs7, Bbs8 and Bbs9, was significantly decreased in the hypothalamus of HFD fed mice vs. to mice fed ND, by qRT‐PCR (n=6 each, p<0.05). Additionally, we found that Bbs1 gene expression was significantly down‐regulated in the hypothalamus of mice fasted for 16 hrs compared to non‐fasted mice (n=6 each, p<0.05). To gain mechanistic insights, we used mouse hypothalamic GT1‐7 cells. Interestingly, we found that exposing GT1‐7 cells to nutrients (leucine (10 mM) or glucose (4.5 g/dl)), but not insulin (10 nM) for 16 hrs significantly decreased Bbs1 expression (n=3, p<0.05). Furthermore, intracerebroventricular injection of leucine (4 μg) decreased Bbs1 expression in the hypothalamus (n=3, p=0.053). Inhibition of the nutrient sensor, mTOR complex 1 (mTORC1) with rapamycin (100 nM) restored Bbs1 expression in GT1‐7 cells treated with leucine, implicating the mTORC1 pathway in the regulation of Bbs1 gene expression in GT1‐7 cells. Given that mTORC1 interacts with IKKα/β, we then tested IKK inhibition with BMS 345541 (500 nM). We found that this also restored Bbs1 gene expression in GT1‐7 cells treated with leucine. In contrast, NFkB p65 inhibition (NBP2‐29321, 25 mM) did not alter leucine‐induced down‐regulation of Bbs1 expression in GT1‐7 cells. We conclude that overnutrition‐induced decrease in hypothalamic Bbs1 gene expression may impair the BBSome function leading to the development of obesity.