Sensory neurons expressing calcitonin gene-related peptide regulate adaptive thermogenesis and diet-induced obesity
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ABSTRACT:
PROVIDER: PRJNA631694 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR11768302.fastq.gz | Fastqsanger.gz | |||
| SRR11768303.fastq.gz | Fastqsanger.gz | |||
| SRR11768304.fastq.gz | Fastqsanger.gz | |||
| SRR11768305.fastq.gz | Fastqsanger.gz | |||
| SRR11768306.fastq.gz | Fastqsanger.gz |
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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.
| S-EPMC7820934 | biostudies-literature
Project description:We report role of CGRP+ neurons in the regulation of themogenesis on High fat diet in adipose tissues. We have used RNA Sequencing approach to identify genes that are differentially expressed in BAT and IWAT in HFD fed animals regulating thermogenic program.
2020-06-30 | GSE150267 | GEO
Project description:Various physiological stimuli, such as cold environment, diet, and hormones, trigger brown adipose tissue (BAT) to produce heat through sympathetic nervous system (SNS)- and -adrenergic receptors (ARs). The AR stimulation increases intracellular cAMP levels through heterotrimeric G proteins and adenylate cyclases, but the processes by which cAMP modulates brown adipocyte function are not fully understood. Here we described that specific ablation of cAMP production in brown adipocytes led to reduced lipolysis, mitochondrial biogenesis, uncoupling protein 1 (Ucp1) expression, and consequently defective adaptive thermogenesis. Elevated cAMP signaling by sympathetic activation inhibited Salt-inducible kinase 2 (Sik2) through protein kinase A (PKA)-mediated phosphorylation in brown adipose tissue. Inhibition of SIKs enhanced Ucp1 expression in differentiated brown adipocytes and Sik2 knockout mice exhibited enhanced adaptive thermogenesis at thermoneutrality in an Ucp1-dependent manner. Taken together, our data indicate that suppressing Sik2 by PKA-mediated phosphorylation is a requisite for SNS-induced Ucp1 expression and adaptive thermogenesis in BAT, and targeting Sik2 may present a novel therapeutic strategy to ramp up BAT thermogenic activity in humans.
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Project description:In obesity, misalignment of feeding time with the light/dark environment results in disruption of peripheral circadian clocks. Conversely, restricting feeding to the active period mitigates metabolic syndrome through mechanisms that remain unknown. Here we show that adipocyte thermogenesis is essential for the healthful metabolic response to time restricted feeding. Genetic enhancement of adipocyte thermogenesis through ablation of Zfp423 attenuates obesity caused by circadian mistimed high fat diet feeding through a mechanism involving creatine metabolism. Circadian control of adipocyte creatine metabolism underlies timing of diet-induced thermogenesis, and enhancement of adipocyte circadian rhythms through overexpression of the clock activator Bmal1 ameliorates metabolic complications during diet induced obesity. These findings establish creatine mediated diet-induced thermogenesis as a bioenergetic mechanism driving metabolic benefits during time-restricted feeding.
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Project description:Chronic Arsenic Exposurre Impairs Adaptive Thermogenesis in Male C57BL/6J Mice
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Project description:Purpose: To determine the effects of sodium arsenite in male mice on adaptive thermogenesis. Methods: Male C57BL/6J mice were exposed to sodium arsenite in drinking water at 300 parts per billion (ppb) for 9 weeks Findings: Arsenic-treated mice experienced significantly decreased metabolic heat production when acclimated to chronic cold tolerance testing, as evidenced by indirect calorimetry, despite no change in physical activity. Arsenic exposure increased total fat mass, and unilocular lipid droplet size in both subcutaneous inguinal white adipose tissue (iWAT) and brown adipose tissue (BAT). Conclusion: Chronic arsenic exposure impacts the mitochondria of thermogenic tissues involved in energy expenditure and glucose regulation, providing novel mechanistic evidence for arsenic’s role in metabolic pathologies.
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Project description:Mitochondria are pivotal for cellular metabolism, serving as sources and targets of nutrient intermediates from converging metabolic pathways. Here, we demonstrate that insulin resistance leads to a marked alteration in the mitochondrial proteome of adipocytes. Analysis across multiple insulin resistance models revealed a consistent decrease in the level of the mitochondrial processing peptidase miPEP, suggesting a potential role for miPEP in the aetiology of insulin resistance. Adipocyte specific miPEP knockout mice demonstrated a strong phenotype marked by a browning-independent increment in energy expenditure, enhanced insulin sensitivity, and reduced adiposity, despite normal food intake and physical activity. These phenotypes vanished when mice were housed at thermoneutrality suggesting that miPEP deletion triggers a compensatory enhancement in thermogenesis protecting against metabolic dysfunction. Tissue specific analysis of miPEP deficient mice revealed a selective increment in muscle metabolism evidenced by increased basal and insulin induced glucose uptake and upregulation of the protein Fbp2, involved in energy wasting via futile cycling. These findings suggest that miPEP deletion initiates a compensatory increase in thermogenesis, acting as a protective mechanism against diet-induced insulin resistance.
2024-08-10 | PXD051606 | Pride
Project description:Microbiota Depletion Impairs Adaptive Thermogenesis of Both Brown and Beige Adipose Tissue
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Project description:Obesity results from a caloric imbalance between energy intake, absorption and expenditure. In both rodents and humans, diet-induced thermogenesis contributes to energy expenditure and involves the activation of brown adipose tissue (BAT). We hypothesized that environmental toxicants commonly used as food additives or pesticides might reduce BAT thermogenesis through suppression of uncoupling protein 1 (UCP1) and this may contribute to the development of obesity. Using a step-wise screening approach, we discovered that the organophosphate insecticide chlorpyrifos suppresses UCP1 and mitochondrial respiration in BAT at concentrations as low as 1 pM. In mice housed at thermoneutrality and fed a high-fat diet, chlorpyrifos impaired BAT mitochondrial function and diet-induced thermogenesis, promoting greater obesity, non-alcoholic fatty liver disease (NAFLD) and insulin resistance. This was associated with reductions in cAMP; activation of p38MAPK and AMPK; protein kinases critical for maintaining UCP1 and mitophagy, respectively in BAT. These data indicate that the commonly used pesticide chlorpyrifos, suppresses diet-induced thermogenesis and the activation of BAT, suggesting its use may contribute to the obesity epidemic.
2021-07-19 | GSE178366 | GEO
Project description:Purpose: Interferon regulatory factor 3 (IRF3) is activated by pro-inflammatory cytokines, but its role in regulating adaptive thermogenesis and energy expenditure remains unclear. Here, we report that IRF3 as a negative transcription regulator of adaptive thermogenesis. Adipocyte-specific IRF3 knockout (FI3KO) attenuates HFD-induced obesity by increasing energy expenditure; further studies show that IRF3 suppresses adaptive thermogenesis through ISG15-mediated inhibition of glycolysis in adipocytes. Conversely, overexpression of IRF3 in adipocytes causes reduced thermogenesis gene expression, energy expenditure, and more persistent to HFD-induced obesity. Moreover, Isg15-/- increases adipose thermogenesis and protects mice from HFD-induced obesity and glucose intolerance. Taken together, these data indicate that IRF3 as a transcriptional regulator connecting between inflammatory signaling pathway and energy homeostasis Methods: primary adipocyte mRNA profiles of 8-week-old wild-type (WT) and FI3OE mice were generated by deep sequencing. The sequence reads that passed quality filters were analyzed at the transcript isoform level. qRT–PCR validation was performed using RT-PCR. Conclusions: Our study represents the first detailed analysis of adipocyte transcriptomes from WT and FI3OE iWAT, with biologic replicates, generated by RNA-seq technology. The optimized data analysis workflows reported here should provide a framework for comparative investigations of expression profiles. Our results show that Irf3 adipocyte-speficic overrxpression markedly increases the expression of Isg15 and Herc6, which play important role in regulation of glycolysis.
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