bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2022–04–03
eight papers selected by
José Carlos de Lima-Júnior, University of California San Francisco
  1. Selenoprotein P-mediated reductive stress impairs cold-induced thermogenesis in brown fat.
  2. EBI2 is a negative modulator of brown adipose tissue energy expenditure in mice and human brown adipocytes.
  3. Roles of miR-124-3p/Scd1 in urolithin A-induced brown adipocyte differentiation and succinate-dependent regulation of mitochondrial complex II.
  4. Temporal specificity of IL-6 knockout in enhancing the thermogenic capability of brown adipose tissue.
  5. Leveraging GPCR signaling in thermogenic fat to counteract metabolic diseases.
  6. Time to Target Mitochondrial Reactive Oxygen Species Generation from Complex I.
  7. Stimulation of Gs signaling in MC4R cells by DREADD increases energy expenditure, suppressing food intake, and increasing locomotor activity in mice.
  8. Parent-of-origin effects propagate through networks to shape metabolic traits.
  1. Cell Rep. 2022 Mar 29. pii: S2211-1247(22)00310-2. [Epub ahead of print]38(13): 110566
    Selenoprotein P-mediated reductive stress impairs cold-induced thermogenesis in brown fat.
    Swe Mar Oo, Hein Ko Oo, Hiroaki Takayama, Kiyo-Aki Ishii, Yumie Takeshita, Hisanori Goto, Yujiro Nakano, Susumu Kohno, Chiaki Takahashi, Hiroyuki Nakamura, Yoshiro Saito, Mami Matsushita, Yuko Okamatsu-Ogura, Masayuki Saito, Toshinari Takamura.
      Reactive oxygen species (ROS) activate uncoupler protein 1 (UCP1) in brown adipose tissue (BAT) under physiological cold exposure and noradrenaline (NA) stimulation to increase thermogenesis. However, the endogenous regulator of ROS in activated BAT and its role in pathological conditions remain unclear. We show that serum levels of selenoprotein P (SeP; encoded by SELENOP) negatively correlate with BAT activity in humans. Physiological cold exposure downregulates Selenop in BAT. Selenop knockout mice show higher rectal temperatures and UCP1 sulfenylation during cold exposure. SeP treatment to brown adipocytes eliminated the NA-induced mitochondrial ROS by upregulating glutathione peroxidase 4 and impaired cellular thermogenesis. A high-fat/high-sucrose diet elevates serum SeP levels and diminishes the elevated NA-induced thermogenesis in BAT-Selenop KO mice. Therefore, SeP is the intrinsic factor inducing reductive stress that impairs thermogenesis in BAT and may be a potential therapeutic target for obesity and diabetes.
    Keywords:  BATkine; CP: Metabolism; brown adipose tissue; diabetes mellitus; hepatokine; obesity; redox; reductive stress; selenoprotein P; thermogenesis; uncoupling protein 1
    DOI:  https://doi.org/10.1016/j.celrep.2022.110566
  2. Commun Biol. 2022 Mar 29. 5(1): 280
    EBI2 is a negative modulator of brown adipose tissue energy expenditure in mice and human brown adipocytes.
    Francesca Copperi, Inna Schleis, Martin Roumain, Giulio G Muccioli, Stefano Casola, Martin Klingenspor, Alexander Pfeifer, Thorsten Gnad.
      Pharmacological activation of brown adipose tissue (BAT) is an attractive approach for increasing energy expenditure to counteract obesity. Given the side-effects of known activators of BAT, we studied inhibitors of BAT as a novel, alternative concept to regulate energy expenditure. We focused on G-protein-coupled receptors that are one of the major targets of clinically used drugs. Here, we identify GPR183, also known as EBI2, as the most highly expressed inhibitory G-protein-coupled receptor in BAT among the receptors examined. Activation of EBI2 using its endogenous ligand 7α,25-dihydroxycholesterol significantly decreases BAT-mediated energy expenditure in mice. In contrast, mice deficient for EBI2 show increased energy dissipation in response to cold. Interestingly, only thermogenic adipose tissue depots - BAT and subcutaneous white adipose tissue -respond to 7α,25-dihydroxycholesterol treatment/EBI2 activation but not gonadal white fat, which has the lowest thermogenic capacity. EBI2 activation in brown adipocytes significantly reduces norepinephrine-induced cAMP production, whereas pharmacological inhibition or genetic ablation of EBI2 results in an increased response. Importantly, EBI2 significantly inhibits norepinephrine-induced activation of human brown adipocytes. Our data identify the 7α,25-dihydroxycholesterol/EBI2 signaling pathway as a so far unknown BAT inhibitor. Understanding the inhibitory regulation of BAT might lead to novel pharmacological approaches to increase the activity of thermogenic adipose tissue and whole body energy expenditure in humans.
    DOI:  https://doi.org/10.1038/s42003-022-03201-6
  3. Biochem Biophys Res Commun. 2022 Mar 24. pii: S0006-291X(22)00457-0. [Epub ahead of print]
    Roles of miR-124-3p/Scd1 in urolithin A-induced brown adipocyte differentiation and succinate-dependent regulation of mitochondrial complex II.
    Qian Li, Lina Wang, Huan Liu, Weiyuan Ren, Zhiying Zhang, Bo Xia.
      Brown adipocytes have been linked to managing human obesity and related metabolic diseases. A large number of natural products have emerged that can activate brown adipocytes tissue (BAT) to active thermogenesis, but the epigenetic mechanisms have not been fully resolved. In this study, we identified the induction of miR-124-3p by urolithin A (UA) as a means to increase the thermogenic activity of brown adipocytes. Overexpression of miR-124-3p enhances thermogenesis by increasing mitochondrial content in brown adipocytes. Mechanistically, to clarify that miR-124-3p affects fatty acid synthesis using bioinformatics methods, it is clear that miR-124 affects the synthesis of fatty acids through the enrichment analysis of the KEGG pathway, and using dual luci. ferase to determine the target gene as stearoyl-CoA desaturase 1 (SCD1) while controlling rates of fatty acids synthesis and de novo brown fat biogenesis. Finally, in the overexpression of miR-124-3p and UA-treated BAT, succinate accumulation was enhanced in cells and fueled mitochondrial complex II activities. This study highlights a miR-124-3p/SCD1/succinate pathway that stimulates thermogenesis of BAT via the modulatory roles of UA.
    Keywords:  Mitochondrial complex II; SCD1; Succinate; Urolithin A; miR-124-3p
    DOI:  https://doi.org/10.1016/j.bbrc.2022.03.112
  4. J Physiol Biochem. 2022 Mar 29.
    Temporal specificity of IL-6 knockout in enhancing the thermogenic capability of brown adipose tissue.
    Mei Dong, Cheng Gao, Yanxin Jia, Weijia Xu, Yan Liu, Xin Wen, Qingxin Liu, Hai Lin, Haifang Li.
      Although interleukin-6 (IL-6) has been regarded as a homeostatic regulator of fat metabolism, its role in brown adipose thermogenesis remains to be further clarified. By using wild-type (WT) and IL-6-knockout (KO) mice, this study aims to investigate whether IL-6 regulates the thermogenic capability of brown adipose tissue (BAT) at both young and elderly stages. We demonstrated that IL-6 KO enhances BAT thermogenesis at a young age, as evidenced by the increased mRNA and protein expression levels of thermogenic genes, and the elevated interscapular surface temperature. The IL-6-KO enhancement of BAT thermogenesis is associated with improved respiratory exchange ratio (RER) and glucose homeostasis at young stages. However, these improvements disappear in elderly KO mice, which is likely attributable to the highly increased expression of other inflammatory cytokines, such as Tnfα, Il-1β, and Il-10. Our findings indicate that the lack of IL-6 has a temporal-specific contribution to the promotion of BAT thermogenesis.
    Keywords:  Brown adipose tissue; Glucose homeostasis; IL-6; Inflammatory cytokines; Thermogenesis
    DOI:  https://doi.org/10.1007/s13105-021-00847-4
  5. Mol Metab. 2022 Mar 23. pii: S2212-8778(22)00043-6. [Epub ahead of print] 101474
    Leveraging GPCR signaling in thermogenic fat to counteract metabolic diseases.
    Olivia Sveidahl Johansen, Tao Ma, Zachary Gerhart-Hines.
      
    DOI:  https://doi.org/10.1016/j.molmet.2022.101474
  6. Function (Oxf). 2022 ;3(2): zqac010
    Time to Target Mitochondrial Reactive Oxygen Species Generation from Complex I.
    Qun Chen, Edward J Lesnefsky.
      
    DOI:  https://doi.org/10.1093/function/zqac010
  7. Am J Physiol Endocrinol Metab. 2022 Mar 28.
    Stimulation of Gs signaling in MC4R cells by DREADD increases energy expenditure, suppressing food intake, and increasing locomotor activity in mice.
    Shigenobu Matsumura, Motoki Miyakita, Haruka Miyamori, Satomi Kyo, Daisuke Shima, Takumi Yokokawa, Fuka Ishikawa, Tsutomu Sasaki, Tomoki Jinno, Jin Tanaka, Tsuyoshi Goto, Keiko Momma, Kengo Ishihara, Rebecca Berdeaux, Kazuo Inoue.
      The melanocortin 4 receptor (MC4R) plays an important role in the regulation of appetite and energy expenditure in humans and rodents. Impairment of MC4R signaling causes severe obesity. MC4R mainly couples to the G-protein Gs. Ligand binding to MC4R activates adenylyl cyclase resulting in increased intracellular cAMP levels. cAMP acts as a secondary messenger, regulating various cellular processes. MC4R can also couple with Gq and other signaling pathways. Therefore, the contribution of MC4R/Gs signaling to energy metabolism and appetite remains unclear. To study the effect of Gs signaling activation in MC4R cells on whole-body energy metabolism and appetite, we generated a novel mouse strain that expresses a Gs-DREADD (Gs-coupled designer receptors exclusively activated by designer drugs: GsD) selectively in MC4R-expressing cells (GsD-MC4R mice). Chemogenetic activation of the GsD by a designer drug (deschloroclozapine: DCZ; 0.01~0.1 mg/kg BW) in MC4R-expressing cells significantly increased oxygen consumption and locomotor activity. In addition, GsD activation significantly reduced the respiratory exchange ratio, promoting fatty acid oxidation, but did not affect core (rectal) temperature. A low dose of DCZ (0.01 mg/kg BW) did not suppress food intake, but a high dose of DCZ (0.1 mg/kg BW) suppressed food intake in MC4R-GsD mice, although either DCZ dose (0.01 or 0.1 mg/kg BW) did not affect food intake in the control mice. In conclusion, the current study demonstrated that the stimulation of Gs signaling in MC4R-expressing cells increases energy expenditure and locomotor activity and suppresses appetite.
    Keywords:  DREADD; MC4R; appetite; cAMP; energy expenditure
    DOI:  https://doi.org/10.1152/ajpendo.00439.2021
  8. Elife. 2022 Mar 31. pii: e72989. [Epub ahead of print]11
    Parent-of-origin effects propagate through networks to shape metabolic traits.
    Juan F Macias-Velasco, Celine L St Pierre, Jessica P Wayhart, Li Yin, Larry Spears, Mario A Miranda, Caryn Carson, Katsuhiko Funai, James Cheverud, Clay F Semenkovich, Heather A Lawson.
      Parent-of-origin effects are unexpectedly common in complex traits, including metabolic and neurological traits. Parent-of-origin effects can be modified by the environment, but the architecture of these gene-by-environmental effects on phenotypes remains to be unraveled. Previously, quantitative trait loci (QTL) showing context-specific parent-of-origin effects on metabolic traits were mapped in the F16 generation of an advanced intercross between LG/J and SM/J inbred mice. However, these QTL were not enriched for known imprinted genes, suggesting another mechanism is needed to explain these parent-of-origin effects phenomena. We propose that non-imprinted genes can generate complex parent-of-origin effects on metabolic traits through interactions with imprinted genes. Here, we employ data from mouse populations at different levels of intercrossing (F0, F1, F2, F16) of the LG/J and SM/J inbred mouse lines to test this hypothesis. Using multiple populations and incorporating genetic, genomic, and physiological data, we leverage orthogonal evidence to identify networks of genes through which parent-of-origin effects propagate. We identify a network comprised of 3 imprinted and 6 non-imprinted genes that show parent-of-origin effects. This epistatic network forms a nutritional responsive pathway and the genes comprising it jointly serve cellular functions associated with growth. We focus on 2 genes, Nnat and F2r, whose interaction associates with serum glucose levels across generations in high fat-fed females. Single-cell RNAseq reveals that Nnat expression increases and F2r expression decreases in pre-adipocytes along an adipogenic trajectory, a result that is consistent with our observations in bulk white adipose tissue.
    Keywords:  evolutionary biology; genetics; genomics; mouse
    DOI:  https://doi.org/10.7554/eLife.72989
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