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  • EMBO reports: 19 (4)

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Activation of hypothalamic RIP‐Cre neurons promotes beiging of WAT via sympathetic nervous system

Baile Wang, Ang Li, Xiaomu Li, Philip WL Ho, Donghai Wu, Xiaoqi Wang, Zhuohao Liu, Kelvin KL Wu, Sonata SY Yau, View ORCID ProfileAimin Xu, View ORCID ProfileKenneth KY Cheng
DOI 10.15252/embr.201744977 | Published online 21.02.2018
EMBO reports (2018) 19, e44977
Baile Wang
State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China Department of Medicine, The University of Hong Kong, Hong Kong, China
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Ang Li
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
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Xiaomu Li
Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
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Philip WL Ho
Department of Medicine, The University of Hong Kong, Hong Kong, China
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Donghai Wu
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
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Xiaoqi Wang
Department of Surgery, The University of Hong Kong, Hong Kong, China
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Zhuohao Liu
State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China Department of Medicine, The University of Hong Kong, Hong Kong, China
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Kelvin KL Wu
Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, China
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Sonata SY Yau
Department of Rehabilitation Science, The Hong Kong Polytechnic University, Hong Kong, China
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Aimin Xu
State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China Department of Medicine, The University of Hong Kong, Hong Kong, China Department of Pharmacology & Pharmacy, The University of Hong Kong, Hong Kong, China
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Kenneth KY Cheng
Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, China
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Author Affiliations

  1. Baile Wang1,2,
  2. Ang Li3,
  3. Xiaomu Li4,
  4. Philip WL Ho2,
  5. Donghai Wu5,
  6. Xiaoqi Wang6,
  7. Zhuohao Liu1,2,
  8. Kelvin KL Wu7,
  9. Sonata SY Yau8,
  10. Aimin Xu (amxu{at}hku.hk)*,1,2,9 and
  11. Kenneth KY Cheng (kenneth.ky.cheng{at}polyu.edu.hk)*,7
  1. 1State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China
  2. 2Department of Medicine, The University of Hong Kong, Hong Kong, China
  3. 3Guangdong‐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. 4Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
  5. 5Key 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. 6Department of Surgery, The University of Hong Kong, Hong Kong, China
  7. 7Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, China
  8. 8Department of Rehabilitation Science, The Hong Kong Polytechnic University, Hong Kong, China
  9. 9Department of Pharmacology & Pharmacy, The University of Hong Kong, Hong Kong, China
  1. ↵* Corresponding author. Tel: +852 3917 9754; E‐mail: amxu{at}hku.hk
    Corresponding author. Tel: +852 3400 8912; E‐mail: kenneth.ky.cheng{at}polyu.edu.hk
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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.

See also: M C Miletta & T L Horvath (April 2018)

Synopsis

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The adaptor protein APPL2 induces activation of RIP‐Cre neurons in the VMH, which enhances sympathetic outflow to sWAT, sWAT beiging and cold tolerance.

  • Ablation of APPL2 in RIP‐Cre neurons in the VMH suppresses beiging in sWAT without influencing BAT metabolism, leading to cold intolerance and increased adiposity.

  • APPL2 activates VMH RIP‐Cre neurons through AMPK inhibition.

  • Pharmacogenetic activation of RIP‐Cre neurons induces beiging and increases energy expenditure in mice.

  • AMPK
  • beiging
  • hypothalamus
  • obesity
  • sympathetic nervous system

EMBO Reports (2018) 19: e44977

  • Received August 8, 2017.
  • Revision received January 23, 2018.
  • Accepted January 25, 2018.
  • © 2018 The Authors
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Volume 19, Issue 4
01 April 2018 | pp -
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