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Sensory neurons expressing Calcitonin Gene-Related Peptide α regulate adaptive thermogenesis and diet-induced obesity.

Research paper by Kuldeep K Makwana, Harshita H Chodavarapu, Nancy N Morones, Jingyi J Chi, William W Barr, Edward E Novinbakht, Yidan Y Wang, Peter Tuan PT Nguyen, Predrag P Jovanovic, Paul P Cohen, Celine E CE Riera

Indexed on: 10 Jan '21Published on: 08 Jan '21Published in: Molecular Metabolism



Abstract

Heat-sensory neurons arising from the dorsal root ganglia (DRG) play a pivotal role in the detection of cutaneous temperature and transmission of external signals to the brain, ensuring the maintenance of thermoregulation. However, whether these thermoreceptor neurons contribute to adaptive thermogenesis has remained elusive. Additionally, it remains unknown whether these neurons play a role in obesity and energy metabolism. We performed genetic ablation of heat sensing neurons expressing Calcitonin Gene-Related Peptide α (CGRPα) and assessed whole-body energy expenditure, weight gain, glucose tolerance and insulin sensitivity in normal chow and high fat diet-fed mice. Ex-vivo lipolysis and transcriptional characterization were combined with adipose tissue clearing methods to visualize and probe the role of sensory nerves in adipose tissue. Adaptive thermogenesis was explored using infrared imaging of intrascapular brown adipose tissue (iBAT), tail and core temperature upon various stimuli including diet, external temperature and the cooling agent icilin. Here, we show that genetic ablation of heat sensing CGRPα neurons promotes resistance to weight gain upon high fat diet (HFD) feeding and increases energy expenditure in mice. Mechanistically, we find that loss of CGRPα-expressing sensory neurons is associated with reduced lipid deposition in adipose tissue, enhanced expression of fatty-acid oxidation genes, higher ex-vivo lipolysis in primary white adipocytes and enhanced mitochondrial respiration from iBAT. Remarkably, mice lacking CGRPα sensory neurons manifest increased tail cutaneous vasoconstriction at room temperature. This exacerbated cold perception was not associated with reduced core temperature, suggesting that heat production and heat conservation mechanisms are engaged. Specific denervation of CGRPα neurons in intrascapular BAT did not contribute to the increased metabolic rate observed upon global sensory denervation. Taken together, these findings highlight an important role for cutaneous thermoreceptors in regulating energy metabolism, by triggering counter-regulatory responses involving energy dissipation processes including lipid fuel utilization and cutaneous vasodilation. Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.

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