Unraveling Molecular and Metabolic Gut-Brain Signalling Disruptions and Potential Therapy in New Bardet-Biedl Syndrome Mouse.

Obesity is a cardinal feature of Bardet-Biedl syndrome (BBS), a syndromic ciliopathy caused by mutations in genes for BBS 1-21. BBS proteins control the function of primary cilia that act as a sensory antenna on virtually all mammalian cells. The mechanisms of BBS-induced obesity remain poorly understood, resulting in a lack of therapeutic options for these patients. The overarching goal of the study was to define underlying mechanisms involved in the pathogenesis of BBS-induced obesity and use this knowledge to identify novel therapeutic targets. Given the importance of cilia in interoceptive and homeostatic sensing, we hypothesized that disruption of cilia function by BBS mutation would impair negative feedback resulting in a proinflammatory microenvironment in adipose tissue and disruption of neuroendocrine control of feeding in hypothalamus. In this study, we first characterized the metabolic phenotype of a novel BBS5 knockout mouse (BBS5-/-; n=6-12/strain/gender). Next, we performed immunophenotyping of adipocytes and unbiased RNA sequencing of the hypothalamus of BBS5-/- and WT mice. To validate the predictions from transcriptomic data, we performed pharmacological-based feeding experiments and tested a putative therapeutic for BBS-induced obesity. We found that BBS5-/- mice exhibits all the classic symptoms observed in human patients with BBS, including hyperphagia, cognitive impairments, glucose, and insulin intolerance, and 3 to 4-fold increased fat mass on chow diet compared to wildtype mice (p<0.001). BBS5-/- mice had increased proinflammatory M1 macrophages and decreased functional regulatory T-cells in adipocytes suggesting that extrinsic factors promote fat mass gain. Pathway analysis of the transcriptomics data revealed altered endocrine receptor signaling in the hypothalamus of BBS5-/- mice. Feeding experiments confirmed the development of both leptin and cholecystokinin resistance independent of body weight (p>0.05). The receptor for glucagon-like-peptide-1 (GLP1) was found to be upregulated in the hypothalamus of BBS5-/- mice (p<0.001). Chronic daily pharmacological administration of GLP1 receptor agonist (Semaglutide) for two weeks significantly reduced food intake, body weight, elevated glucose levels, and fat mass (p<0.001). In conclusion, BBS5-/- mice are a valuable new translational tool to elucidate interoceptive and homeostatic gut-brain axis alterations in BBS-induced obesity. We identify adipose inflammation, and impaired hypothalamic leptin, insulin, and cholecystokinin signalling as underlying mechanisms for the metabolic pathogenesis of ciliopathy. Our results support using GLP1 receptor agonist as a novel therapeutic strategy for treating obesity in patients with BBS.