bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2025–01–26
eleven papers selected by
José Carlos de Lima-Júnior, Washington University
  1. Transcriptomic Signatures of Cold Acclimated Adipocytes Reveal CXCL12 as a Brown Autocrine and Paracrine Chemokine.
  2. Metabolic dysfunction in mice with adipocyte specific ablation of the adenosine A2A receptor.
  3. Regulation of UCP1 expression by PPARα and pemafibrate in human beige adipocytes.
  4. Mitochondrial NAD+ transporter SLC25A51 linked to human aortic disease.
  5. Homeobox C4 transcription factor promotes adipose tissue thermogenesis.
  6. Purification and characterization of recombinant human mitochondrial proton-pumping nicotinamide nucleotide transhydrogenase.
  7. Mitochondrial NAD+ deficiency in vascular smooth muscle impairs collagen III turnover to trigger thoracic and abdominal aortic aneurysm.
  8. Chronic intermittent fasting impairs β cell maturation and function in adolescent mice.
  9. Precise modelling of mitochondrial diseases using optimized mitoBEs.
  10. Commentary: Why do many cell biology papers contain fundamental bioenergetic errors?
  11. The (dys)regulation of energy storage in obesity.
  1. Mol Metab. 2025 Jan 21. pii: S2212-8778(25)00009-2. [Epub ahead of print] 102102
    Transcriptomic Signatures of Cold Acclimated Adipocytes Reveal CXCL12 as a Brown Autocrine and Paracrine Chemokine.
    Marina Agueda-Oyarzabal, Marie S Isidor, Kaja Plucińska, Lars R Ingerslev, Oksana Dmytriyeva, Patricia S S Petersen, Sara Laftih, Axel B Pontoppidan, Jo B Henningsen, Kaja Rupar, Erin L Brown, Thue W Schwartz, Romain Barrès, Zachary Gerhart-Hines, Camilla C Schéele, Brice Emanuelli.
      Besides its thermogenic capacity, brown adipose tissue (BAT) performs important secretory functions that regulate metabolism. However, the BAT microenvironment and factors involved in BAT homeostasis and adaptation to cold remain poorly characterized. We therefore aimed to study brown adipocyte-derived secreted factors that may be involved in adipocyte function and/or may orchestrate intercellular communications. For this, mRNA levels in mature adipocytes from mouse adipose depots were assessed using RNA sequencing upon chronic cold acclimation, and bioinformatic analysis was used to identify secreted factors. Among 858 cold-sensitive transcripts in BAT adipocytes were 210 secreted factor-encoding genes, and Cxcl12 was the top brown adipocyte-enriched cytokine. Cxcl12 mRNA expression analysis by RT-qPCR and fluorescence in situ hybridization specified Cxcl12 distribution in various cell types, and indicated its enrichment in cold-acclimated brown adipocytes. We found that CXCL12 secretion from BAT was increased after chronic cold, yet its level in plasma remained unchanged, suggesting a local/paracrine function. Cxcl12 knockdown in mature brown adipocytes impaired thermogenesis, as assessed by norepinephrine (NE)-induced glycerol release and mitochondrial respiration. However, knockdown of Cxcl12 did not impact β-adrenergic signaling, suggesting that CXCL12 regulates adipocyte function downstream of the β-adrenergic pathway. Moreover, we provide evidence for CXCL12 to exert intercellular cross-talk via its capacity to promote macrophage chemotaxis and neurite outgrowth. Collectively, our results indicate that CXCL12 is a brown adipocyte-enriched, cold-induced secreted factor involved in adipocyte function and the BAT microenvironment communication network.
    Keywords:  Brown adipocyte; CXCL12; cold acclimation; intercellular communication; secretome
    DOI:  https://doi.org/10.1016/j.molmet.2025.102102
  2. J Biol Chem. 2025 Jan 17. pii: S0021-9258(25)00053-5. [Epub ahead of print] 108206
    Metabolic dysfunction in mice with adipocyte specific ablation of the adenosine A2A receptor.
    Narendra Verma, Luce Perie, Michele Silvestro, Anupama Verma, Bruce N Cronstein, Bhama Ramkhelawon, Elisabetta Mueller.
      It has been well established that adenosine plays a key role in the control of inflammation through G protein coupled receptors and recently shown that it can regulate thermogenesis. Here we investigated the specific requirements of the adenosine A2A receptor (A2AR) in mature adipocytes for thermogenic functionality and metabolic homeostasis. We generated fat tissue specific adenosine A2A receptor knock-out mice to assess the influence of signaling through this receptor on brown and beige fat functionality, obesity, insulin sensitivity, inflammation and liver function. Fat specific A2AR knock-out and wild type littermate mice were compared for potential differences in cold tolerance and energy metabolism. In addition, we measured glucose metabolism, AT inflammation and liver phenotypes in mice of the two genotypes after exposure to a diet rich in fat. Our results provide novel evidence indicating that loss of the adenosine A2A receptor specifically in adipocytes is associated with cold intolerance and decreased oxygen consumption. Furthermore, mice with fat specific ablation of the A2AR exposed to a diet rich in fat showed increased propensity to obesity, decreased insulin sensitivity, elevated adipose tissue inflammation and hepato-steatosis and -steatitis. Overall, our data provide novel evidence that A2AR in mature adipocytes safeguards metabolic homeostasis, suggesting the possibility of targeting this receptor selectively in fat for the treatment of metabolic disease.
    Keywords:  UCP1; adenosine A2A receptor; brown and beige adipose tissue; insulin resistance; obesity
    DOI:  https://doi.org/10.1016/j.jbc.2025.108206
  3. Life Sci. 2025 Jan 17. pii: S0024-3205(25)00039-6. [Epub ahead of print] 123406
    Regulation of UCP1 expression by PPARα and pemafibrate in human beige adipocytes.
    Pierre-Louis Batrow, Christian H Roux, Nadine Gautier, Luc Martin, Brigitte Sibille, Hervé Guillou, Catherine Postic, Dominique Langin, Isabelle Mothe-Satney, Ez-Zoubir Amri.
       AIMS: Thermogenic adipocytes are able to dissipate energy as heat from lipids and carbohydrates through enhanced uncoupled respiration, due to UCP1 activity. PPAR family of transcription factors plays an important role in adipocyte biology. The purpose of this work was to characterize the role of PPARα and pemafibrate in the control of thermogenic adipocyte formation and function.
    MATERIALS AND METHODS: We used human multipotent adipose-derived stem cells and primary cultures of stroma-vascular fraction cells, transfected with siRNA against PPARα, differentiated into white or beige adipocytes, by the treatment of rosiglitazone or pemafibrate. The expression of key marker genes of adipogenesis and thermogenesis was determined using RT-qPCR and Western blotting. An RNAseq analysis was also performed.
    KEY FINDINGS: We show that inhibition of PPARα mRNA increases UCP1 mRNA and protein expression in beige adipocytes induced by rosiglitazone. Knock-down of PPARα also increases stimulated glycerol release. Pemafibrate, described as a selective PPARα modulator, induces adipogenesis and the expression of UCP1 in the absence of PPARα expression. These effects are inhibited by a specific PPARγ antagonist highly suggesting that the pemafibrate effects in adipogenesis and beiging were mediated by PPARγ.
    SIGNIFICANCE: Conversion of white into thermogenic adipocytes is mainly due to the activation of PPARγ. Moreover, we show that PPARα seems to act as a hindrance for PPARγ-dependent beiging. Our data question the role of PPARα in human adipocyte browning and the specificity of pemafibrate in adipocytes.
    Keywords:  Beige adipocyte; PPARα; PPARγ; Pemafibrate; UCP1; White adipocyte
    DOI:  https://doi.org/10.1016/j.lfs.2025.123406
  4. Nat Cardiovasc Res. 2025 Jan 22.
    Mitochondrial NAD+ transporter SLC25A51 linked to human aortic disease.
    Gabriel K Adzika, Ricardo A Velázquez Aponte, Joseph A Baur.
      
    DOI:  https://doi.org/10.1038/s44161-024-00599-6
  5. Diabetes. 2025 Jan 24. pii: db240675. [Epub ahead of print]
    Homeobox C4 transcription factor promotes adipose tissue thermogenesis.
    Ting Yang, Yuxuan Wang, Hang Li, Fengshou Shi, Siqi Xu, Yingting Wu, Jiaqi Xin, Yi Liu, Mengxi Jiang.
      The homeobox (HOX) family has shown potential in adipose development and function, yet the specific HOX proteins fueling adipose thermogenesis remain elusive. In this study, we uncovered the novel function of HOXC4 in stimulating adipose thermogenesis. Our bioinformatic analysis indicated an enrichment of Hoxc4 co-expressed genes in metabolic pathways and linked HOXC4 polymorphisms to metabolic parameters, suggesting its involvement in metabolic regulation. In mouse brown adipose tissue, HOXC4 expression negatively correlated with body weight and positively correlated with Ucp1 expression. Through gain- and loss-of-function experiments in mice, we established that HOXC4 is both sufficient and necessary for adipose thermogenesis, leading to enhanced cold tolerance and protection against diet-induced obesity and insulin resistance. Human and mouse primary adipocyte models further confirmed that the thermogenic activation function of HOXC4 is cell-autonomous. Mechanistically, HOXC4 collaborates with cofactor NCOA1 via its hexapeptide motif to form a transcriptional complex at the Ucp1 promoter, thereby promoting Ucp1 transcription and adipose thermogenesis. These findings delineate a novel mechanism by which HOXC4 drives thermogenic transcription and adipose energy metabolism, offering potential therapeutic targets for obesity-related metabolic disorders.
    DOI:  https://doi.org/10.2337/db24-0675
  6. Biochim Biophys Acta Bioenerg. 2025 Jan 17. pii: S0005-2728(25)00006-4. [Epub ahead of print] 149540
    Purification and characterization of recombinant human mitochondrial proton-pumping nicotinamide nucleotide transhydrogenase.
    Sangjin Hong, Simone Graf, Christoph von Ballmoos, Robert B Gennis.
      The human mitochondrial nicotinamide nucleotide transhydrogenase (NNT) uses the proton motive force to drive hydride transfer from NADH to NADP+ and is a major contributor to the generation of mitochondrial NADPH. NNT plays a critical role in maintaining cellular redox balance. NNT-deficiency results in oxidative damage and its absence results in familial glucocorticoid deficiency. Recently it has also become clear that NNT is a tumor promoter whose presence in mouse models of non-small cell lung cancer results in enhanced tumor growth and aggressiveness. The presence of NNT mitigates the effects of oxidative stress and facilitates cancer cell proliferation, suggesting NNT-inhibition as a promising therapeutic strategy. The human NNT is a homodimer in which each subunit has a molecular weight of 114 kDa and 14 transmembrane spans. Here we report on the development of a system for isolating full-length recombinant human NNT using Escherichia coli. The purified enzyme is catalytically active, and the enzyme reconstituted into proteoliposomes pumps protons and generates a proton motive force capable of driving ATP synthesis by E. coli ATP synthase. The recombinant human NNT will facilitate structural and biochemical studies as well as provide a useful tool to develop and characterize potential anti-cancer therapeutics.
    Keywords:  Cancer; Familial glucocorticoid deficiency; Heterologous overexpression; Human nicotinamide nucleotide transhydrogenase; Integral membrane protein
    DOI:  https://doi.org/10.1016/j.bbabio.2025.149540
  7. Nat Cardiovasc Res. 2025 Jan 22.
    Mitochondrial NAD+ deficiency in vascular smooth muscle impairs collagen III turnover to trigger thoracic and abdominal aortic aneurysm.
    Jingjing Zhang, Yuyi Tang, Shan Zhang, Zhuxin Xie, Wenrui Ma, Shaowen Liu, Yixuan Fang, Shufen Zheng, Ce Huang, Guoquan Yan, Mieradilijiang Abudupataer, Yue Xin, Jingqiao Zhu, Wenjing Han, Weizhong Wang, Fenglin Shen, Hao Lai, Yang Liu, Dan Ye, Fa-Xing Yu, Yanhui Xu, Cuiping Pan, Chunsheng Wang, Kai Zhu, Weijia Zhang.
      Thoracic and abdominal aortic aneurysm poses a substantial mortality risk in adults, yet many of its underlying factors remain unidentified. Here, we identify mitochondrial nicotinamide adenine dinucleotide (NAD)⁺ deficiency as a causal factor for the development of aortic aneurysm. Multiomics analysis of 150 surgical aortic specimens indicated impaired NAD+ salvage and mitochondrial transport in human thoracic aortic aneurysm, with expression of the NAD+ transporter SLC25A51 inversely correlating with disease severity and postoperative progression. Genome-wide gene-based association analysis further linked low SLC25A51 expression to risk of aortic aneurysm and dissection. In mouse models, smooth muscle-specific knockout of Nampt, Nmnat1, Nmnat3, Slc25a51, Nadk2 and Aldh18a1, genes involved in NAD+ salvage and transport, induced aortic aneurysm, with Slc25a51 deletion producing the most severe effects. Using these models, we suggest a mechanism that may explain the disease pathogenesis: the production of type III procollagen during aortic medial matrix turnover imposes a high demand for proline, an essential amino acid component of collagen. Deficiency in the mitochondrial NAD⁺ pool, regulated by NAD⁺ salvage and transport, hinders proline biosynthesis in mitochondria, contributing to thoracic and abdominal aortic aneurysm.
    DOI:  https://doi.org/10.1038/s44161-024-00606-w
  8. Cell Rep. 2025 Jan 18. pii: S2211-1247(24)01576-6. [Epub ahead of print]44(2): 115225
    Chronic intermittent fasting impairs β cell maturation and function in adolescent mice.
    Leonardo Matta, Peter Weber, Suheda Erener, Alina Walth-Hummel, Daniela Hass, Lea K Bühler, Katarina Klepac, Julia Szendroedi, Joel Guerra, Maria Rohm, Michael Sterr, Heiko Lickert, Alexander Bartelt, Stephan Herzig.
      Intermittent fasting (IF) is a nutritional lifestyle intervention with broad metabolic benefits, but whether the impact of IF depends on the individual's age is unclear. Here, we investigated the effects of IF on systemic metabolism and β cell function in old, middle-aged, and young mice. Short-term IF improves glucose homeostasis across all age groups without altering islet function and morphology. In contrast, while chronic IF is beneficial for adult mice, it results in impaired β cell function in the young. Using single-cell RNA sequencing (scRNA-seq), we delineate that the β cell maturation and function scores are reduced in young mice. In human islets, a similar pattern is observed in type 1 (T1D), but not type 2 (T2D), diabetes, suggesting that the impact of chronic IF in adolescence is linked to the development of β cell dysfunction. Our study suggests considering the duration of IF in younger persons, as it may worsen rather than reduce diabetes outcomes.
    Keywords:  CP: Metabolism; Langerhans’ islets; diabetes; glucose metabolism; insulin; intermittent fasting; pancreas; weight loss; β cells
    DOI:  https://doi.org/10.1016/j.celrep.2024.115225
  9. Nature. 2025 Jan 22.
    Precise modelling of mitochondrial diseases using optimized mitoBEs.
    Xiaoxue Zhang, Xue Zhang, Jiwu Ren, Jiayi Li, Xiaoxu Wei, Ying Yu, Zongyi Yi, Wensheng Wei.
      The development of animal models is crucial for studying and treating mitochondrial diseases. Here we optimized adenine and cytosine deaminases to reduce off-target effects on the transcriptome and the mitochondrial genome, improving the accuracy and efficiency of our newly developed mitochondrial base editors (mitoBEs)1. Using these upgraded mitoBEs (version 2 (v2)), we targeted 70 mouse mitochondrial DNA mutations analogous to human pathogenic variants2, establishing a foundation for mitochondrial disease mouse models. Circular RNA-encoded mitoBEs v2 achieved up to 82% editing efficiency in mice without detectable off-target effects in the nuclear genome. The edited mitochondrial DNA persisted across various tissues and was maternally inherited, resulting in F1 generation mice with mutation loads as high as 100% and some mice exhibiting editing only at the target site. By optimizing the transcription activator-like effector (TALE) binding site, we developed a single-base-editing mouse model for the mt-Nd5 A12784G mutation. Phenotypic evaluations led to the creation of mouse models for the mt-Atp6 T8591C and mt-Nd5 A12784G mutations, exhibiting phenotypes corresponding to the reduced heart rate seen in Leigh syndrome and the vision loss characteristic of Leber's hereditary optic neuropathy, respectively. Moreover, the mt-Atp6 T8591C mutation proved to be more deleterious than mt-Nd5 A12784G, affecting embryonic development and rapidly diminishing through successive generations. These upgraded mitoBEs offer a highly efficient and precise strategy for constructing mitochondrial disease models, laying a foundation for further research in this field.
    DOI:  https://doi.org/10.1038/s41586-024-08469-8
  10. Biochim Biophys Acta Bioenerg. 2025 Jan 17. pii: S0005-2728(25)00007-6. [Epub ahead of print]1866(2): 149541
    Commentary: Why do many cell biology papers contain fundamental bioenergetic errors?
    David G Nicholls.
      To professional bioenergeticists, the thermodynamic and kinetic constraints on mitochondrial function are self-evident. It is therefore profoundly concerning that high-profile cell biology papers continue to appear containing fundamental bioenergetic errors that appear to have evaded the scrutiny of the principal investigator, co-authors, editors and, apparently, at least some of the referees. The problem is not new, and seems to stem from a perception that bioenergetics is a 'difficult' subject, both at undergraduate level, if it is taught in any depth, and in research, where cell biologists are faced with biophysical concepts such as protonmotive force, ion flux, redox potential and Gibbs free energy.
    Keywords:  Commentary; Proton circuit; Protonmotive force; Thermodynamics
    DOI:  https://doi.org/10.1016/j.bbabio.2025.149541
  11. Physiol Rev. 2025 Jan 17.
    The (dys)regulation of energy storage in obesity.
    Barry E Levin, Nori Geary, Thomas A Lutz.
      Metabolic energy stored mainly as adipose tissue is homeostatically regulated. There is strong evidence that human body weight (BW) is physiologically regulated, i.e. maintained within a relatively narrow range in most mammals, including humans. Nevertheless, the prevalence of obesity has increased markedly in recent decades and now constitutes major medical and socioeconomic problems worldwide. This review focuses on understanding this paradox and the clinical issues that it has spawned: how and why do individuals become obese and how can we help those with obesity lose excess BW and body fat and maintain whatever loss they achieve. Excess BW gain occurs when physiological responses that usually resist short-term weight gain fail to compensate for excess caloric intake occurring over extended periods of time, often over many years or even decades. On the other hand, the difficulties of achieving BW loss and maintenance of reduced BW in obese subjects are due, in part, to the operation of the same physiological regulatory system that helps maintain a healthy BW in individuals without obesity. But, given obesity's association with many pathological conditions, we maintain that the physiological processes that resist BW loss and persistently drive regain are examples of dysregulation. Here we review research in humans and animals addressing these and other unresolved issues in the physiology of obesity. We bring important unresolved problems into focus, and, in some cases, propose hypotheses that can further elucidate their mechanisms to provide research opportunities into modalities that might lead to more effective treatments of obesity.
    Keywords:  Central nervous system; energy homeostasis; leptin; obesity; weight regain
    DOI:  https://doi.org/10.1152/physrev.00002.2024
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