Sensory neurons expressing calcitonin gene-related peptide alpha regulate adaptive thermogenesis and diet-induced obesity.
Publication Year:
2021
PubMed ID:
33412345
Funding Grants:
Public Summary:
Special nerve cells in the skin called heat-sensing neurons help detect temperature and send signals to the brain to regulate body heat. But it wasn’t clear if these nerves also affect how the body uses energy and controls weight.
In this study, scientists removed a specific group of heat-sensing neurons in mice and found that these mice gained less weight when fed a high-fat diet. They also burned more energy.
The mice without these neurons showed less fat stored in their bodies and had fat cells that broke down fat more easily. Their brown fat (which helps generate heat) worked harder too. Interestingly, these mice reacted more strongly to cold by narrowing blood vessels in their tails but kept their core body temperature normal, meaning their bodies both produced and conserved heat better.
Removing these neurons specifically in brown fat didn’t have the same effect, so the overall energy increase came from signals outside of that area.
Scientific Abstract:
OBJECTIVES: Heat-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. METHODS: We used genetic ablation of heat-sensing neurons expressing calcitonin gene-related peptide alpha (CGRPalpha) 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. RESULTS: In this report, we show that genetic ablation of heat-sensing CGRPalpha neurons promotes resistance to weight gain upon high-fat diet (HFD) feeding and increases energy expenditure in mice. Mechanistically, we found that loss of CGRPalpha-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 CGRPalpha 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 CGRPalpha neurons in intrascapular BAT did not contribute to the increased metabolic rate observed upon global sensory denervation. CONCLUSIONS: Taken 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.