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Impact of Adaptive Thermogenesis in Mice on the Treatment of Obesity.

ABSTRACT: Obesity and associated metabolic diseases have become a priority area of study due to the exponential increase in their prevalence and the corresponding health and economic impact. In the last decade, brown adipose tissue has become an attractive target to treat obesity. However, environmental variables such as temperature and the dynamics of energy expenditure could influence brown adipose tissue activity. Currently, most metabolic studies are carried out at a room temperature of 21 °C, which is considered a thermoneutral zone for adult humans. However, in mice this chronic cold temperature triggers an increase in their adaptive thermogenesis. In this review, we aim to cover important aspects related to the adaptation of animals to room temperature, the influence of housing and temperature on the development of metabolic phenotypes in experimental mice and their translation to human physiology. Mice studies performed in chronic cold or thermoneutral conditions allow us to better understand underlying physiological mechanisms for successful, reproducible translation into humans in the fight against obesity and metabolic diseases.

SUBMITTER: Bastias-Perez M

PROVIDER: S-EPMC7072509 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Impact of Adaptive Thermogenesis in Mice on the Treatment of Obesity.

Bastías-Pérez Marianela M Zagmutt Sebastián S Soler-Vázquez M Carmen MC Serra Dolors D Mera Paula P Herrero Laura L

Cells 20200128 2

Obesity and associated metabolic diseases have become a priority area of study due to the exponential increase in their prevalence and the corresponding health and economic impact. In the last decade, brown adipose tissue has become an attractive target to treat obesity. However, environmental variables such as temperature and the dynamics of energy expenditure could influence brown adipose tissue activity. Currently, most metabolic studies are carried out at a room temperature of 21 °C, which i ...[more]

PMID: 32012991

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Project description:We compared maximal cold-induced heat production (HPmax) and cold limits between warm (WA; 27°C), moderate cold (MCA; 18°C), or cold acclimated (CA; 5°C) wild-type and uncoupling-protein 1 knockout (UCP1-KO) mice. In wild-type mice, HPmax was successively increased after MCA and CA, and the cold limit was lowered to -8.3°C and -18.0°C, respectively. UCP1-KO mice also increased HPmax in response to MCA and CA, although to a lesser extent. Direct comparison revealed a maximal cold-induced recruitment of heat production by +473 mW and +227 mW in wild-type and UCP1-KO mice, respectively. The increase in cold tolerance of UCP1-KO mice from -0.9°C in MCA to -10.1°C in CA could not be directly related to changes in HPmax, indicating that UCP1-KO mice used the dissipated heat more efficiently than wild-type mice. As judged from respiratory quotients, acutely cold-challenged UCP1-KO mice showed a delayed transition toward lipid oxidation, and 5-h cold exposure revealed diminished physical activity and less variability in the control of metabolic rate. We conclude that BAT is required for maximal adaptive thermogenesis but also allows metabolic flexibility and a rapid switch toward sustained lipid-fuelled thermogenesis as an acute response to cold. In both CA groups, expression of contractile proteins (myosin heavy-chain isoforms) showed minor training effects in skeletal muscles, while cardiac muscle of UCP1-KO mice had novel expression of beta cardiac isoform. Neither respiration nor basal proton conductance of skeletal muscle mitochondria were different between genotypes. In subcutaneous white adipose tissue of UCP1-KO mice, cold exposure increased cytochrome-c oxidase activity and expression of the cell death-inducing DFFA-like effector A by 3.6-fold and 15-fold, respectively, indicating the recruitment of mitochondria-rich brown adipocyte-like cells. Absence of functional BAT leads to remodeling of white adipose tissue, which may significantly contribute to adaptive thermogenesis during cold acclimation.

Project description:Stress-associated conditions such as psychoemotional reactivity and depression have been paradoxically linked to either weight gain or weight loss. This bi-directional effect of stress is not understood at the functional level. Here we tested the hypothesis that pre-stress level of adaptive thermogenesis and brown adipose tissue (BAT) functions explain the vulnerability or resilience to stress-induced obesity.We used wt and triple ?1,?2,?3-Adrenergic Receptors knockout (?-less) mice exposed to a model of chronic subordination stress (CSS) at either room temperature (22 °C) or murine thermoneutrality (30 °C). A combined behavioral, physiological, molecular, and immunohistochemical analysis was conducted to determine stress-induced modulation of energy balance and BAT structure and function. Immortalized brown adipocytes were used for in vitro assays.Departing from our initial observation that ?ARs are dispensable for cold-induced BAT browning, we demonstrated that under physiological conditions promoting low adaptive thermogenesis and BAT activity (e.g. thermoneutrality or genetic deletion of the ?ARs), exposure to CSS acted as a stimulus for BAT activation and thermogenesis, resulting in resistance to diet-induced obesity despite the presence of hyperphagia. Conversely, in wt mice acclimatized to room temperature, and therefore characterized by sustained BAT function, exposure to CSS increased vulnerability to obesity. Exposure to CSS enhanced the sympathetic innervation of BAT in wt acclimatized to thermoneutrality and in ?-less mice. Despite increased sympathetic innervation suggesting adrenergic-mediated browning, norepinephrine did not promote browning in ?ARs knockout brown adipocytes, which led us to identify an alternative sympathetic/brown adipocytes purinergic pathway in the BAT. This pathway is downregulated under conditions of low adaptive thermogenesis requirements, is induced by stress, and elicits activation of UCP1 in wt and ?-less brown adipocytes. Importantly, this purinergic pathway is conserved in human BAT.Our findings demonstrate that thermogenesis and BAT function are determinant of the resilience or vulnerability to stress-induced obesity. Our data support a model in which adrenergic and purinergic pathways exert complementary/synergistic functions in BAT, thus suggesting an alternative to ?ARs agonists for the activation of human BAT.

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

Impact of Adaptive Thermogenesis in Mice on the Treatment of Obesity.

Publications

Impact of Adaptive Thermogenesis in Mice on the Treatment of Obesity.

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