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

EMBO Reports
Baile WangKenneth Ky Cheng

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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Citations

Nov 15, 2018·International Journal of Molecular Sciences·Baile Wang, Kenneth King-Yip Cheng
Jul 23, 2019·Journal of Neuroendocrinology·Pamela R HirschbergVanessa H Routh
Mar 28, 2018·EMBO Reports·Maria Consolata Miletta, Tamas L Horvath
Oct 28, 2019·JCI Insight·Caio Henrique MazucantiJosephine M Egan
Oct 20, 2020·Frontiers in Endocrinology·Hailan LiuFang Hu
Oct 31, 2020·Proceedings of the National Academy of Sciences of the United States of America·Baile WangKenneth K Y Cheng
May 4, 2021·Endocrinology·Zhi ZhangStephanie M Correa

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