bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2025–04–13
eleven papers selected by
José Carlos de Lima-Júnior, Washington University
  1. The Futile Creatine Cycle powers UCP1-independent thermogenesis in classical BAT.
  2. Identification of a molecular resistor that controls UCP1-independent Ca2+ cycling thermogenesis in adipose tissue.
  3. TMEM65 joins the mitochondrial Ca2+ club.
  4. Preadipocyte IL-13/IL-13Rα1 signaling regulates beige adipogenesis through modulation of PPARγ activity.
  5. Deubiquitinating Enzyme USP2 Regulates Brown Adipose Tissue Thermogenesis via Controlling EBF2 Stabilization.
  6. CRISPR-Cas9 Screening Reveals Microproteins Regulating Adipocyte Proliferation and Lipid Metabolism.
  7. Pre-fertilization-origin preservation of brown fat-mediated energy expenditure in humans.
  8. TMEM65 regulates and is required for NCLX-dependent mitochondrial calcium efflux.
  9. Intergenerational metabolic effects of cold exposure.
  10. Suppression of hypothalamic oestrogenic signal sustains hyperprolactinemia and metabolic adaptation in lactating mice.
  11. Glycolysis model shows that allostery maintains high ATP and limits accumulation of intermediates.
  1. Nat Commun. 2025 Apr 04. 16(1): 3221
    The Futile Creatine Cycle powers UCP1-independent thermogenesis in classical BAT.
    Jakub Bunk, Mohammed F Hussain, Maria Delgado-Martin, Bozena Samborska, Mina Ersin, Abhirup Shaw, Janane F Rahbani, Lawrence Kazak.
      Classical brown adipose tissue (BAT) is traditionally viewed as relying exclusively on uncoupling protein 1 (UCP1) for thermogenesis via inducible proton leak. However, the physiological significance of UCP1-independent mechanisms linking substrate oxidation to ATP turnover in classical BAT has remained unclear. Here, we identify the Futile Creatine Cycle (FCC), a mitochondrial-localized energy-wasting pathway involving creatine phosphorylation by creatine kinase b (CKB) and phosphocreatine hydrolysis by tissue-nonspecific alkaline phosphatase (TNAP), as a key UCP1-independent thermogenic mechanism in classical BAT. Reintroducing mitochondrial-targeted CKB exclusively into interscapular brown adipocytes in vivo restores thermogenesis and cold tolerance in mice lacking native UCP1 and CKB, in a TNAP-dependent manner. Furthermore, mice with inducible adipocyte-specific co-deletion of TNAP and UCP1 exhibit severe cold-intolerance. These findings challenge the view that BAT thermogenesis depends solely on UCP1 because of insufficient ATP synthase activity and establishes the FCC as a physiologically relevant thermogenic pathway in classical BAT.
    DOI:  https://doi.org/10.1038/s41467-025-58294-4
  2. Cell Metab. 2025 Apr 02. pii: S1550-4131(25)00112-3. [Epub ahead of print]
    Identification of a molecular resistor that controls UCP1-independent Ca2+ cycling thermogenesis in adipose tissue.
    Christopher Auger, Mark Li, Masanori Fujimoto, Kenji Ikeda, Jin-Seon Yook, Timothy R O'Leary, María Paula Huertas Caycedo, Cai Xiaohan, Satoshi Oikawa, Anthony R P Verkerke, Kosaku Shinoda, Patrick R Griffin, Kenji Inaba, Roland H Stimson, Shingo Kajimura.
      Adipose tissue thermogenesis contributes to energy balance via mitochondrial uncoupling protein 1 (UCP1) and UCP1-independent pathways. Among UCP1-independent thermogenic mechanisms, one involves Ca2+ cycling via SERCA2b in adipose tissue; however, the underlying molecular basis remains elusive. Here, we report that an endoplasmic reticulum (ER) membrane-anchored peptide, C4orf3 (also known as another regulin [ALN]), uncouples SERCA2b Ca2+ transport from its ATP hydrolysis, rendering the SERCA2b-C4orf3 complex exothermic. Loss of C4orf3/ALN improved the energetic efficiency of SERCA2b-dependent Ca2+ transport without affecting SERCA2 expression, thereby reducing adipose tissue thermogenesis and increasing the adiposity of mice. Notably, genetic depletion of C4orf3 resulted in compensatory activation of UCP1-dependent thermogenesis following cold challenge. We demonstrated that genetic loss of both C4orf3 and Ucp1 additively impaired cold tolerance in vivo. Together, this study identifies C4orf3 as the molecular resistor to SERCA2b-mediated Ca2+ import that plays a key role in UCP1-independent thermogenesis and energy balance.
    Keywords:  Ca(2+) cycling; UCP1-independent; energy balance; obesity; thermogenesis
    DOI:  https://doi.org/10.1016/j.cmet.2025.03.009
  3. Nat Metab. 2025 Apr 08.
    TMEM65 joins the mitochondrial Ca2+ club.
    Yasemin Sancak.
      
    DOI:  https://doi.org/10.1038/s42255-025-01271-4
  4. J Clin Invest. 2025 Apr 08. pii: e169152. [Epub ahead of print]
    Preadipocyte IL-13/IL-13Rα1 signaling regulates beige adipogenesis through modulation of PPARγ activity.
    Alexandra R Yesian, Mayer M Chalom, Nelson H Knudsen, Alec L Hyde, Jean Personnaz, Hyunjii Cho, Yae-Huei Liou, Kyle A Starost, Chia-Wei Lee, Dong-Yan Tsai, Hsing-Wei Ho, Jr-Shiuan Lin, Jun Li, Frank B Hu, Alexander S Banks, Chih-Hao Lee.
      Type 2 innate lymphoid cells (ILC2) regulate the proliferation of preadipocytes that give rise to beige adipocytes. Whether and how ILC2 downstream Th2 cytokines control beige adipogenesis remain unclear. We employed cell systems and genetic models to examine the mechanism through which interleukin-13 (IL-13), an ILC2-derived Th2 cytokine, controls beige adipocyte differentiation. IL-13 priming in preadipocytes drives beige adipogenesis by upregulating beige-promoting metabolic programs, including mitochondrial oxidative metabolism and PPARγ-related pathways. The latter is mediated by increased expression and activity of PPARγ through IL-13 receptor α1 (IL-13Rα1) downstream effectors, STAT6 and p38 MAPK, respectively. Il13 knockout (Il13KO) or preadipocyte Il13ra1 knockout (Il13ra1KO) mice are refractory to cold- or β-3 adrenergic agonist-induced beiging in inguinal white adipose tissue, whereas Il4 knockout mice show no defects in beige adipogenesis. Il13KO and Il13ra1KO mouse models exhibit increased body weight/fat mass and dysregulated glucose metabolism but have a mild cold intolerant phenotype, likely due to their intact brown adipocyte recruitment. We also find that genetic variants of human IL13RA1 are associated with body mass index and type 2 diabetes. These results suggest that IL-13 signaling-regulated beige adipocyte function may play a predominant role in modulating metabolic homeostasis rather than in thermoregulation.
    Keywords:  Adipose tissue; Cell biology; Glucose metabolism; Metabolism; Obesity
    DOI:  https://doi.org/10.1172/JCI169152
  5. Mol Metab. 2025 Apr 04. pii: S2212-8778(25)00046-8. [Epub ahead of print] 102139
    Deubiquitinating Enzyme USP2 Regulates Brown Adipose Tissue Thermogenesis via Controlling EBF2 Stabilization.
    Yuejie Xu, Ying Chen, Ningning Bai, Yingying Su, Yafen Ye, Rong Zhang, Ying Yang, Caizhi Liu, Cheng Hu, Jiemin Pan.
       OBJECTIVE: The activation of brown adipose tissue (BAT) promotes energy expenditure is recognized as a promising therapeutic strategy for combating obesity. The deubiquitinating enzyme family members are widely involved in the process of energy metabolism. However, the specific deubiquitinating enzyme member that affects the BAT thermogenesis remains largely unexplored.
    METHODS: Adeno-associated virus, lentivirus and small molecule inhibitor were applied to generate USP2 gain- or loss-of-function both in vivo and in vitro. OxyMax comprehensive laboratory animal monitoring system, seahorse and transmission electron microscopy were used to determine the energy metabolism. Quantitative proteomics, immunofluorescence staining and co-immunoprecipitation were performed to reveal the potential substrates of USP2.
    RESULTS: USP2 is upregulated upon thermogenic activation in adipose, and has a close correlation with UCP1 mRNA levels in human adipose tissue. BAT-specific Usp2 knockdown or systemic USP2 inhibition resulted in impaired thermogenic programs both in vivo and in vitro. Conversely, overexpression of Usp2 in BAT conferred protection against high-fat diet-induced obesity and associated metabolic disorders. Proteome-wide analysis identified EBF2 as the substrate of USP2 that mediates the thermogenic function of USP2 in BAT.
    CONCLUSIONS: Our data demonstrated the vital role of USP2 in regulating BAT activation and systemic energy homeostasis. Activation of USP2-EBF2 interaction could be a potential therapeutic strategy against obesity.
    Keywords:  Brown adipose tissue; Deubiquitylation; EBF2; Thermogenesis; USP2
    DOI:  https://doi.org/10.1016/j.molmet.2025.102139
  6. bioRxiv. 2025 Mar 25. pii: 2025.03.21.644636. [Epub ahead of print]
    CRISPR-Cas9 Screening Reveals Microproteins Regulating Adipocyte Proliferation and Lipid Metabolism.
    Victor J Pai, Hazel Shan, Cynthia Donaldson, Joan Vaughan, Carolyn O'Connor, Michelle Liem, Antonio Pinto, Jolene Diedrich, Alan Saghatelian.
      Small open reading frames (smORFs) encode microproteins that play crucial roles in various biological processes, yet their functions in adipocyte biology remain largely unexplored. In a previous study, we identified thousands of smORFs in white and brown adipocytes derived from the stromal vascular fraction (SVF) of mice using ribosome profiling (Ribo-Seq). Here, we expand on this work by identifying additional smORFs related to adipocytes using the in vitro 3T3-L1 preadipocyte model. To systematically investigate the functional relevance of these smORFs, we designed a custom CRISPR/Cas9 guide RNA (sgRNA) library and screened for smORFs influencing adipocyte proliferation and differentiation. Through a dropout screen and fluorescence-assisted cell sorting (FACS) of lipid droplets, we identified dozens of smORFs that regulate either cell proliferation or lipid accumulation. Among these, we validated a novel microprotein as a key regulator of adipocyte differentiation. These findings highlight the potential of CRISPR/Cas9-based screening to uncover functional smORFs and provide a framework for further exploration of microproteins in adipocyte biology and metabolic regulation.
    Significance: Obesity and its associated metabolic disorders pose significant public health challenges, yet the molecular mechanisms regulating adipocyte function remain incompletely understood. Small open reading frames (smORFs) and their encoded microproteins represent an emerging class of regulatory elements with potential roles in metabolism. Here, we leveraged CRISPR/Cas9 screening to functionally characterize smORFs in adipocytes, identifying novel regulators of cell proliferation and lipid metabolism. Our findings demonstrate that conservation is not a prerequisite for smORF function, as we validated a mouse-specific microprotein that modulates adipocyte differentiation. This work establishes a robust pipeline for unbiased smORF discovery and highlights the potential for species-specific microproteins to regulate adipose biology. Future studies in human adipocytes may uncover additional microproteins with therapeutic relevance for obesity and metabolic disease.
    DOI:  https://doi.org/10.1101/2025.03.21.644636
  7. Nat Metab. 2025 Apr 07.
    Pre-fertilization-origin preservation of brown fat-mediated energy expenditure in humans.
    Takeshi Yoneshiro, Mami Matsushita, Sayuri Fuse-Hamaoka, Miyuki Kuroiwa, Yuko Kurosawa, Yosuke Yamada, Makoto Arai, Yuchen Wei, Makoto Iida, Kenichi Kuma, Toshimitsu Kameya, Tomoya Harada, Yoshihiro Matsumura, Tsuyoshi Osawa, Yoshiko Aoki, Hisashi Nakamura, Takafumi Hamaoka, Juro Sakai, Masayuki Saito.
      Environmental thermal stress substantially affects cellular plasticity of thermogenic adipocytes and energy balance through transcriptional and epigenetic mechanisms in rodents. However, roles of cold-adaptive epigenetic regulation of brown adipose tissue (BAT) in systemic energy metabolism in humans remained poorly understood. Here we report that individuals whose mothers conceived during cold seasons exhibit higher BAT activity, adaptive thermogenesis, increased daily total energy expenditure and lower body mass index and visceral fat accumulation. Structural equation modelling indicated that conception during the cold season protects against age-associated increase in body mass index through BAT activation in offspring. Meteorological analysis revealed that lower outdoor temperatures and greater fluctuations in daily temperatures during the fertilization period are key determinants of BAT activity. These findings suggest that BAT metabolic fate and susceptibility of metabolic diseases are preprogrammed by the epigenetic inheritance of cold exposure before the fertilization in humans.
    DOI:  https://doi.org/10.1038/s42255-025-01249-2
  8. Nat Metab. 2025 Apr 08.
    TMEM65 regulates and is required for NCLX-dependent mitochondrial calcium efflux.
    Joanne F Garbincius, Oniel Salik, Henry M Cohen, Carmen Choya-Foces, Adam S Mangold, Angelina D Makhoul, Anna E Schmidt, Dima Y Khalil, Joshua J Doolittle, Anya S Wilkinson, Emma K Murray, Michael P Lazaropoulos, Alycia N Hildebrand, Dhanendra Tomar, John W Elrod.
      The balance between mitochondrial calcium (mCa2+) uptake and efflux is essential for ATP production and cellular homeostasis. The mitochondrial sodium-calcium exchanger, NCLX, is a critical route of mCa2+ efflux in excitable tissues, such as the heart and brain, and animal models support NCLX as a promising therapeutic target to limit pathogenic mCa2+ overload. However, the mechanisms that regulate NCLX activity are largely unknown. Using proximity biotinylation proteomic screening, we identify the mitochondrial inner membrane protein TMEM65 as an NCLX binding partner that enhances sodium (Na+)-dependent mCa2+ efflux. Mechanistically, acute pharmacological NCLX inhibition or genetic deletion of NCLX ablates the TMEM65-dependent increase in mCa2+ efflux, and loss-of-function studies show that TMEM65 is required for Na+-dependent mCa2+ efflux. In line with these findings, knockdown of Tmem65 in mice promotes mCa2+ overload in the heart and skeletal muscle and impairs both cardiac and neuromuscular function. Collectively, our results show that loss of TMEM65 function in excitable tissue disrupts NCLX-dependent mCa2+ efflux, causing pathogenic mCa2+ overload, cell death, and organ-level dysfunction. These findings demonstrate the essential role of TMEM65 in regulating NCLX-dependent mCa2+ efflux and suggest modulation of TMEM65 as a therapeutic strategy for a variety of diseases.
    DOI:  https://doi.org/10.1038/s42255-025-01250-9
  9. Nat Metab. 2025 Apr 07.
    Intergenerational metabolic effects of cold exposure.
    R Teperino.
      
    DOI:  https://doi.org/10.1038/s42255-025-01222-z
  10. Nat Metab. 2025 Apr 10.
    Suppression of hypothalamic oestrogenic signal sustains hyperprolactinemia and metabolic adaptation in lactating mice.
    Meng Yu, Bing Feng, Jonathan C Bean, Qianru Zhao, Yongjie Yang, Hailan Liu, Yongxiang Li, Benjamin P Eappen, Hesong Liu, Longlong Tu, Kristine M Conde, Mengjie Wang, Xi Chen, Na Yin, Darah Ave Threat, Nathan Xu, Junying Han, Peiyu Gao, Yi Zhu, Darryl L Hadsell, Yang He, Pingwen Xu, Yanlin He, Chunmei Wang.
      17β-oestradiol (E2) inhibits overeating and promotes brown adipose tissue (BAT) thermogenesis, whereas prolactin (PRL) does the opposite. During lactation, the simultaneous decline in E2 and surge in PRL contribute to maternal metabolic adaptations, including hyperphagia and suppressed BAT thermogenesis. However, the underlying neuroendocrine mechanisms remain unclear. Here, we find that oestrogen receptor alpha (ERα)-expressing neurons in the medial basal hypothalamus (MBH), specifically the arcuate nucleus of the hypothalamus and the ventrolateral subdivision of the ventromedial hypothalamus (vlVMH), are suppressed during lactation. Deletion of ERα from MBH neurons in virgin female mice induces metabolic phenotypes characteristic of lactation, including hyperprolactinemia, hyperphagia and suppressed BAT thermogenesis. By contrast, activation of ERαvlVMH neurons in lactating mice attenuates these phenotypes. Overall, our study reveals an inhibitory effect of E2-ERαvlVMH signalling on PRL production, which is suppressed during lactation to sustain hyperprolactinemia and metabolic adaptations.
    DOI:  https://doi.org/10.1038/s42255-025-01268-z
  11. Biophys J. 2025 Apr 03. pii: S0006-3495(25)00211-5. [Epub ahead of print]
    Glycolysis model shows that allostery maintains high ATP and limits accumulation of intermediates.
    Mangyu Choe, Tal Einav, Rob Phillips, Denis V Titov.
      Glycolysis is a conserved metabolic pathway that produces ATP and biosynthetic precursors. It is not well understood how the control of mammalian glycolytic enzymes through allosteric feedback and mass action accomplishes various tasks of ATP homeostasis, such as controlling the rate of ATP production, maintaining high and stable ATP levels, ensuring that ATP hydrolysis generates a net excess of energy, and maintaining glycolytic intermediate concentrations within physiological levels. To investigate these questions, we developed a biophysical model of glycolysis based on enzyme rate equations derived from in vitro kinetic data. This is the first biophysical model of human glycolysis that successfully recapitulates the above tasks of ATP homeostasis and predicts absolute concentrations of glycolytic intermediates and isotope tracing kinetics that align with experimental measurements in human cells. We use the model to show that mass action alone is sufficient to control the ATP production rate and maintain the high energy of ATP hydrolysis. Meanwhile, allosteric regulation of hexokinase (HK) and phosphofructokinase (PFK) by ATP, ADP, inorganic phosphate, and glucose-6-phosphate is required to maintain high ATP levels and to prevent uncontrolled accumulation of phosphorylated intermediates of glycolysis. Allosteric feedback achieves the latter by maintaining HK and PFK enzyme activity at one-half of ATP demand and, thus, inhibiting the reaction of Harden and Young, which otherwise converts glucose to supraphysiological levels of phosphorylated glycolytic intermediates at the expense of ATP. Our methodology provides a roadmap for a quantitative understanding of how metabolic homeostasis emerges from the activities of individual enzymes.
    Keywords:  allosteric feedback; glycolysis; metabolism; modeling
    DOI:  https://doi.org/10.1016/j.bpj.2025.03.037
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