bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2024–01–14
twelve papers selected by
José Carlos de Lima-Júnior, Washington University
  1. EPAC1 enhances brown fat growth and beige adipogenesis.
  2. Brown adipose tissue CoQ deficiency activates the integrated stress response and FGF21-dependent mitohormesis.
  3. CLCF1 inhibits energy expenditure via suppressing brown fat thermogenesis.
  4. Adipose knockout of H-ferritin improves energy metabolism in mice.
  5. Depletion of JunB increases adipocyte thermogenic capacity and ameliorates diet-induced insulin resistance.
  6. Adults with metabolically healthy overweight or obesity present more brown adipose tissue and higher thermogenesis than their metabolically unhealthy counterparts.
  7. Brown adipose tissue activation in humans increases plasma levels of lipid mediators.
  8. EPAC1 boosts thermogenic adipocyte formation.
  9. Human Genetic Variation at rs10071329 Correlates with Adiposity-related Traits, Modulates PPARGC1B Expression, and Alters Brown Adipocyte Function.
  10. Hypoxia and intra-complex genetic suppressors rescue complex I mutants by a shared mechanism.
  11. Deletion of the mitochondrial calcium uniporter in adipose tissue promotes energy expenditure and alleviates diet-induced obesity.
  12. Identification of TMEM126A as OXA1L-interacting protein reveals cotranslational quality control in mitochondria.
  1. Nat Cell Biol. 2024 Jan 09.
    EPAC1 enhances brown fat growth and beige adipogenesis.
    Laia Reverte-Salisa, Sana Siddig, Staffan Hildebrand, Xi Yao, Jelena Zurkovic, Michelle Y Jaeckstein, Joerg Heeren, Frank Lezoualc'h, Natalie Krahmer, Alexander Pfeifer.
      Brown adipose tissue (BAT) is a central thermogenic organ that enhances energy expenditure and cardiometabolic health. However, regulators that specifically increase the number of thermogenic adipocytes are still an unmet need. Here, we show that the cAMP-binding protein EPAC1 is a central regulator of adaptive BAT growth. In vivo, selective pharmacological activation of EPAC1 increases BAT mass and browning of white fat, leading to higher energy expenditure and reduced diet-induced obesity. Mechanistically, EPAC1 coordinates a network of regulators for proliferation specifically in thermogenic adipocytes, but not in white adipocytes. We pinpoint the effects of EPAC1 to PDGFRα-positive preadipocytes, and the loss of EPAC1 in these cells impedes BAT growth and worsens diet-induced obesity. Importantly, EPAC1 activation enhances the proliferation and differentiation of human brown adipocytes and human brown fat organoids. Notably, a coding variant of RAPGEF3 (encoding EPAC1) that is positively correlated with body mass index abolishes noradrenaline-induced proliferation of brown adipocytes. Thus, EPAC1 might be an attractive target to enhance thermogenic adipocyte number and energy expenditure to combat metabolic diseases.
    DOI:  https://doi.org/10.1038/s41556-023-01311-9
  2. EMBO J. 2024 Jan 11.
    Brown adipose tissue CoQ deficiency activates the integrated stress response and FGF21-dependent mitohormesis.
    Ching-Fang Chang, Amanda L Gunawan, Irene Liparulo, Peter-James H Zushin, Kaitlyn Vitangcol, Greg A Timblin, Kaoru Saijo, Biao Wang, Güneş Parlakgül, Ana Paula Arruda, Andreas Stahl.
      Coenzyme Q (CoQ) is essential for mitochondrial respiration and required for thermogenic activity in brown adipose tissues (BAT). CoQ deficiency leads to a wide range of pathological manifestations, but mechanistic consequences of CoQ deficiency in specific tissues, such as BAT, remain poorly understood. Here, we show that pharmacological or genetic CoQ deficiency in BAT leads to stress signals causing accumulation of cytosolic mitochondrial RNAs and activation of the eIF2α kinase PKR, resulting in activation of the integrated stress response (ISR) with suppression of UCP1 but induction of FGF21 expression. Strikingly, despite diminished UCP1 levels, BAT CoQ deficiency displays increased whole-body metabolic rates at room temperature and thermoneutrality resulting in decreased weight gain on high-fat diets (HFD). In line with enhanced metabolic rates, BAT and inguinal white adipose tissue (iWAT) interorgan crosstalk caused increased browning of iWAT in BAT-specific CoQ deficient animals. This mitohormesis-like effect depends on the ATF4-FGF21 axis and BAT-secreted FGF21, revealing an unexpected role for CoQ in the modulation of whole-body energy expenditure with wide-ranging implications for primary and secondary CoQ deficiencies.
    Keywords:  Brown Adipose Tissue; Coenzyme Q; FGF21; Mitochondrial Unfolded Protein Response; Mitohormesis
    DOI:  https://doi.org/10.1038/s44318-023-00008-x
  3. Proc Natl Acad Sci U S A. 2024 Jan 16. 121(3): e2310711121
    CLCF1 inhibits energy expenditure via suppressing brown fat thermogenesis.
    Youwen Yuan, Kangli Li, Xueru Ye, Shiyi Wen, Yanan Zhang, Fei Teng, Xuan Zhou, Yajuan Deng, Xiaoyu Yang, Weiwei Wang, Jiayang Lin, Shenjian Luo, Peizhen Zhang, Guojun Shi, Huijie Zhang.
      Brown adipose tissue (BAT) is the main site of nonshivering thermogenesis which plays an important role in thermogenesis and energy metabolism. However, the regulatory factors that inhibit BAT activity remain largely unknown. Here, cardiotrophin-like cytokine factor 1 (CLCF1) is identified as a negative regulator of thermogenesis in BAT. Adenovirus-mediated overexpression of CLCF1 in BAT greatly impairs the thermogenic capacity of BAT and reduces the metabolic rate. Consistently, BAT-specific ablation of CLCF1 enhances the BAT function and energy expenditure under both thermoneutral and cold conditions. Mechanistically, adenylate cyclase 3 (ADCY3) is identified as a downstream target of CLCF1 to mediate its role in regulating thermogenesis. Furthermore, CLCF1 is identified to negatively regulate the PERK-ATF4 signaling axis to modulate the transcriptional activity of ADCY3, which activates the PKA substrate phosphorylation. Moreover, CLCF1 deletion in BAT protects the mice against diet-induced obesity by promoting BAT activation and further attenuating impaired glucose and lipid metabolism. Therefore, our results reveal the essential role of CLCF1 in regulating BAT thermogenesis and suggest that inhibiting CLCF1 signaling might be a potential therapeutic strategy for improving obesity-related metabolic disorders.
    Keywords:  CLCF1; brown adipose tissue; obesity; thermogenesis
    DOI:  https://doi.org/10.1073/pnas.2310711121
  4. Mol Metab. 2024 Jan 05. pii: S2212-8778(24)00002-4. [Epub ahead of print] 101871
    Adipose knockout of H-ferritin improves energy metabolism in mice.
    Binyu Lu, Shanshan Guo, Jialin Zhao, Xiaoting Wang, Bing Zhou.
       OBJECTIVE: Ferritin, the principal iron storage protein, is essential to iron homeostasis. How iron homeostasis affects the adipose tissue is not well understood. We investigated the role of ferritin heavy chain in adipocytes in energy metabolism.
    METHODS: We generated adipocyte-specific ferritin heavy chain (Fth, also known as Fth1) knockout mice, herein referred to as FthAKO. These mice were analyzed for iron homeostasis, oxidative stress, mitochondrial biogenesis and activity, adaptive thermogenesis, insulin sensitivity, and metabolic measurements. Mouse embryonic fibroblasts and primary mouse adipocytes were used for in vitro experiments.
    RESULTS: In FthAKO mice, the adipose iron homeostasis was disrupted, accompanied by elevated expression of adipokines, dramatically induced heme oxygenase 1(Hmox1) expression, and a notable decrease in the mitochondrial ROS level. Cytosolic ROS elevation in the adipose tissue of FthAKO mice was very mild, and we only observed this in the brown adipose tissue (BAT) but not in the white adipose tissue (WAT). FthAKO mice presented an altered metabolic profile and showed increased insulin sensitivity, glucose tolerance, and improved adaptive thermogenesis. Interestingly, loss of ferritin resulted in enhanced mitochondrial respiration capacity and a preference for lipid metabolism.
    CONCLUSIONS: These findings indicate that ferritin in adipocytes is indispensable to intracellular iron homeostasis and regulates systemic lipid and glucose metabolism.
    Keywords:  Adipocyte; Fth1; Glucose metabolism; Iron homeostasis; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.molmet.2024.101871
  5. Nat Metab. 2024 Jan 08.
    Depletion of JunB increases adipocyte thermogenic capacity and ameliorates diet-induced insulin resistance.
    Xing Zhang, Xiaofeng Ding, Chunqing Wang, Que Le, Dandan Wu, Anying Song, Guixiang Huang, Liping Luo, Yan Luo, Xin Yang, Aleyah E Goins, Sharina P Desai, Chengrui Qiu, Floyd D Silva, Lily Elizabeth Feldman, Jianlin Zhou, Michael F Spafford, Nathan H Boyd, Eric R Prossnitz, Xuexian O Yang, Qiong A Wang, Meilian Liu.
      The coexistence of brown adipocytes with low and high thermogenic activity is a fundamental feature of brown adipose tissue heterogeneity and plasticity. However, the mechanisms that govern thermogenic adipocyte heterogeneity and its significance in obesity and metabolic disease remain poorly understood. Here we show that in male mice, a population of transcription factor jun-B (JunB)-enriched (JunB+) adipocytes within the brown adipose tissue exhibits lower thermogenic capacity compared to high-thermogenic adipocytes. The JunB+ adipocyte population expands in obesity. Depletion of JunB in adipocytes increases the fraction of adipocytes exhibiting high thermogenic capacity, leading to enhanced basal and cold-induced energy expenditure and protection against diet-induced obesity and insulin resistance. Mechanistically, JunB antagonizes the stimulatory effects of PPARγ coactivator-1α on high-thermogenic adipocyte formation by directly binding to the promoter of oestrogen-related receptor alpha, a PPARγ coactivator-1α downstream effector. Taken together, our study uncovers that JunB shapes thermogenic adipocyte heterogeneity, serving a critical role in maintaining systemic metabolic health.
    DOI:  https://doi.org/10.1038/s42255-023-00945-1
  6. EBioMedicine. 2024 Jan 06. pii: S2352-3964(23)00514-5. [Epub ahead of print]100 104948
    Adults with metabolically healthy overweight or obesity present more brown adipose tissue and higher thermogenesis than their metabolically unhealthy counterparts.
    Lucas Jurado-Fasoli, Guillermo Sanchez-Delgado, Juan M A Alcantara, Francisco M Acosta, Rocio Sanchez-Sanchez, Idoia Labayen, Francisco B Ortega, Borja Martinez-Tellez, Jonatan R Ruiz.
       BACKGROUND: There is a subset of individuals with overweight/obesity characterized by a lower risk of cardiometabolic complications, the so-called metabolically healthy overweight/obesity (MHOO) phenotype. Despite the relatively higher levels of subcutaneous adipose tissue and lower visceral adipose tissue observed in individuals with MHOO than individuals with metabolically unhealthy overweight/obesity (MUOO), little is known about the differences in brown adipose tissue (BAT).
    METHODS: This study included 53 young adults (28 women) with a body mass index (BMI) ≥25 kg/m2 which were classified as MHOO (n = 34) or MUOO (n = 19). BAT was assessed through a static 18F-FDG positron emission tomography/computed tomography scan after a 2-h personalized cooling protocol. Energy expenditure, skin temperature, and thermal perception were assessed during a standardized mixed meal test (3.5 h) and a 1-h personalized cold exposure. Body composition was assessed by dual-energy x-ray absorptiometry, energy intake was determined during an ad libitum meal test and dietary recalls, and physical activity levels were determined by a wrist-worn accelerometer.
    FINDINGS: Participants with MHOO presented higher BAT volume (+124%, P = 0.008), SUVmean (+63%, P = 0.001), and SUVpeak (+133%, P = 0.003) than MUOO, despite having similar BAT mean radiodensity (P = 0.354). In addition, individuals with MHOO exhibited marginally higher meal-induced thermogenesis (P = 0.096) and cold-induced thermogenesis (+158%, P = 0.050). Moreover, MHOO participants showed higher supraclavicular skin temperature than MUOO during the first hour of the postprandial period and during the cold exposure, while no statistically significant differences were observed in other skin temperature parameters. We observed no statistically significant differences between MHOO and MUOO in thermal perception, body composition, outdoor ambient temperature exposure, resting metabolic rate, energy intake, or physical activity levels.
    INTERPRETATION: Adults with MHOO present higher BAT volume and activity than MUOO. The higher meal- and cold-induced thermogenesis and cold-induced supraclavicular skin temperature are compatible with a higher BAT activity. Overall, these results suggest that BAT presence and activity might be linked to a healthier phenotype in young adults with overweight or obesity.
    FUNDING: See acknowledgments section.
    Keywords:  Adaptive thermogenesis; Brown fat; Cardiometabolic health; Metabolism; Thermoregulation
    DOI:  https://doi.org/10.1016/j.ebiom.2023.104948
  7. J Clin Endocrinol Metab. 2024 Jan 10. pii: dgae016. [Epub ahead of print]
    Brown adipose tissue activation in humans increases plasma levels of lipid mediators.
    Mary E Walker, Sean D Kodani, Hebe Agustina Mena, Yu-Hua Tseng, Aaron M Cypess, Matthew Spite.
       CONTEXT: Activation of brown adipose tissue (BAT) thermogenesis improves insulin sensitivity and is beneficial in obesity. Emerging evidence indicates that BAT activation increases lipid mediators that play autocrine and endocrine roles to regulate metabolism and inflammation.
    OBJECTIVE: The goal of the study was to determine the relationship between two distinct approaches of BAT activation (cold exposure and mirabegron treatment) with lipid mediators in humans.
    METHODS: Healthy female subjects (n = 14) were treated with β3-adrenergic receptor agonist mirabegron (100 mg) daily for 28 days. A subset of female subjects (n = 8) was additionally exposed to cold temperatures (14-16°C) for 2 hours using a cooling vest prior to initiating mirabegron treatment.
    MAIN OUTCOME MEASURES: A panel of lipid mediators was assessed in plasma using targeted liquid chromatography-tandem mass spectrometry, and their relationship to anthropometric and metabolic parameters was determined.
    RESULTS: Activation of BAT with cold exposure acutely increased levels of lipoxygenase and cyclooxygenase products, including 12-hydroxyeicosapentaenoic acid (HEPE), 12-hydroxyeicosatetraenoic acid (HETE), 5-HETE, 14-hydroxydocosahexaenoic acid (HDHA), an isomer of maresin 2 (MaR2), 17-HDHA, protectin D1 (PD1), and prostaglandin E2 (PGE2). Mirabegron treatment similarly increased these products acutely, although levels of some mediators were blunted after chronic mirabegron treatment. Selected lipid mediators, including a MaR2 isomer, 17-HDHA, 5-HETE, and 15-HETE, positively correlated with non-esterified fatty acids and negatively correlated with the respiratory quotient, while PD1, 15-HETE, and 5-HETE positively correlated with adiponectin.
    CONCLUSION: These results indicate that selected lipid mediators may serve as biomarkers of BAT activation.
    Keywords:  Brown Adipose Tissue; Cold-exposure; Lipid Mediators
    DOI:  https://doi.org/10.1210/clinem/dgae016
  8. Nat Cell Biol. 2024 Jan 09.
    EPAC1 boosts thermogenic adipocyte formation.
    Evan D Rosen.
      
    DOI:  https://doi.org/10.1038/s41556-023-01304-8
  9. Diabetes. 2024 Jan 08. pii: db230531. [Epub ahead of print]
    Human Genetic Variation at rs10071329 Correlates with Adiposity-related Traits, Modulates PPARGC1B Expression, and Alters Brown Adipocyte Function.
    Mi Huang, Rashmi B Prasad, Daniel E Coral, Line Hjort, Daniel T R Minja, Hindrik Mulder, Paul W Franks, Sebastian Kalamajski.
      Human genetic variation in PPARGC1B has been associated with adiposity, but the genetic variants that affect PPARGC1B expression have not been experimentally determined. Here, guided by previous observational data, we used CRISPR/Cas9 to scarlessly edit the alleles of the candidate causal genetic variant rs10071329 in a human brown adipocyte cell line (hBAs). Switching the rs10071329 genotype from A/A to G/G enhanced PPARGC1B expression throughout the adipogenic differentiation, identifying rs10071329 as a cis-eQTL. The higher PPARGC1B expression in G/G cells coincided with greater accumulation of triglycerides, and higher expression of mitochondria-encoded genes, but without significant effects on adipogenic marker expression. Furthermore, G/G cells had improved basal- and norepinephrine-stimulated mitochondrial respiration, possibly relating to enhanced mitochondrial gene expression. The G/G cells also exhibited increased norepinephrine-stimulated glycerol release, indicating improved lipolysis. Altogether, our results showed that rs10071329 is a cis-eQTL, with the G/G genotype conferring enhanced PPARGC1B expression, with consequent improved mitochondrial function and response to norepinephrine in brown adipocytes. This genetic variant, and as yet undetermined eQTLs, at PPARGC1B could prove useful in genotype-based precision medicine for obesity treatment.
    DOI:  https://doi.org/10.2337/db23-0531
  10. Cell. 2024 Jan 05. pii: S0092-8674(23)01342-9. [Epub ahead of print]
    Hypoxia and intra-complex genetic suppressors rescue complex I mutants by a shared mechanism.
    Joshua D Meisel, Maria Miranda, Owen S Skinner, Presli P Wiesenthal, Sandra M Wellner, Alexis A Jourdain, Gary Ruvkun, Vamsi K Mootha.
      The electron transport chain (ETC) of mitochondria, bacteria, and archaea couples electron flow to proton pumping and is adapted to diverse oxygen environments. Remarkably, in mice, neurological disease due to ETC complex I dysfunction is rescued by hypoxia through unknown mechanisms. Here, we show that hypoxia rescue and hyperoxia sensitivity of complex I deficiency are evolutionarily conserved to C. elegans and are specific to mutants that compromise the electron-conducting matrix arm. We show that hypoxia rescue does not involve the hypoxia-inducible factor pathway or attenuation of reactive oxygen species. To discover the mechanism, we use C. elegans genetic screens to identify suppressor mutations in the complex I accessory subunit NDUFA6/nuo-3 that phenocopy hypoxia rescue. We show that NDUFA6/nuo-3(G60D) or hypoxia directly restores complex I forward activity, with downstream rescue of ETC flux and, in some cases, complex I levels. Additional screens identify residues within the ubiquinone binding pocket as being required for the rescue by NDUFA6/nuo-3(G60D) or hypoxia. This reveals oxygen-sensitive coupling between an accessory subunit and the quinone binding pocket of complex I that can restore forward activity in the same manner as hypoxia.
    Keywords:  C. elegans; NADH:ubiquinone oxidoreductase; NDUFA6; NDUFS4; complex I; electron transport chain; hyperoxia; hypoxia; mitochondria; oxygen
    DOI:  https://doi.org/10.1016/j.cell.2023.12.010
  11. Mol Metab. 2024 Jan 08. pii: S2212-8778(24)00004-8. [Epub ahead of print] 101873
    Deletion of the mitochondrial calcium uniporter in adipose tissue promotes energy expenditure and alleviates diet-induced obesity.
    Mengting Jia, Siqi Liu, Yang Xiao, Zhiwang Zhang, Mingming Li, Xinyu Qi, Xinyi Qi, Lin Yu, Caiyong Zhang, Tianyu Jiang, Tingli Pan, Yu Sun, Jingsu Yu, Songtao Su, Yixing Li, Turtushikh Damba, Khongorzul Batchuluun, Yunxiao Liang, Lei Zhou.
       OBJECTIVES: Studies have shown a correlation between obesity and mitochondrial calcium homeostasis, yet it is unclear whether and how Mcu regulates adipocyte lipid deposition. This study aims to provide new potential target for the treatment of obesity and related metabolic diseases, and to explore the function of Mcu in adipose tissue.
    METHODS: We firstly investigated the role of mitoxantrone, an Mcu inhibitor, in the regulation of glucose and lipid metabolism in mouse adipocytes (3T3-L1 cells). Secondly, C57BL/6J mice were used as a research model to investigate the effects of Mcu inhibitors on fat accumulation and glucose metabolism in mice on a high-fat diet (HFD), and by using CRISPR/Cas9 technology, adipose tissue-specific Mcu knockdown mice (Mcufl/+ AKO) and Mcu knockout of mice (Mcufl/fl AKO) were obtained, to further investigate the direct effects of Mcu on fat deposition, glucose tolerance and insulin sensitivity in mice on a high-fat diet.
    RESULTS: We found the Mcu inhibitor reduced adipocytes lipid accumulation and adipose tissues mass in mice fed an HFD. Both Mcufl/+ AKO mice and Mcufl/fl AKO mice were resistant to HFD-induced obesity, compared to control mice. Mice with Mcufl/fl AKO showed improved glucose tolerance and insulin sensitivity as well as reduced hepatic lipid accumulation. Mechanistically, inhibition of Mcu promoted mitochondrial biogenesis and adipocyte browning, increase energy expenditure and alleviates diet-induced obesity.
    CONCLUSION: Our study demonstrates a link between adipocyte lipid accumulation and mCa2+ levels, suggesting that adipose-specific Mcu deficiency alleviates HFD-induced obesity and ameliorates metabolic disorders such as insulin resistance and hepatic steatosis. These effects may be achieved by increasing mitochondrial biosynthesis, promoting white fat browning and enhancing energy metabolism.
    Keywords:  Mcu; adipose tissue; calcium homeostasis; energy expenditure; mitoxantrone; obesity
    DOI:  https://doi.org/10.1016/j.molmet.2024.101873
  12. Mol Cell. 2023 Dec 29. pii: S1097-2765(23)01031-6. [Epub ahead of print]
    Identification of TMEM126A as OXA1L-interacting protein reveals cotranslational quality control in mitochondria.
    Sabine Poerschke, Silke Oeljeklaus, Luis Daniel Cruz-Zaragoza, Alexander Schenzielorz, Drishan Dahal, Hauke Sven Hillen, Hirak Das, Laura Sophie Kremer, Anusha Valpadashi, Mirjam Breuer, Johannes Sattmann, Ricarda Richter-Dennerlein, Bettina Warscheid, Sven Dennerlein, Peter Rehling.
      Cellular proteostasis requires transport of polypeptides across membranes. Although defective transport processes trigger cytosolic rescue and quality control mechanisms that clear translocases and membranes from unproductive cargo, proteins that are synthesized within mitochondria are not accessible to these mechanisms. Mitochondrial-encoded proteins are inserted cotranslationally into the inner membrane by the conserved insertase OXA1L. Here, we identify TMEM126A as a OXA1L-interacting protein. TMEM126A associates with mitochondrial ribosomes and translation products. Loss of TMEM126A leads to the destabilization of mitochondrial translation products, triggering an inner membrane quality control process, in which newly synthesized proteins are degraded by the mitochondrial iAAA protease. Our data reveal that TMEM126A cooperates with OXA1L in protein insertion into the membrane. Upon loss of TMEM126A, the cargo-blocked OXA1L insertase complexes undergo proteolytic clearance by the iAAA protease machinery together with its cargo.
    Keywords:  mitochondria; mitochondrial quality control; mitochondrial translation
    DOI:  https://doi.org/10.1016/j.molcel.2023.12.013
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