AMPK activation protects against diet induced obesity through Ucp1-independent thermogenesis in subcutaneous white adipose tissue.
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ABSTRACT:
SUBMITTER: Pollard AE
PROVIDER: S-EPMC6420092 | biostudies-literature | 2019 Mar
REPOSITORIES: biostudies-literature
Publications
AMPK activation protects against diet induced obesity through Ucp1-independent thermogenesis in subcutaneous white adipose tissue.
Pollard Alice E AE Martins Luís L Muckett Phillip J PJ Khadayate Sanjay S Bornot Aurélie A Clausen Maryam M Admyre Therese T Bjursell Mikael M Fiadeiro Rebeca R Wilson Laura L Whilding Chad C Kotiadis Vassilios N VN Duchen Michael R MR Sutton Daniel D Penfold Lucy L Sardini Alessandro A Bohlooly-Y Mohammad M Smith David M DM Read Jon A JA Snowden Michael A MA Woods Angela A Carling David D
Nature metabolism 20190225 3
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Project description:Purpose: To investigate alterations in subcutaneous white adipose gene expression induced by genetic AMPK activation in vivo, in mice fed a chow or a high-fat diet. Methods: Subcutaneous white adipose tissue mRNA profiles of wild-type transgenic (WT-Tg) mice and mice expressing a gain-of-function AMPK mutant gamma1 subunit (D316A-Tg) were generated by deep sequencing. Results: RNA sequencing revealed over 3000 differentially expressed genes between WT-Tg and D316A-Tg subcutaneous white adipose tissue (WATsc) from mice fed a high fat diet (HFD), of which many were classified as 'skeletal muscle-associated'. Interestingly, uncoupling protein 1 (UCP1), associated with 'beige' adipocyte formation in WATsc, was not differentially expressed. On a chow diet, many differentially expressed genes were also identified, with gene ontology analysis identifiying glycolysis, TCA cycle and brown fat differentiation as highly enriched; key features of brown adipocyte identity. HFD-associated skeletal-muscle associated gene expression was either not significantly altered, or significantly down-regulated on a chow diet, indicating a diet-induced gene signature in D316A-Tg WATsc. Conclusions: Our study revealed gene signatures indicative of brown adipocyte development on a chow diet, where no overt metabolic phenotype was observed in gain-of-function animals. When fed a HFD, WATsc from D316A-Tg mice displayed a muscle-like gene signature, expressing key components of creatine and calcium thermogenic cycles including Ckmt2 (creatine kinase, mitochondrial 2) Atp2a1 (SERCA1-sarco/endoplasmic reticulum ATPase 1) and ryr1 (ryanodine receptor 1). UCP1 expression was not altered between WT-Tg and D316A-Tg mice fed a HFD. Our findings suggest a novel role for AMPK in the regulation of white adipocyte identity and a potentially novel cell population that, when metabolically challenged, preferrentially utilise muscle-like thermogenic futile cycles independent of UCP1 to mediate whole organism energy expenditure.
2019-02-01 | GSE120429 | GEO
Project description:AMPK activation protects against diet induced obesity through Ucp1-independent thermogenesis in subcutaneous white adipose
| PRJNA493063 | ENA
Project description:Pharmacological activation of adaptive thermogenesis to increase energy expenditure is considered to be a novel strategy for obesity. Peroxisome-proliferator-activated receptor γ co-activator-1α (PGC-1α), which serves as an inducible co-activator in energy expenditure, is highly expressed in brown adipose tissues (BAT). In this study, we found a PGC-1α transcriptional activator, natural compound rutaecarpine (Rut), which promoted brown adipocytes mitochondrial biogenesis and thermogenesis in vitro. Chronic Rut treatment reduced the body weight gain and mitigated insulin sensitivity through brown and beige adipocyte thermogenesis. Mechanistic study showed that Rut activated the energy metabolic pathway AMP-activated protein kinase (AMPK)/PGC-1α axis, and deficiency of AMPK abolished the beneficial metabolic phenotype of the Rut treatment in vitro and in vivo. In summary, a PGC-1α transcriptional activator Rut was found to activate brown and beige adipose thermogenesis to resist diet-induced obesity through AMPK pathway. Our findings serve as a further understanding of the natural compound in adipose tissue and provides a possible strategy to combat obesity and related metabolic disorders.
| S-EPMC9027001 | biostudies-literature
Project description:Low-protein/high-carbohydrate (LPHC) diet has been suggested to promote metabolic health and longevity in adult humans and animal models. However, the complex molecular underpinnings of how LPHC diet leads to metabolic benefits remain elusive. Through a multi-layered approach, here we observed that LPHC diet promotes an energy-dissipating response consisting in the parallel recruitment of canonical and non-canonical (muscular) thermogenic systems in subcutaneous white adipose tissue (sWAT). In particular, we measured Ucp1 induction in association with up-regulation of actomyosin components and several Serca (Serca1, Serca2a, Serca2b) ATPases. In beige adipocytes, we observed that AMPK activation is responsible for transducing the amino acid lowering in an enhanced fat catabolism, which sustains both Ucp1-and Serca-dependent energy dissipation. Limiting AMPK activation counteracts the expression of brown fat and muscular genes, including Ucp1 and Serca, as well as mitochondrial oxidative genes. We observed that mitochondrial reactive oxygen species are the upstream molecules controlling AMPK-mediated metabolic rewiring in amino acid-restricted beige adipocytes. Our findings delineate a novel metabolic phenotype of responses to amino acid shortage, which recapitulates some of the benefits of cool temperature in sWAT. In conclusion, this highlights LPHC diet as a valuable and practicable strategy to prevent metabolic diseases through the enhancement of mitochondrial oxidative metabolism and the recruitment of different energy dissipating routes in beige adipocytes.
| S-EPMC7358542 | biostudies-literature
Project description:FXR, encoded by Nh1r4, is a nuclear receptor crucial in regulating bile acid, lipid, and glucose metabolism. Prior research has indicated that activating FXR in the liver and small intestine may offer protection against obesity and metabolic diseases. This study demonstrates the essential role of the FXR-ApoC2 pathway in promoting the browning of white adipose tissue (WAT). Increased FXR by treatment with the FXR agonist farnesol upregulated beige adipocyte markers, including UCP1, PGC1α, and PRDM16, and increased the FXR target gene, ApoC2, in beige adipocytes and cold-exposed mice. However, these effects were not observed in mature white adipocytes. Remarkably, the knockdown of FXR results in a significantly reduced expression of UCP1, PGC1α, PRDM16, and ApoC2 in beige adipocytes. While studying the interaction between the nuclear receptor RXRα and FXR in transcription regulation, it was found that the knockdown of RXRα did not control the expression of FXR under beige adipogenesis. We further investigated whether the expression of beige-related markers could be altered under ApoC2 overexpression to ascertain the mechanism of action of FXR in relation to ApoC2 regulation. The overexpression of ApoC2 in both preadipocytes and beige adipocytes led to a significant increase in the expression of UCP1 and PGC1α. These results indicate that the FXR-mediated ApoC2 pathway is essential in the browning of WAT by inducing beige adipogenesis from preadipocytes.
| S-EPMC11871442 | biostudies-literature
Project description:Obesity results from increased energy intake or defects in energy expenditure. Brown adipose tissue (BAT) is specialized for energy expenditure, a process called adaptive thermogenesis. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) controls BAT-mediated thermogenesis by regulating the expression of Ucp1 Inhibitor of differentiation 1 (Id1) is a helix-loop-helix transcription factor that plays an important role in cell proliferation and differentiation. We demonstrate a novel function of Id1 in BAT thermogenesis and programming of beige adipocytes in white adipose tissue (WAT). We found that adipose tissue-specific overexpression of Id1 causes age-associated and high-fat diet-induced obesity in mice. Id1 suppresses BAT thermogenesis by binding to and suppressing PGC1α transcriptional activity. In WAT, Id1 is mainly localized in the stromal vascular fraction, where the adipose progenitor/precursors reside. Lack of Id1 increases beige gene and Ucp1 expression in the WAT in response to cold exposure. Furthermore, brown-like differentiation is increased in Id1-deficient mouse embryonic fibroblasts. At the molecular level, Id1 directly interacts with and suppresses Ebf2 transcriptional activity, leading to reduced expression of Prdm16, which determines beige/brown adipocyte cell fate. Overall, the study highlights the existence of novel regulatory mechanisms between Id1/PGC1α and Id1/Ebf2 in controlling brown fat metabolism, which has significant implications in the treatment of obesity and its associated diseases, such as diabetes.
| S-EPMC5440025 | biostudies-literature
Project description:The goal of this study was to define the functional role of adipocyte-specific expression of the RNA binding protein Human antigen R (HuR). Mice with an adipocyte-specific deletion of HuR (Adipo-HuR-/- ) were generated by crossing HuR floxed (HuRfl/fl ) mice with mice expressing adiponectin-driven cre-recombinase (Adipoq-cre). Our results show that Adipo-HuR-/- mice display a lean phenotype compared to wild-type littermate controls. HuR deletion results in a diet-independent reduction in percent body fat composition along with an increase in energy expenditure. Functionally, Adipo-HuR-/- mice show a significant impairment in acute adaptive thermogenesis (six hours at 4°C), but uncoupling protein 1 (UCP1) protein expression in brown adipose tissue (BAT) is unchanged compared to control. Pharmacological inhibition of HuR also results in a marked decline in core body temperature following acute cold challenge independent of UCP1 protein expression. Among the 588 HuR-dependent genes in BAT identified by RNA-seq analysis, gene ontology analysis shows a significant enrichment in mediators of calcium transport and signalling, almost all of which are decreased in Adipo-HuR-/- mice compared to control. In conclusion, adipocyte expression of HuR plays a central role in metabolic homoeostasis and mediates UCP1-independent thermogenesis in BAT, potentially through post-transcriptional control of intracellular calcium transport.Abbreviations: Adipo-HuR-/-: Adipocyte-specific HuR deletion mice; BAT: Brown adipose tissue; HuR: Human antigen R; UCP1: Uncoupling protein 1.
| S-EPMC7469577 | biostudies-literature
Project description:Thermogenesis by uncoupling protein 1 (UCP1) is one of the primary mechanisms by which brown adipose tissue (BAT) increases energy expenditure. UCP1 resides in the inner mitochondrial membrane (IMM), where it dissipates membrane potential independent of adenosine triphosphate (ATP) synthase. Here, we provide evidence that phosphatidylethanolamine (PE) modulates UCP1-dependent proton conductance across the IMM to modulate thermogenesis. Mitochondrial lipidomic analyses revealed PE as a signature molecule whose abundance bidirectionally responds to changes in thermogenic burden. Reduction in mitochondrial PE by deletion of phosphatidylserine decarboxylase (PSD) made mice cold intolerant and insensitive to β3 adrenergic receptor agonist-induced increase in whole-body oxygen consumption. High-resolution respirometry and fluorometry of BAT mitochondria showed that loss of mitochondrial PE specifically lowers UCP1-dependent respiration without compromising electron transfer efficiency or ATP synthesis. These findings were confirmed by a reduction in UCP1 proton current in PE-deficient mitoplasts. Thus, PE performs a previously unknown role as a temperature-responsive rheostat that regulates UCP1-dependent thermogenesis.
| S-EPMC9956115 | biostudies-literature
Project description:ObjectiveObesity is the result of positive energy balance. It can be caused by excessive energy consumption but also by decreased energy dissipation, which occurs under several conditions including when the development or activation of brown adipose tissue (BAT) is impaired. Here we evaluated whether iRhom2, the essential cofactor for the Tumour Necrosis Factor (TNF) sheddase ADAM17/TACE, plays a role in the pathophysiology of metabolic syndrome.MethodsWe challenged WT versus iRhom2 KO mice to positive energy balance by chronic exposure to a high fat diet and then compared their metabolic phenotypes. We also carried out ex vivo assays with primary and immortalized mouse brown adipocytes to establish the autonomy of the effect of loss of iRhom2 on thermogenesis and respiration.ResultsDeletion of iRhom2 protected mice from weight gain, dyslipidemia, adipose tissue inflammation, and hepatic steatosis and improved insulin sensitivity when challenged by a high fat diet. Crucially, the loss of iRhom2 promotes thermogenesis via BAT activation and beige adipocyte recruitment, enabling iRhom2 KO mice to dissipate excess energy more efficiently than WT animals. This effect on enhanced thermogenesis is cell-autonomous in brown adipocytes as iRhom2 KOs exhibit elevated UCP1 levels and increased mitochondrial proton leak.ConclusionOur data suggest that iRhom2 is a negative regulator of thermogenesis and plays a role in the control of adipose tissue homeostasis during metabolic disease.
| S-EPMC6909339 | biostudies-literature
Project description:Hyperthermia (HT) has broad potential for disease treatment and health maintenance. Previous studies have shown that far-infrared rays (FIRs) at 8-10 μm can potentially reduce inflammation, oxidative stress, and gut microbiota imbalance. However, the effects of FIR HT on energy metabolism require further investigation. To investigate the effects of graphene-FIR HT therapy on diet-induced obesity and their regulatory mechanisms in energy metabolism disorders. After 8 weeks of hyperthermia, mice fed standard chow or a high-fat diet (HFD) underwent body composition analysis. Energy expenditure was measured using metabolic cages. The protein changes in adipose tissue were detected by molecular technology. Graphene-FIR therapy effectively mitigated body fat accumulation, improved dyslipidemia, and impaired liver function while enhancing insulin sensitivity. Furthermore, graphene-FIR therapy increased VO2, VCO2, and EE levels in HFD mice to exhibit enhanced metabolic activity. The therapy activated the AMPK/PGC-1α/SIRT1 pathway in adipose tissue, increasing the expression of uncoupling protein 1 (UCP1) and glucose transporter protein four (GLUT4), activating the thermogenic program in adipose tissue, and improving energy metabolism disorder in HFD mice. In short, graphene-FIR therapy represents a comprehensive approach to improving the metabolic health of HFD mice.
| S-EPMC11900916 | biostudies-literature