bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2022–09–11
seven papers selected by
José Carlos de Lima-Júnior, University of California San Francisco
  1. A brown fat-selective mechanism of mitochondrial calcium import?
  2. Adipocyte-derived lactate is a signalling metabolite that potentiates adipose macrophage inflammation via targeting PHD2.
  3. Dietary lipids inhibit mitochondria transfer to macrophages to divert adipocyte-derived mitochondria into the blood.
  4. AcroBATics: how dying brown adipocytes trigger browning.
  5. Beiging of perivascular adipose tissue regulates its inflammation and vascular remodeling.
  6. Metabolomics reveals inosine 5'-monophosphate is increased during mice adipocyte browning.
  7. Genetic- and diet-induced ω-3 fatty acid enrichment enhances TRPV4-mediated vasodilation in mice.
  1. Cell Metab. 2022 Sep 06. pii: S1550-4131(22)00354-0. [Epub ahead of print]34(9): 1231-1233
    A brown fat-selective mechanism of mitochondrial calcium import?
    Janane F Rahbani, Lawrence Kazak.
      In this issue of Cell Metabolism, Xue et al. propose that the mitochondrial calcium uniporter (MCU) binds uncoupling protein 1 (UCP1) via the MCU regulator (EMRE) to form a protein complex that the authors term the "thermoporter." Through gain- and loss-of-function experiments, the authors infer that the thermoporter promotes calcium influx into the mitochondrial matrix to enhance NADH production, which supports thermogenesis in brown adipose tissue (BAT).
    DOI:  https://doi.org/10.1016/j.cmet.2022.08.011
  2. Nat Commun. 2022 Sep 05. 13(1): 5208
    Adipocyte-derived lactate is a signalling metabolite that potentiates adipose macrophage inflammation via targeting PHD2.
    Tianshi Feng, Xuemei Zhao, Ping Gu, Wah Yang, Cunchuan Wang, Qingyu Guo, Qiaoyun Long, Qing Liu, Ying Cheng, Jin Li, Cynthia Kwan Yui Cheung, Donghai Wu, Xinyu Kong, Yong Xu, Dewei Ye, Shuang Hua, Kerry Loomes, Aimin Xu, Xiaoyan Hui.
      Adipose tissue macrophage (ATM) inflammation is involved with meta-inflammation and pathology of metabolic complications. Here we report that in adipocytes, elevated lactate production, previously regarded as the waste product of glycolysis, serves as a danger signal to promote ATM polarization to an inflammatory state in the context of obesity. Adipocyte-selective deletion of lactate dehydrogenase A (Ldha), the enzyme converting pyruvate to lactate, protects mice from obesity-associated glucose intolerance and insulin resistance, accompanied by a lower percentage of inflammatory ATM and reduced production of pro-inflammatory cytokines such as interleukin 1β (IL-1β). Mechanistically, lactate, at its physiological concentration, fosters the activation of inflammatory macrophages by directly binding to the catalytic domain of prolyl hydroxylase domain-containing 2 (PHD2) in a competitive manner with α-ketoglutarate and stabilizes hypoxia inducible factor (HIF-1α). Lactate-induced IL-1β was abolished in PHD2-deficient macrophages. Human adipose lactate level is positively linked with local inflammatory features and insulin resistance index independent of the body mass index (BMI). Our study shows a critical function of adipocyte-derived lactate in promoting the pro-inflammatory microenvironment in adipose and identifies PHD2 as a direct sensor of lactate, which functions to connect chronic inflammation and energy metabolism.
    DOI:  https://doi.org/10.1038/s41467-022-32871-3
  3. Cell Metab. 2022 Aug 30. pii: S1550-4131(22)00353-9. [Epub ahead of print]
    Dietary lipids inhibit mitochondria transfer to macrophages to divert adipocyte-derived mitochondria into the blood.
    Nicholas Borcherding, Wentong Jia, Rocky Giwa, Rachael L Field, John R Moley, Benjamin J Kopecky, Mandy M Chan, Bin Q Yang, Jessica M Sabio, Emma C Walker, Omar Osorio, Andrea L Bredemeyer, Terri Pietka, Jennifer Alexander-Brett, Sharon Celeste Morley, Maxim N Artyomov, Nada A Abumrad, Joel Schilling, Kory Lavine, Clair Crewe, Jonathan R Brestoff.
      Adipocytes transfer mitochondria to macrophages in white and brown adipose tissues to maintain metabolic homeostasis. In obesity, adipocyte-to-macrophage mitochondria transfer is impaired, and instead, adipocytes release mitochondria into the blood to induce a protective antioxidant response in the heart. We found that adipocyte-to-macrophage mitochondria transfer in white adipose tissue is inhibited in murine obesity elicited by a lard-based high-fat diet, but not a hydrogenated-coconut-oil-based high-fat diet, aging, or a corn-starch diet. The long-chain fatty acids enriched in lard suppress mitochondria capture by macrophages, diverting adipocyte-derived mitochondria into the blood for delivery to other organs, such as the heart. The depletion of macrophages rapidly increased the number of adipocyte-derived mitochondria in the blood. These findings suggest that dietary lipids regulate mitochondria uptake by macrophages locally in white adipose tissue to determine whether adipocyte-derived mitochondria are released into systemic circulation to support the metabolic adaptation of distant organs in response to nutrient stress.
    Keywords:  CD36; EXT1; aging; beige fat; brown adipose tissue; cell-free mitochondria; fatty acids; heparan sulfate; horizontal mitochondria transfer; intercellular mitochondria transfer; lipids; macrophage; mitochondria; obesity; palmitate; white adipose tissue
    DOI:  https://doi.org/10.1016/j.cmet.2022.08.010
  4. Nat Rev Endocrinol. 2022 Sep 05.
    AcroBATics: how dying brown adipocytes trigger browning.
    Julia Zinngrebe, Pamela Fischer-Posovszky.
      
    DOI:  https://doi.org/10.1038/s41574-022-00743-x
  5. Nat Commun. 2022 Sep 07. 13(1): 5117
    Beiging of perivascular adipose tissue regulates its inflammation and vascular remodeling.
    Yusuke Adachi, Kazutaka Ueda, Seitaro Nomura, Kaoru Ito, Manami Katoh, Mikako Katagiri, Shintaro Yamada, Masaki Hashimoto, Bowen Zhai, Genri Numata, Akira Otani, Munetoshi Hinata, Yuta Hiraike, Hironori Waki, Norifumi Takeda, Hiroyuki Morita, Tetsuo Ushiku, Toshimasa Yamauchi, Eiki Takimoto, Issei Komuro.
      Although inflammation plays critical roles in the development of atherosclerosis, its regulatory mechanisms remain incompletely understood. Perivascular adipose tissue (PVAT) has been reported to undergo inflammatory changes in response to vascular injury. Here, we show that vascular injury induces the beiging (brown adipose tissue-like phenotype change) of PVAT, which fine-tunes inflammatory response and thus vascular remodeling as a protective mechanism. In a mouse model of endovascular injury, macrophages accumulate in PVAT, causing beiging phenotype change. Inhibition of PVAT beiging by genetically silencing PRDM16, a key regulator to beiging, exacerbates inflammation and vascular remodeling following injury. Conversely, activation of PVAT beiging attenuates inflammation and pathological vascular remodeling. Single-cell RNA sequencing reveals that beige adipocytes abundantly express neuregulin 4 (Nrg4) which critically regulate alternative macrophage activation. Importantly, significant beiging is observed in the diseased aortic PVAT in patients with acute aortic dissection. Taken together, vascular injury induces the beiging of adjacent PVAT with macrophage accumulation, where NRG4 secreted from the beige PVAT facilitates alternative activation of macrophages, leading to the resolution of vascular inflammation. Our study demonstrates the pivotal roles of PVAT in vascular inflammation and remodeling and will open a new avenue for treating atherosclerosis.
    DOI:  https://doi.org/10.1038/s41467-022-32658-6
  6. J Biol Chem. 2022 Sep 02. pii: S0021-9258(22)00899-7. [Epub ahead of print] 102456
    Metabolomics reveals inosine 5'-monophosphate is increased during mice adipocyte browning.
    Haruya Takahashi, Motohiro Tokura, Satoko Kawarasaki, Hiroyuki Nagai, Mari Iwase, Kento Nishitani, Haruka Okaze, Shinsuke Mohri, Tetsuro Ito, Takeshi Ara, Huei-Fen Jheng, Wataru Nomura, Teruo Kawada, Kazuo Inoue, Tsuyoshi Goto.
      Adipocyte browning is one of the potential strategies for the prevention of obesity-related metabolic syndromes, but it is a complex process. Although previous studies make it increasingly clear that several transcription factors and enzymes are essential to induce browning, it is unclear what dynamic and metabolic changes occur in induction of browning. Here, we analyzed the effect of a beta-adrenergic receptor agonist (CL316243, accelerator of browning) on metabolic change in mice adipose tissue and plasma using metabolome analysis and speculated that browning is regulated partly by inosine 5'-monophosphate (IMP) metabolism. To test this hypothesis, we investigated whether Ucp-1, a functional marker of browning, mRNA expression is influenced by IMP metabolism using immortalized adipocytes. Our study showed that mycophenolic acid (MPA), an IMP dehydrogenase inhibitor, increases the mRNA expression of Ucp-1 in immortalized adipocytes. Furthermore, we performed a single administration of mycophenolate mofetil (MMF), a prodrug of MPA, to mice and demonstrated that MMF induces adipocyte browning and miniaturization of adipocyte size, leading to adipose tissue weight loss. These findings showed that IMP metabolism has a significant effect on adipocyte browning, suggesting that the regulator of IMP metabolism has the potential to prevent obesity.
    Keywords:  Metabolome analysis; adipocytes; browning; purine metabolism
    DOI:  https://doi.org/10.1016/j.jbc.2022.102456
  7. Cell Rep. 2022 Sep 06. pii: S2211-1247(22)01130-5. [Epub ahead of print]40(10): 111306
    Genetic- and diet-induced ω-3 fatty acid enrichment enhances TRPV4-mediated vasodilation in mice.
    Rebeca Caires, Tessa A C Garrud, Luis O Romero, Carlos Fernández-Peña, Valeria Vásquez, Jonathan H Jaggar, Julio F Cordero-Morales.
      TRPV4 channel activation in endothelial cells leads to vasodilation, while impairment of TRPV4 activity is implicated in vascular dysfunction. Strategies that increase TRPV4 activity could enhance vasodilation and ameliorate vascular disorders. Here, we show that supplementation with eicosapentaenoic acid (EPA), an ω-3 polyunsaturated fatty acid known to have beneficial cardiovascular effects, increases TRPV4 activity in human endothelial cells of various vascular beds. Mice carrying the C. elegans FAT-1 enzyme, which converts ω-6 to ω-3 polyunsaturated fatty acids, display higher EPA content and increased TRPV4-mediated vasodilation in mesenteric arteries. Likewise, mice fed an EPA-enriched diet exhibit enhanced and prolonged TRPV4-dependent vasodilation in an endothelial cell-specific manner. We also show that EPA supplementation reduces TRPV4 desensitization, which contributes to the prolonged vasodilation. Neutralization of positive charges in the TRPV4 N terminus impairs the effect of EPA on channel desensitization. These findings highlight the beneficial effects of manipulating fatty acid content to enhance TRPV4-mediated vasodilation.
    Keywords:  CP: Metabolism; EPA; LC-MS; TRPV4; desensitization; eicosapentaenoic acid; electrophysiology; endothelial cells; fat-1 transgenic mice; myography; omega-3 PUFA; vasodilation
    DOI:  https://doi.org/10.1016/j.celrep.2022.111306
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