Role of brainstem primary cilia in metabolic homeostasis

Abstract

Primary cilia possess an array of receptors and signaling from this organelle is critical for neuronal function. BBS1 is an important component of a receptor trafficking complex (BBSome) that facilitates signaling in both primary cilia and plasma membrane. Humans harboring BBS1 mutations develop obesity and type 2 diabetes. Recent studies from our lab and others have shown that BBS1 deletion in hypothalamic neurons lead to obesity and glucose dysregulation. However, the role of hindbrain BBS1 in metabolic control is unknown. We hypothesized that brainstem BBS1 regulates metabolism through primary cilia function. As an initial step towards testing this hypothesis, we deleted BBS1 selectively from hindbrain neurons by crossing Phox2bCre mice with BBS1fl/fl mice and assessed metabolic parameters. Cre expression in hindbrain nuclei was validated by crossing these mice on a Cre-dependent tdTomato background. Both male and female Phox2bCre/BBS1fl/fl mice fed a chow diet exhibited reduced body weight (P<0.05) during adolescence (5-8 weeks old) but had normal weights in adulthood (9-20 weeks) relative to control littermates. In both sexes, hindbrain BBS1 deletion impaired glucose clearance at 20 weeks of age, independent of insulin sensitivity, as indicated by elevated area under the curve (AUC) in glucose (male AUC 31368±1986 vs. 25497±1834, female AUC 22643±1427 vs. 19304±800, P<0.05), but not insulin (male AUC 11505±905 vs. 10416±680, female AUC 8314±333 vs. 9098±525), tolerance test. Interestingly, male Phox2bCre/BBS1fl/fl mice maintained on an obesogenic (high fat-sucrose) diet displayed blunted weight gain during the first 14 weeks of age (P<0.05) which tended to be reduced relative to controls up to 20 weeks of age. Remarkably, NMR-based body composition revealed reduced lean (22.9±0.6 vs. 24.9±0.6 g, P<0.05), but not fat (23.8±1.4 vs. 23.7±1.2 g), mass in diet-induced obese adult Phox2bCre/BBS1fl/fl mice. These data suggest that hindbrain BBS1 is important for weight gain during adolescence and glucose handling in both male and female mice. Moreover, these results suggest that brainstem BBS1 negatively regulates weight gain induced by a high fat/sucrose diet. Since BBS1 has functions independent of cilia, we directly tested the role of hindbrain primary cilia on metabolic homeostasis. For this, we assessed how brainstem ablation of cilia through deletion of IFT88 protein (Phox2bCre/IFT88fl/fl mice) affect metabolic parameters. Male, but not female, Phox2bCre/IFT88fl/fl animals displayed reduced body weight during adolescence (P<0.05). Glucose tolerance test showed normal glucose regulation in adulthood (male AUC 28565±2007 vs. 28762±2321, female AUC 23820±836 vs.22601±175). Collectively, these data show a sex-dependent role for brainstem primary cilia in body weight gain during adolescence. Furthermore, our findings reveal that the critical role of hindbrain BBS1 in glucose homeostasis is independent of its function in primary cilia. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.