bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2023–11–12
thirteen papers selected by
José Carlos de Lima-Júnior, Washington University
  1. Cristae formation is a mechanical buckling event controlled by the inner mitochondrial membrane lipidome.
  2. Foxj3 regulates thermogenesis of brown and beige fat via induction of PGC-1α.
  3. Brown fat thermogenesis and branched-chain amino acids in metabolic disease.
  4. Transcriptional repression of beige fat innervation via a YAP/TAZ-S100B axis.
  5. Standardized in vitro Models of Human Adipose Tissue Reveal Metabolic Flexibility in Brown Adipocyte Thermogenesis.
  6. Pharmacologic activation of a compensatory integrated stress response kinase promotes mitochondrial remodeling in PERK-deficient cells.
  7. High-Fat Diet Feeding Disrupts the Coupling of Thermoregulation to Energy Homeostasis.
  8. NRF2 is essential for adaptative browning of white adipocytes.
  9. Protocol for the in vitro isolation and culture of mature adipocytes and white adipose tissue explants from humans and mice.
  10. IL-27 increases energy storage in white adipocytes by enhancing glucose uptake and fatty acid esterification.
  11. Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice.
  12. Exercise training adaptations in liver glycogen and glycerolipids require hepatic AMP-activated protein kinase in mice.
  13. Breast adipose tissue-derived extracellular vesicles from obese women alter tumor cell metabolism.
  1. EMBO J. 2023 Nov 07. e114054
    Cristae formation is a mechanical buckling event controlled by the inner mitochondrial membrane lipidome.
    Kailash Venkatraman, Christopher T Lee, Guadalupe C Garcia, Arijit Mahapatra, Daniel Milshteyn, Guy Perkins, Keun-Young Kim, H Amalia Pasolli, Sebastien Phan, Jennifer Lippincott-Schwartz, Mark H Ellisman, Padmini Rangamani, Itay Budin.
      Cristae are high-curvature structures in the inner mitochondrial membrane (IMM) that are crucial for ATP production. While cristae-shaping proteins have been defined, analogous lipid-based mechanisms have yet to be elucidated. Here, we combine experimental lipidome dissection with multi-scale modeling to investigate how lipid interactions dictate IMM morphology and ATP generation. When modulating phospholipid (PL) saturation in engineered yeast strains, we observed a surprisingly abrupt breakpoint in IMM topology driven by a continuous loss of ATP synthase organization at cristae ridges. We found that cardiolipin (CL) specifically buffers the inner mitochondrial membrane against curvature loss, an effect that is independent of ATP synthase dimerization. To explain this interaction, we developed a continuum model for cristae tubule formation that integrates both lipid and protein-mediated curvatures. This model highlighted a snapthrough instability, which drives IMM collapse upon small changes in membrane properties. We also showed that cardiolipin is essential in low-oxygen conditions that promote PL saturation. These results demonstrate that the mechanical function of cardiolipin is dependent on the surrounding lipid and protein components of the IMM.
    Keywords:  cardiolipin; cristae; lipids; mechanics; mitochondria
    DOI:  https://doi.org/10.15252/embj.2023114054
  2. Diabetes. 2023 Nov 08. pii: db230454. [Epub ahead of print]
    Foxj3 regulates thermogenesis of brown and beige fat via induction of PGC-1α.
    Jincan Huang, Yujie Zhang, Xuenan Zhou, Jiani Song, Yueyao Feng, Tongtong Qiu, Sufang Sheng, Menglin Zhang, Xi Zhang, Jingran Hao, Lei Zhang, Yinliang Zhang, Xiaorong Li, Ming Liu, Yongsheng Chang.
      Enhancing the development and thermogenesis in brown and beige fat represents a potential treatment for obesity. In the present study, we show that Foxj3 expression in fat is stimulated by cold exposure and a β-adrenergic agonist. Adipose-specific Foxj3 knockout impairs the thermogenic function of brown fat, leading to morphological whitening of brown fat and obesity. Adipose Foxj3-deficient mice display increased fasting blood glucose levels and hepatic steatosis on a chow diet. Foxj3 deficiency inhibits the browning of inguinal white adipose tissue (iWAT) following β3-agonist treatment of mice. Furthermore, depletion of Foxj3 in primary brown adipocytes reduces the expression of thermogenic genes and cellular respiration, indicating that the Foxj3 effects on the thermogenic program are cell autonomous. In contrast, Foxj3 overexpression in primary brown adipocytes enhances the thermogenic program. Moreover, AAV-mediated Foxj3 overexpression in brown fat and inguinal WAT increases energy expenditure and improves systemic metabolism on either a chow diet or a high-fat diet. Finally, Foxj3 deletion in fat inhibits the β3 agonist-mediated induction of WAT browning and brown adipose tissue thermogenesis. Mechanistically, cold-inducible Foxj3 stimulates the expression of PGC-1α and UCP1, subsequently promoting energy expenditure. The present study identifies Foxj3 as a critical regulator of fat thermogenesis, and targeting Foxj3 in fat might be a therapeutic strategy for treating obesity and metabolic diseases.
    DOI:  https://doi.org/10.2337/db23-0454
  3. Endocr J. 2023 Nov 09.
    Brown fat thermogenesis and branched-chain amino acids in metabolic disease.
    Zachary Brown, Takeshi Yoneshiro.
      Since the 1960s, researchers have recognized an association between elevated plasma branched chain amino acids (BCAA) and metabolic disease, including type 2 diabetes mellitus and obesity, but the cause for it remained poorly understood. Recent advances in metabolomics, advanced imaging techniques, and genetic analyses over the past decade have enabled newfound insights into the mechanism of BCAA metabolic dysregulation across a variety of peripheral tissues and its impact on metabolic disease, suggesting a key role for brown adipose tissue (BAT) in determining BCAA metabolic homeostasis. Previous investigations into BAT have emphasized fatty acids and glucose as substrates for BAT thermogenesis. Here, we address the importance of BAT in systemic BCAA metabolism, driven via the newly identified mitochondrial BCAA carrier (MBC), as well as the impact of BAT-driven BCAA clearance on glucose homeostasis and metabolic disease. The newly identified MBC offers new therapeutic avenues by which BAT activity may be enhanced to improve metabolic and cardiovascular health, as well as other diseases in which increases of circulating BCAA may play a role in pathogenicity.
    Keywords:  Beige adipocytes; Branched-chain amino acids; Brown adipose tissue; Diabetes; Transporter
    DOI:  https://doi.org/10.1507/endocrj.EJ23-0205
  4. Nat Commun. 2023 Nov 04. 14(1): 7102
    Transcriptional repression of beige fat innervation via a YAP/TAZ-S100B axis.
    Xun Huang, Xinmeng Li, Hongyu Shen, Yiheng Zhao, Zhao Zhou, Yushuang Wang, Jingfei Yao, Kaili Xue, Dongmei Wu, Yifu Qiu.
      Sympathetic innervation is essential for the development of functional beige fat that maintains body temperature and metabolic homeostasis, yet the molecular mechanisms controlling this innervation remain largely unknown. Here, we show that adipocyte YAP/TAZ inhibit sympathetic innervation of beige fat by transcriptional repression of neurotropic factor S100B. Adipocyte-specific loss of Yap/Taz induces S100b expression to stimulate sympathetic innervation and biogenesis of functional beige fat both in subcutaneous white adipose tissue (WAT) and browning-resistant visceral WAT. Mechanistically, YAP/TAZ compete with C/EBPβ for binding to the zinc finger-2 domain of PRDM16 to suppress S100b transcription, which is released by adrenergic-stimulated YAP/TAZ phosphorylation and inactivation. Importantly, Yap/Taz loss in adipocytes or AAV-S100B overexpression in visceral WAT restricts both age-associated and diet-induced obesity, and improves metabolic homeostasis by enhancing energy expenditure of mice. Together, our data reveal that YAP/TAZ act as a brake on the beige fat innervation by blocking PRDM16-C/EBPβ-mediated S100b expression.
    DOI:  https://doi.org/10.1038/s41467-023-43021-8
  5. Endocrinology. 2023 Nov 07. pii: bqad161. [Epub ahead of print]
    Standardized in vitro Models of Human Adipose Tissue Reveal Metabolic Flexibility in Brown Adipocyte Thermogenesis.
    Cheryl Cero, Weiguo Shu, Amy L Reese, Diana Douglas, Michael Maddox, Ajeet P Singh, Sahara L Ali, Alexander R Zhu, Jacqueline M Katz, Anne E Pierce, Kelly T Long, Naris Nilubol, Raymond H Cypess, Jonathan L Jacobs, Fang Tian, Aaron M Cypess.
      Functional human brown and white adipose tissue (BAT and WAT) are vital for thermoregulation and nutritional homeostasis, while obesity and other stressors lead, respectively, to cold intolerance and metabolic disease. Understanding BAT and WAT physiology and dysfunction necessitates clinical trials complemented by mechanistic experiments at the cellular level. These require standardized in vitro models, currently lacking, that establish references for gene expression and function. In response, we generated and characterized a pair of immortalized, clonal human brown (hBA) and white (hWA) preadipocytes derived from the perirenal and subcutaneous depots, respectively, of a 40-year-old male. Cells were immortalized with hTERT and confirmed to be of a mesenchymal, non-hematopoietic lineage based on FACS sorting and DNA barcoding. Functional assessments showed that the hWA and hBA phenocopied primary adipocytes in terms of adrenergic signaling, lipolysis, and thermogenesis. Compared to hWA, the hBA were metabolically distinct, with higher rates of glucose uptake, lactate metabolism, and greater basal, maximal, and non-mitochondrial respiration, which provide a mechanistic explanation for the association between obesity and BAT dysfunction. hBA also responded to the stress of maximal respiration by using both endogenous and exogenous fatty acids. In contrast to certain mouse models, hBA adrenergic thermogenesis was mediated by several mechanisms, not principally via uncoupling protein 1 (UCP1). Transcriptomics via RNA-seq were consistent with the functional studies and established a molecular signature for each cell type before and after differentiation. These standardized cells are anticipated to become a common resource for future physiological, pharmacological, and genetic studies of human adipocytes.
    Keywords:  bioenergetics; bioinformatics; brown adipose tissue; in vitro model; white adipose tissue
    DOI:  https://doi.org/10.1210/endocr/bqad161
  6. Cell Chem Biol. 2023 Oct 26. pii: S2451-9456(23)00367-7. [Epub ahead of print]
    Pharmacologic activation of a compensatory integrated stress response kinase promotes mitochondrial remodeling in PERK-deficient cells.
    Valerie Perea, Kelsey R Baron, Vivian Dolina, Giovanni Aviles, Grace Kim, Jessica D Rosarda, Xiaoyan Guo, Martin Kampmann, R Luke Wiseman.
      The integrated stress response (ISR) comprises the eIF2α kinases PERK, GCN2, HRI, and PKR, which induce translational and transcriptional signaling in response to diverse insults. Deficiencies in PERK signaling lead to mitochondrial dysfunction and contribute to the pathogenesis of numerous diseases. We define the potential for pharmacologic activation of compensatory eIF2α kinases to rescue ISR signaling and promote mitochondrial adaptation in PERK-deficient cells. We show that the HRI activator BtdCPU and GCN2 activator halofuginone promote ISR signaling and rescue ER stress sensitivity in PERK-deficient cells. However, BtdCPU induces mitochondrial depolarization, leading to mitochondrial fragmentation and activation of the OMA1-DELE1-HRI signaling axis. In contrast, halofuginone promotes mitochondrial elongation and adaptive mitochondrial respiration, mimicking regulation induced by PERK. This shows halofuginone can compensate for deficiencies in PERK signaling and promote adaptive mitochondrial remodeling, highlighting the potential for pharmacologic ISR activation to mitigate mitochondrial dysfunction and motivating the pursuit of highly selective ISR activators.
    Keywords:  ISR; UPR; integrated stress response; pharmacologic activator; stress-responsive signaling pathway; unfolded protein response
    DOI:  https://doi.org/10.1016/j.chembiol.2023.10.006
  7. Mol Metab. 2023 Nov 04. pii: S2212-8778(23)00169-2. [Epub ahead of print] 101835
    High-Fat Diet Feeding Disrupts the Coupling of Thermoregulation to Energy Homeostasis.
    Jennifer D Deem, David Tingley, Christina A Watts, Kayoko Ogimoto, Caeley L Bryan, Bao Anh N Phan, Vincent Damian, Michael R Bruchas, Jarrad M Scarlett, Michael W Schwartz, Gregory J Morton.
       OBJECTIVE: Preserving core body temperature across a wide range of ambient temperatures requires adaptive changes of thermogenesis that must be offset by corresponding changes of energy intake if body fat stores are also to be preserved. Among neurons implicated in the integration of thermoregulation with energy homeostasis are those that express both neuropeptide Y (NPY) and agouti-related protein (AgRP) (referred to herein as AgRP neurons). Specifically, cold-induced activation of AgRP neurons was recently shown to be required for cold exposure to increase food intake in mice. Here, we investigated how consuming a high-fat diet (HFD) impacts various adaptive responses to cold exposure as well as the responsiveness of AgRP neurons to cold.
    METHODS: To test this, we used immunohistochemistry, in vivo fiber photometry and indirect calorimetry for continuous measures of core temperature, energy expenditure, and energy intake in both chow- and HFD-fed mice housed at different ambient temperatures.
    RESULTS: We show that while both core temperature and the thermogenic response to cold are maintained normally in HFD-fed mice, the increase of energy intake needed to preserve body fat stores is blunted, resulting in weight loss. Using both immunohistochemistry and in vivo fiber photometry we show that although cold-induced AgRP neuron activation is detected regardless of diet, the number of cold-responsive neurons appears to be blunted in HFD-fed mice.
    CONCLUSIONS: We conclude that HFD-feeding disrupts the integration of systems governing thermoregulation and energy homeostasis that protect body fat mass during cold exposure.
    Keywords:  AgRP neurons; core temperature; energy expenditure; energy intake; high-fat diet; thermoregulation
    DOI:  https://doi.org/10.1016/j.molmet.2023.101835
  8. Redox Biol. 2023 Oct 31. pii: S2213-2317(23)00352-X. [Epub ahead of print]68 102951
    NRF2 is essential for adaptative browning of white adipocytes.
    Marco Bauzá-Thorbrügge, Eduard Peris, Shabnam Zamani, Peter Micallef, Alexandra Paul, Stefano Bartesaghi, Anna Benrick, Ingrid Wernstedt Asterholm.
      White adipose tissue browning, defined by accelerated mitochondrial metabolism and biogenesis, is considered a promising mean to treat or prevent obesity-associated metabolic disturbances. We hypothesize that redox stress acutely leads to increased production of reactive oxygen species (ROS), which activate electrophile sensor nuclear factor erythroid 2-Related Factor 2 (NRF2) that over time results in an adaptive adipose tissue browning process. To test this, we have exploited adipocyte-specific NRF2 knockout mice and cultured adipocytes and analyzed time- and dose-dependent effect of NAC and lactate treatment on antioxidant expression and browning-like processes. We found that short-term antioxidant treatment with N-acetylcysteine (NAC) induced reductive stress as evident from increased intracellular NADH levels, increased ROS-production, reduced oxygen consumption rate (OCR), and increased NRF2 levels in white adipocytes. In contrast, and in line with our hypothesis, longer-term NAC treatment led to a NRF2-dependent browning response. Lactate treatment elicited similar effects as NAC, and mechanistically, these NRF2-dependent adipocyte browning responses in vitro were mediated by increased heme oxygenase-1 (HMOX1) activity. Moreover, this NRF2-HMOX1 axis was also important for β3-adrenergic receptor activation-induced adipose tissue browning in vivo. In conclusion, our findings show that administration of exogenous antioxidants can affect biological function not solely through ROS neutralization, but also through reductive stress. We also demonstrate that NRF2 is essential for white adipose tissue browning processes.
    Keywords:  Adipose tissue; Lactate; N-acetylcysteine; NRF2; Redox stress
    DOI:  https://doi.org/10.1016/j.redox.2023.102951
  9. STAR Protoc. 2023 Nov 03. pii: S2666-1667(23)00660-3. [Epub ahead of print]4(4): 102693
    Protocol for the in vitro isolation and culture of mature adipocytes and white adipose tissue explants from humans and mice.
    Teresa Villanueva-Carmona, Lídia Cedó, Catalina Núñez-Roa, Elsa Maymó-Masip, Joan Vendrell, Sonia Fernández-Veledo.
      White adipose tissue (WAT) explants culture allows the study of this tissue ex vivo, maintaining its structure and properties. Concurrently, isolating mature adipocytes facilitates research into fat cell metabolism and hormonal regulation. Here, we present a protocol for obtaining, isolating, and processing mature adipocytes, alongside the cultivation of WAT explants from humans and mice. We describe steps for WAT retrieval, culturing of WAT explants, WAT digestion, and adipocytes separation. We then detail procedures for culturing isolated mature adipocytes. For complete details on the use and execution of this protocol, please refer to Villanueva-Carmona et al. (2023).1.
    Keywords:  Cell Culture; Cell Isolation; Metabolism; Model Organisms
    DOI:  https://doi.org/10.1016/j.xpro.2023.102693
  10. Adipocyte. 2023 Dec;12(1): 2276346
    IL-27 increases energy storage in white adipocytes by enhancing glucose uptake and fatty acid esterification.
    Chiara Scaffidi, Annie Srdic, Daniel Konrad, Stephan Wueest.
      The cytokine interleukin (IL)-27 has been reported to induce thermogenesis in white adipocytes. However, it remains unknown whether IL-27-mediated adipocyte energy dissipation is paralleled by an elevated energy supply from lipids and/or carbohydrates. We hypothesized that IL-27 increases lipolysis and glucose uptake in white adipocytes, thereby providing substrates for thermogenesis. Unexpectedly, we found that treatment of 3T3-L1 adipocytes with IL-27 reduced intra- and extracellular free fatty acid (FFA) concentrations and that phosphorylation of hormone-sensitive lipase (HSL) was not affected by IL-27. These results were confirmed in subcutaneous white adipocytes. Further, application of IL-27 to 3T3-L1 adipocytes increased intracellular triglyceride (TG) content but not mitochondrial ATP production nor expression of enzymes involved in beta-oxidation indicating that elevated esterification rather than oxidation causes FFA disappearance. In addition, IL-27 significantly increased GLUT1 protein levels, basal glucose uptake as well as glycolytic ATP production, suggesting that increased glycolytic flux due to IL-27 provides the glycerol backbone for TG synthesis. In conclusion, our findings suggest IL-27 increases glucose uptake and TG deposition in white adipocytes.
    Keywords:  Free fatty acid; lipolysis; obesity; triglyceride; white adipose tissue
    DOI:  https://doi.org/10.1080/21623945.2023.2276346
  11. Cell Metab. 2023 Nov 07. pii: S1550-4131(23)00374-1. [Epub ahead of print]35(11): 1976-1995.e6
    Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice.
    Cara L Green, Michaela E Trautman, Krittisak Chaiyakul, Raghav Jain, Yasmine H Alam, Reji Babygirija, Heidi H Pak, Michelle M Sonsalla, Mariah F Calubag, Chung-Yang Yeh, Anneliese Bleicher, Grace Novak, Teresa T Liu, Sarah Newman, Will A Ricke, Kristina A Matkowskyj, Irene M Ong, Cholsoon Jang, Judith Simcox, Dudley W Lamming.
      Low-protein diets promote health and longevity in diverse species. Restriction of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine recapitulates many of these benefits in young C57BL/6J mice. Restriction of dietary isoleucine (IleR) is sufficient to promote metabolic health and is required for many benefits of a low-protein diet in C57BL/6J males. Here, we test the hypothesis that IleR will promote healthy aging in genetically heterogeneous adult UM-HET3 mice. We find that IleR improves metabolic health in young and old HET3 mice, promoting leanness and glycemic control in both sexes, and reprograms hepatic metabolism in a sex-specific manner. IleR reduces frailty and extends the lifespan of male and female mice, but to a greater degree in males. Our results demonstrate that IleR increases healthspan and longevity in genetically diverse mice and suggests that IleR, or pharmaceuticals that mimic this effect, may have potential as a geroprotective intervention.
    Keywords:  aging; branched-chain amino acids; frailty; isoleucine; lifespan; metabolic health; mice; nutritional interventions; protein restriction
    DOI:  https://doi.org/10.1016/j.cmet.2023.10.005
  12. Am J Physiol Endocrinol Metab. 2023 Nov 08.
    Exercise training adaptations in liver glycogen and glycerolipids require hepatic AMP-activated protein kinase in mice.
    Curtis C Hughey, Deanna P Bracy, Ferrol I Rome, Mickael Goelzer, E Patrick Donahue, Benoit Viollet, Marc Foretz, David H Wasserman.
      Regular exercise elicits adaptations in glucose and lipid metabolism that allow the body to meet energy demands of subsequent exercise bouts more effectively and mitigate metabolic diseases including fatty liver. Energy discharged during the acute exercise bouts that comprise exercise training may be a catalyst for liver adaptations. During acute exercise, liver glycogenolysis and gluconeogenesis are accelerated to supply glucose to working muscle. Lower liver energy state imposed by gluconeogenesis and related pathways activates AMP-activated protein kinase (AMPK), which conserves ATP partly by promoting lipid oxidation. This study tested the hypothesis that AMPK is necessary for liver glucose and lipid adaptations to training. Liver-specific AMPKα1α2 knockout (AMPKα1α2fl/fl+AlbCre) mice and littermate controls (AMPKα1α2fl/fl) completed sedentary and exercise training protocols. Liver nutrient fluxes were quantified at rest or during acute exercise following training. Liver metabolites and molecular regulators of metabolism were assessed. Training increased liver glycogen in AMPKα1α2fl/fl mice, but not in AMPKα1α2fl/fl+AlbCre mice. The inability to increase glycogen led to lower glycogenolysis, glucose production, and circulating glucose during acute exercise in trained AMPKα1α2fl/fl+AlbCre mice. Deletion of AMPKα1α2 attenuated training-induced declines in liver diacylglycerides. In particular, training lowered the concentration of unsaturated and elongated fatty acids comprising diacylglycerides in AMPKα1α2fl/fl mice, but not in AMPKα1α2fl/fl+AlbCre mice. Training increased liver triacylglycerides and the desaturation and elongation of fatty acids in triacylglycerides of AMPKα1α2fl/fl+AlbCre mice. These lipid responses were independent of differences in tricarboxylic acid cycle fluxes. In conclusion, AMPK is required for liver training adaptations that are critical to glucose and lipid metabolism.
    Keywords:  aerobic exercise; gluconeogenesis; glycogenolysis; metabolic flux analysis; mitochondrial oxidative metabolism
    DOI:  https://doi.org/10.1152/ajpendo.00289.2023
  13. EMBO Rep. 2023 Nov 06. e57339
    Breast adipose tissue-derived extracellular vesicles from obese women alter tumor cell metabolism.
    Shuchen Liu, Alberto Benito-Martin, Fanny A Pelissier Vatter, Sarah Z Hanif, Catherine Liu, Priya Bhardwaj, Praveen Sethupathy, Alaa R Farghli, Phoebe Piloco, Paul Paik, Malik Mushannen, Xue Dong, David M Otterburn, Leslie Cohen, Rohan Bareja, Jan Krumsiek, Leona Cohen-Gould, Samuel Calto, Jason A Spector, Olivier Elemento, David C Lyden, Kristy A Brown.
      Breast adipose tissue is an important contributor to the obesity-breast cancer link. Extracellular vesicles (EVs) are nanosized particles containing selective cargo, such as miRNAs, that act locally or circulate to distant sites to modulate target cell functions. Here, we find that long-term education of breast cancer cells with EVs obtained from breast adipose tissue of women who are overweight or obese (O-EVs) results in increased proliferation. RNA-seq analysis of O-EV-educated cells demonstrates increased expression of genes involved in oxidative phosphorylation, such as ATP synthase and NADH: ubiquinone oxidoreductase. O-EVs increase respiratory complex protein expression, mitochondrial density, and mitochondrial respiration in tumor cells. The mitochondrial complex I inhibitor metformin reverses O-EV-induced cell proliferation. Several miRNAs-miR-155-5p, miR-10a-3p, and miR-30a-3p-which promote mitochondrial respiration and proliferation, are enriched in O-EVs relative to EVs from lean women. O-EV-induced proliferation and mitochondrial activity are associated with stimulation of the Akt/mTOR/P70S6K pathway, and are reversed upon silencing of P70S6K. This study reveals a new facet of the obesity-breast cancer link with human breast adipose tissue-derived EVs causing metabolic reprogramming of breast cancer cells.
    Keywords:  breast cancer; extracellular vesicles; mitochondrial respiration; obesity; proliferation
    DOI:  https://doi.org/10.15252/embr.202357339
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