BBSome ablation in SF1 neurons causes obesity without comorbidities.

Mohamed Rouabhi, Deng-Fu Guo, Donald A Morgan, Zhiyong Zhu, Miguel López, Leonid Zingman, Justin L Grobe, Kamal Rahmouni

Molecular metabolism 2021 Jun

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The hypothalamic ventromedial nucleus (VMH) plays a major role in metabolic control, but the molecular mechanisms involved remain poorly defined. We analyzed the relevance of the BBSome, a protein complex composed of 8 Bardet-Biedl syndrome (BBS) proteins including BBS1, in VMH steroidogenic factor 1 (SF1) neurons for the control of energy homeostasis and related physiological processes. We generated mice bearing selective BBSome disruption, through Bbs1 gene deletion, in SF1 neurons (SF1Cre/Bbs1fl/fl). We analyzed the consequence on body weight, glucose homeostasis, and cardiovascular autonomic function of BBSome loss in SF1 neurons. SF1Cre/Bbs1fl/fl mice had increased body weight and adiposity under normal chow conditions. Food intake, energy absorption, and digestive efficiency were not altered by Bbs1 gene deletion in SF1 neurons. SF1Cre/Bbs1fl/fl mice exhibited lower energy expenditure, particularly during the dark cycle. Consistent with this finding, SF1Cre/Bbs1fl/fl mice displayed reduced sympathetic nerve traffic and expression of markers of thermogenesis in brown adipose tissue. SF1Cre/Bbs1fl/fl mice also had lower sympathetic nerve activity to subcutaneous white adipose tissue that was associated with a protein expression profile that promotes lipid accumulation. Notably, despite obesity and hyperinsulinemia, SF1Cre/Bbs1fl/fl mice did not exhibit significant changes in glucose metabolism, insulin sensitivity, blood pressure, and baroreflex sensitivity. Our findings demonstrate that the SF1 neuron BBSome is necessary for the regulation of energy homeostasis through modulation of the activity of the sympathetic nervous system and that the SF1 neuron BBSome is required for the development of obesity-related comorbidities. Copyright © 2021 The Authors. Published by Elsevier GmbH.. All rights reserved.

Citation

Mohamed Rouabhi, Deng-Fu Guo, Donald A Morgan, Zhiyong Zhu, Miguel López, Leonid Zingman, Justin L Grobe, Kamal Rahmouni. BBSome ablation in SF1 neurons causes obesity without comorbidities. Molecular metabolism. 2021 Jun;48:101211