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
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.
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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