Activation of hypothalamic RIP‐Cre neurons promotes beiging of WAT via sympathetic nervous system |
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| Authors: | Baile Wang Ang Li Xiaomu Li Philip WL Ho Donghai Wu Xiaoqi Wang Zhuohao Liu Kelvin KL Wu Sonata SY Yau Aimin Xu Kenneth KY Cheng |
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| Affiliation: | 1. State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China;2. Department of Medicine, The University of Hong Kong, Hong Kong, China;3. Guangdong‐Hong Kong‐Macau Institute of CNS Regeneration, Joint International Research Laboratory of CNS Regeneration Ministry of Education, Guangdong Medical Key Laboratory of Brain Function and Diseases, Jinan University, Guangzhou, China;4. Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China;5. Key Laboratory of Regenerative Biology and Guangdong Provincial, Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China;6. Department of Surgery, The University of Hong Kong, Hong Kong, China;7. Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, China;8. Department of Rehabilitation Science, The Hong Kong Polytechnic University, Hong Kong, China;9. Department of Pharmacology & Pharmacy, The University of Hong Kong, Hong Kong, China |
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| Abstract: | Activation of brown adipose tissue (BAT) and beige fat by cold increases energy expenditure. Although their activation is known to be differentially regulated in part by hypothalamus, the underlying neural pathways and populations remain poorly characterized. Here, we show that activation of rat‐insulin‐promoter‐Cre (RIP‐Cre) neurons in ventromedial hypothalamus (VMH) preferentially promotes recruitment of beige fat via a selective control of sympathetic nervous system (SNS) outflow to subcutaneous white adipose tissue (sWAT), but has no effect on BAT. Genetic ablation of APPL2 in RIP‐Cre neurons diminishes beiging in sWAT without affecting BAT, leading to cold intolerance and obesity in mice. Such defects are reversed by activation of RIP‐Cre neurons, inactivation of VMH AMPK, or treatment with a β3‐adrenergic receptor agonist. Hypothalamic APPL2 enhances neuronal activation in VMH RIP‐Cre neurons and raphe pallidus, thereby eliciting SNS outflow to sWAT and subsequent beiging. These data suggest that beige fat can be selectively activated by VMH RIP‐Cre neurons, in which the APPL2–AMPK signaling axis is crucial for this defending mechanism to cold and obesity. |
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| Keywords: |
AMPK
beiging hypothalamus obesity sympathetic nervous system |
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