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Dissociation of Adaptive Thermogenesis from Glucose Homeostasis in Microbiome-Deficient Mice.

ABSTRACT: Recent studies suggest that a key mechanism whereby the gut microbiome influences energy balance and glucose homeostasis is through the recruitment of brown and beige adipocytes, primary mediators of the adaptive thermogenic response. To test this, we assessed energy expenditure and glucose metabolism in two complementary mouse models of gut microbial deficiency, which were exposed to a broad range of thermal and dietary stresses. Neither ablation of the gut microbiome, nor the substantial microbial perturbations induced by cold ambient temperatures, influenced energy expenditure during cold exposure or high-fat feeding. Nevertheless, we demonstrated a critical role for gut microbial metabolism in maintaining euglycemia through the production of amino acid metabolites that optimized hepatic TCA (tricarboxylic acid) cycle fluxes in support of gluconeogenesis. These results distinguish the dispensability of the gut microbiome for the regulation of energy expenditure from its critical contribution to the maintenance of glucose homeostasis.

SUBMITTER: Krisko TI

PROVIDER: S-EPMC7888548 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Dissociation of Adaptive Thermogenesis from Glucose Homeostasis in Microbiome-Deficient Mice.

Krisko Tibor I TI Nicholls Hayley T HT Bare Curtis J CJ Holman Corey D CD Putzel Gregory G GG Jansen Robert S RS Sun Natalie N Rhee Kyu Y KY Banks Alexander S AS Cohen David E DE

Cell metabolism 20200220 3

Recent studies suggest that a key mechanism whereby the gut microbiome influences energy balance and glucose homeostasis is through the recruitment of brown and beige adipocytes, primary mediators of the adaptive thermogenic response. To test this, we assessed energy expenditure and glucose metabolism in two complementary mouse models of gut microbial deficiency, which were exposed to a broad range of thermal and dietary stresses. Neither ablation of the gut microbiome, nor the substantial micro ...[more]

PMID: 32084379

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Project description:ObjectiveRecent studies indicate that brown adipose tissue, in addition to its role in thermogenesis, has a role in the regulation of whole-body metabolism. Here we characterize the metabolic effects of deleting Rab10, a protein key for insulin stimulation of glucose uptake into white adipocytes, solely from brown adipocytes.MethodsWe used a murine brown adipocyte cell line and stromal vascular fraction-derived in vitro differentiated brown adipocytes to study the role of Rab10 in insulin-stimulated GLUT4 translocation to the plasma membrane and insulin-stimulated glucose uptake. We generated a brown adipocyte-specific Rab10 knockout for in vivo studies of metabolism and thermoregulation.ResultsWe demonstrate that deletion of Rab10 from brown adipocytes results in a two-fold reduction of insulin-stimulated glucose transport by reducing translocation of the GLUT4 glucose transporter to the plasma membrane, an effect linked to whole-body glucose intolerance and insulin resistance in female mice. This effect on metabolism is independent of the thermogenic function of brown adipocytes, thereby revealing a metabolism-specific role for brown adipocytes in female mice. The reduced glucose uptake induced by Rab10 deletion disrupts ChREBP regulation of de novo lipogenesis (DNL) genes, providing a potential link between DNL in brown adipocytes and whole-body metabolic regulation in female mice. However, deletion of Rab10 from male mice does not induce systemic insulin resistance, although ChREBP regulation is disrupted.ConclusionsOur studies of Rab10 reveal the role of insulin-regulated glucose transport into brown adipocytes in whole-body metabolic homeostasis of female mice. Importantly, the contribution of brown adipocytes to whole-body metabolic regulation is independent of its role in thermogenesis. It is unclear whether the whole-body metabolic sexual dimorphism is because female mice are permissive to the effects of Rab10 deletion from brown adipocytes or because male mice are resistant to the effect.

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.

Dataset Information

Dissociation of Adaptive Thermogenesis from Glucose Homeostasis in Microbiome-Deficient Mice.

Publications

Dissociation of Adaptive Thermogenesis from Glucose Homeostasis in Microbiome-Deficient Mice.

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