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Melanocortin 4 receptors in autonomic neurons regulate thermogenesis and glycemia.

ABSTRACT: Whether melanocortin 4 receptors (MC4Rs) in extra-hypothalamic neurons, including cholinergic autonomic pre-ganglionic neurons, are required to control energy and glucose homeostasis is unclear. We found that MC4Rs in sympathetic, but not parasympathetic, pre-ganglionic neurons were required to regulate energy expenditure and body weight, including thermogenic responses to diet and cold exposure and 'beiging' of white adipose tissue. Deletion of Mc4r genes in both sympathetic and parasympathetic cholinergic neurons impaired glucose homeostasis.

SUBMITTER: Berglund ED

PROVIDER: S-EPMC4090093 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Melanocortin 4 receptors in autonomic neurons regulate thermogenesis and glycemia.

Berglund Eric D ED Liu Tiemin T Kong Xingxing X Sohn Jong-Woo JW Vong Linh L Deng Zhuo Z Lee Charlotte E CE Lee Syann S Williams Kevin W KW Olson David P DP Scherer Philipp E PE Lowell Bradford B BB Elmquist Joel K JK

Nature neuroscience 20140608 7

Whether melanocortin 4 receptors (MC4Rs) in extra-hypothalamic neurons, including cholinergic autonomic pre-ganglionic neurons, are required to control energy and glucose homeostasis is unclear. We found that MC4Rs in sympathetic, but not parasympathetic, pre-ganglionic neurons were required to regulate energy expenditure and body weight, including thermogenic responses to diet and cold exposure and 'beiging' of white adipose tissue. Deletion of Mc4r genes in both sympathetic and parasympathetic ...[more]

PMID: 24908101

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Project description:ObjectivesHeat-sensory neurons from the dorsal root ganglia (DRG) play a pivotal role in detecting the cutaneous temperature and transmission of external signals to the brain, ensuring the maintenance of thermoregulation. However, whether these thermoreceptor neurons contribute to adaptive thermogenesis remains elusive. It is also unknown whether these neurons play a role in obesity and energy metabolism.MethodsWe used genetic ablation of heat-sensing neurons expressing calcitonin gene-related peptide α (CGRPα) to assess whole-body energy expenditure, weight gain, glucose tolerance, and insulin sensitivity in normal chow and high-fat diet-fed mice. Exvivo 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.ResultsIn this report, 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 found that loss of CGRPα-expressing sensory neurons was associated with reduced lipid deposition in adipose tissue, enhanced expression of fatty acid oxidation genes, higher exvivo lipolysis in primary white adipocytes, and increased mitochondrial respiration from iBAT. Remarkably, mice lacking CGRPα sensory neurons manifested 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 were engaged. Specific denervation of CGRPα neurons in intrascapular BAT did not contribute to the increased metabolic rate observed upon global sensory denervation.ConclusionsTaken together, these findings highlight an important role of cutaneous thermoreceptors in regulating energy metabolism by triggering counter-regulatory responses involving energy dissipation processes including lipid fuel utilization and cutaneous vasodilation.

Dataset Information

Melanocortin 4 receptors in autonomic neurons regulate thermogenesis and glycemia.

Publications

Melanocortin 4 receptors in autonomic neurons regulate thermogenesis and glycemia.

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