bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2022–03–06
six papers selected by
José Carlos de Lima-Júnior, University of California San Francisco
  1. Nardilysin in adipocytes regulates UCP1 expression and body temperature homeostasis.
  2. Inactivation of type 3 Deiodinase Results in Life-Long Changes in Brown Adipose Tissue Transcriptome in the Male Mouse.
  3. Loss of cytoplasmic FMR1-interacting protein 2 (CYFIP2) induces browning in 3T3-L1 adipocytes via repression of GABA-BR and activation of mTORC1.
  4. Obesity induces resistance to central action of BMP8B through a mechanism involving the BBSome.
  5. Intestinal AMPK modulation of microbiota mediates crosstalk with brown fat to control thermogenesis.
  6. Mineral requirements for mitochondrial function: A connection to redox balance and cellular differentiation.
  1. Sci Rep. 2022 Mar 02. 12(1): 3449
    Nardilysin in adipocytes regulates UCP1 expression and body temperature homeostasis.
    Sayaka Saijo, Mikiko Ohno, Hirotaka Iwasaki, Shintaro Matsuda, Kiyoto Nishi, Yoshinori Hiraoka, Natsuki Ide, Takeshi Kimura, Eiichiro Nishi.
      Brown adipose tissue (BAT) dissipates chemical energy as heat through uncoupling protein 1 (UCP1). The induction of mitochondrial reactive oxygen species (ROS) in BAT was recently identified as a mechanism that supports UCP1-dependent thermogenesis. We previously demonstrated that nardilysin (NRDC) plays critical roles in body temperature homeostasis. Global NRDC-deficient (Nrdc-/-) mice show hypothermia due to a lower set point for body temperature, whereas BAT thermogenesis at room temperature (RT) is enhanced mainly to compensate for poor thermal insulation. To examine the primary role of NRDC in BAT thermogenesis, we generated adipocyte-specific NRDC-deficient (Adipo-KO) mice by mating Nrdc floxed (Nrdcflox/flox) mice with adiponectin-Cre mice. Adipo-KO mice showed hyperthermia at both RT and thermoneutrality. They were also more cold-tolerant than Nrdcflox/flox mice. However, UCP1 mRNA levels were significantly lower in Adipo-KO BAT at RT, thermoneutrality, and 4 °C, whereas no significant differences were observed in UCP1 protein levels at RT and 4 °C. We examined the protein stability of UCP1 using the cycloheximide chase assay and found that NRDC negatively regulated its stability via the ubiquitin-proteasome pathway. NRDC may be also involved in ROS-mediated in vivo thermogenesis because the inhibitory effects of N-acetyl cysteine, an ROS scavenger, on β3 agonist-induced thermogenesis were stronger in Adipo-KO mice. Collectively, the present results demonstrate that NRDC in BAT controls adaptive thermogenesis and body temperature homeostasis possibly via the regulation of UCP1 protein stability and ROS levels.
    DOI:  https://doi.org/10.1038/s41598-022-07379-x
  2. Endocrinology. 2022 Mar 03. pii: bqac026. [Epub ahead of print]
    Inactivation of type 3 Deiodinase Results in Life-Long Changes in Brown Adipose Tissue Transcriptome in the Male Mouse.
    Tatiana L Fonseca, Samuel C Russo, Cristina Luongo, Domenico Salvatore, Antonio C Bianco.
      Adaptive thermogenesis in small mammals and infants takes place in the brown adipose tissue (BAT). Heat is produced via UCP1-mediated uncoupling between oxidation of energy substrates and ATP synthesis. Thyroid hormone signaling plays a role in this process. The deiodinases activate T4 to T3 (D2) or inactivate T4 and T3 to rT3 and T2 (D3), respectively. Using a mouse model with selective inactivation of Dio3 in BAT (flox-Dio3 x UCP1-cre = BAT-D3KO), we now show that knocking out D3 resulted in premature exposure of developing brown adipocytes (E16.5-18.5) to T3 signaling, leading to an earlier expression of key BAT genes, i.e. Cidea, Cox8b, Dio2, Ucp1, and Pgc1α. Adult BAT-D3KO mice exhibited increased expression of 1591 genes as assessed by RNA-seq, including 19 gene sets related to mitochondria, 8 related to fat, and 8 related to glucose homeostasis. The expression of 243 genes was changed by >1.5-fold, 36 of which play a role in metabolic/thermogenic processes. The BAT-D3KO mice weigh less and exhibit smaller white adipocyte area, but maintain normal energy expenditure at room temperature (22°C) and in the cold (4°C). They also defend their core temperature more effecttively and did not lose as much body weight when exposed to cold. We conclude that the coordinated actions of Dio3 in the embryonic BAT define the timing and intensity of T3 signaling during brown adipogenesis. Enhanced T3 signaling during BAT embryogenesis (Dio3 inactivation) results in selective life-long modifications in BAT transcriptome.
    Keywords:  brown fat; deiodinase; metabolism; thyroid hormone
    DOI:  https://doi.org/10.1210/endocr/bqac026
  3. J Cell Biochem. 2022 Mar 01.
    Loss of cytoplasmic FMR1-interacting protein 2 (CYFIP2) induces browning in 3T3-L1 adipocytes via repression of GABA-BR and activation of mTORC1.
    Subramani Manigandan, Jong Won Yun.
      Obesity and related metabolic disorders are epidemic diseases. Promoting thermogenesis and a functional increase in the browning of white adipocytes may counteract obesity. On the other hand, the molecular mechanism that regulates brown and beige fat-mediated thermogenesis is unclear. This article reports a molecular network led by cytoplasmic FMR1-interacting protein 2 (CYFIP2) that negatively regulates adipocyte browning in white adipocytes. Although the function of CYFIP2 in Fragile X Syndrome (FXS) and autism have been reported, its physiological roles in adipocytes remain elusive. Therefore, this study examined the physiological consequences of its deprivation in cultured 3T3-L1 white adipocytes using loss-of-function studies. Combined real-time quantitative reverse-transcription polymerase chain reaction and immunoblot analysis showed that the loss of CYFIP2 induces fat browning, as evidenced by the gene and protein expression levels of the brown fat-associated markers. A deficiency of CYFIP2 promoted mitochondrial biogenesis and significantly enhanced the expression of the core set beige fat-specific genes (Cd137, Cidea, Cited1, Tbx1, and Tmem26) and proteins (PGC-1α, PRDM16, and UCP1). In addition, a CYFIP2 deficiency promoted lipid catabolism and suppressed adipogenesis, lipogenesis, and autophagy. A mechanistic study showed that the loss of CYFIP2 induces browning in white adipocytes, independently via the activation of mTORC1 and suppression of the GABA-BR signaling pathway. The present data revealed a previously unidentified mechanism of CYFIP2 in the browning of white adipocytes and emphasized the potential of CYFIP2 as a pharmacotherapeutic target for treating obesity and other metabolic disorders.
    Keywords:  3T3-L1 adipocytes; CYFIP2; fat browning; obesity; thermogenesis
    DOI:  https://doi.org/10.1002/jcb.30231
  4. Mol Metab. 2022 Feb 23. pii: S2212-8778(22)00034-5. [Epub ahead of print] 101465
    Obesity induces resistance to central action of BMP8B through a mechanism involving the BBSome.
    Eva Rial-Pensado, Oscar Freire-Agulleiro, Marcos Ríos, Deng Fu Guo, Cristina Contreras, Patricia Seoane-Collazo, Sulay Tovar, Rubén Nogueiras, Carlos Diéguez, Kamal Rahmouni, Miguel López.
       OBJECTIVE: Bone morphogenetic protein 8B (BMP8B) plays a major role in the regulation of energy homeostasis by modulating brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) browning. Here, we investigated whether BMP8B role in metabolism is affected by obesity and the possible molecular mechanisms underlying that action.
    METHODS: Central treatments with BMP8B were performed in rats fed standard (SD) and high fat diet (HFD), as well as in genetic modified mice. Energy balance studies, infrared thermographic analysis of BAT and molecular analysis of the hypothalamus, BAT and WAT were carried out.
    RESULTS: We show for the first time that HFD-induced obesity elicits resistance to the central actions of BMP8B on energy balance. This obesity-induced BMP8B resistance is explained by i) lack of effects on AMP-activated protein kinase (AMPK) signaling, ii) decreased BMP receptors signaling and iii) reduced expression of Bardet-Biedl Syndrome 1 (BBS1) protein, a key component of the protein complex BBSome, in the ventromedial nucleus of the hypothalamus (VMH). The possible mechanistic involvement of BBS1 in this process is demonstrated by lack of central response to BMP8B in mice carrying a single missense disease-causing mutation in the Bbs1 gene.
    CONCLUSIONS: Overall, our data uncover a new mechanism of central resistance to hormonal action that may be of relevance in the pathophysiology of obesity.
    Keywords:  AMPK; BAT; BBS1; BMP8B; hypothalamus; obesity
    DOI:  https://doi.org/10.1016/j.molmet.2022.101465
  5. Nat Commun. 2022 Mar 03. 13(1): 1135
    Intestinal AMPK modulation of microbiota mediates crosstalk with brown fat to control thermogenesis.
    Eryun Zhang, Lihua Jin, Yangmeng Wang, Jui Tu, Ruirong Zheng, Lili Ding, Zhipeng Fang, Mingjie Fan, Ismail Al-Abdullah, Rama Natarajan, Ke Ma, Zhengtao Wang, Arthur D Riggs, Sarah C Shuck, Li Yang, Wendong Huang.
      The energy-dissipating capacity of brown adipose tissue through thermogenesis can be targeted to improve energy balance. Mammalian 5'-AMP-activated protein kinase, a key nutrient sensor for maintaining cellular energy status, is a known therapeutic target in Type II diabetes. Despite its well-established roles in regulating glucose metabolism in various tissues, the functions of AMPK in the intestine remain largely unexplored. Here we show that AMPKα1 deficiency in the intestine results in weight gain and impaired glucose tolerance under high fat diet feeding, while metformin administration fails to ameliorate these metabolic disorders in intestinal AMPKα1 knockout mice. Further, AMPKα1 in the intestine communicates with brown adipose tissue to promote thermogenesis. Mechanistically, we uncover a link between intestinal AMPKα1 activation and BAT thermogenic regulation through modulating anti-microbial peptide-controlled gut microbiota and the metabolites. Our findings identify AMPKα1-mediated mechanisms of intestine-BAT communication that may partially underlie the therapeutic effects of metformin.
    DOI:  https://doi.org/10.1038/s41467-022-28743-5
  6. Free Radic Biol Med. 2022 Feb 23. pii: S0891-5849(22)00075-2. [Epub ahead of print]
    Mineral requirements for mitochondrial function: A connection to redox balance and cellular differentiation.
    David W Killilea, Alison N Killilea.
      Professor Bruce Ames demonstrated that nutritional recommendations should be adjusted in order to 'tune-up' metabolism and reduce mitochondria decay, a hallmark of aging and many disease processes. A major subset of tunable nutrients are the minerals, which despite being integral to every aspect of metabolism are often deficient in the typical Western diet. Mitochondria are particularly rich in minerals, where they function as essential cofactors for mitochondrial physiology and overall cellular health. Yet substantial knowledge gaps remain in our understanding of the form and function of these minerals needed for metabolic harmony. Some of the minerals have known activities in the mitochondria but with incomplete regulatory detail, whereas other minerals have no established mitochondrial function at all. A comprehensive metallome of the mitochondria is needed to fully understand the patterns and relationships of minerals within metabolic processes and cellular development. This brief overview serves to highlight the current progress towards understanding mineral homeostasis in the mitochondria and to encourage more research activity in key areas. Future work may likely reveal that adjusting the amounts of specific nutritional minerals has longevity benefits for human health.
    Keywords:  Differentiation; Metals; Minerals; Mitochondria; Redox
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.02.022
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