bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2022–12–04
seven papers selected by
José Carlos de Lima-Júnior, Washington University
  1. Mitochondrial RNA stimulates beige adipocyte development in young mice.
  2. Requirement of hepatic pyruvate carboxylase during fasting, high fat, and ketogenic diet.
  3. Epigenetic regulation of white adipose tissue plasticity and energy metabolism by nucleosome binding HMGN proteins.
  4. Neuronal IRE-1 coordinates an organism-wide cold stress response by regulating fat metabolism.
  5. Temperature-robust rapid eye movement and slow wave sleep in the lizard Laudakia vulgaris.
  6. Acetyl-CoA-mediated autoacetylation of fatty acid synthase as a metabolic switch of de novo lipogenesis in Drosophila.
  7. Metabolon formation regulates branched-chain amino acid oxidation and homeostasis.
  1. Nat Metab. 2022 Nov 28.
    Mitochondrial RNA stimulates beige adipocyte development in young mice.
    Anh Cuong Hoang, László Sasi-Szabó, Tibor Pál, Tamás Szabó, Victoria Diedrich, Annika Herwig, Kathrin Landgraf, Antje Körner, Tamás Röszer.
      Childhood obesity is a serious public health crisis and a critical factor that determines future obesity prevalence. Signals affecting adipocyte development in early postnatal life have a strong potential to trigger childhood obesity; however, these signals are still poorly understood. We show here that mitochondrial (mt)RNA efflux stimulates transcription of nuclear-encoded genes for mitobiogenesis and thermogenesis in adipocytes of young mice and human infants. While cytosolic mtRNA is a potential trigger of the interferon (IFN) response, young adipocytes lack such a response to cytosolic mtRNA due to the suppression of IFN regulatory factor (IRF)7 expression by vitamin D receptor signalling. Adult and obese adipocytes, however, strongly express IRF7 and mount an IFN response to cytosolic mtRNA. In turn, suppressing IRF7 expression in adult adipocytes restores mtRNA-induced mitobiogenesis and thermogenesis and eventually mitigates obesity. Retrograde mitochondrion-to-nucleus signalling by mtRNA is thus a mechanism to evoke thermogenic potential during early adipocyte development and to protect against obesity.
    DOI:  https://doi.org/10.1038/s42255-022-00683-w
  2. J Biol Chem. 2022 Oct 28. pii: S0021-9258(22)01091-2. [Epub ahead of print]298(12): 102648
    Requirement of hepatic pyruvate carboxylase during fasting, high fat, and ketogenic diet.
    Ebru S Selen, Susana Rodriguez, Kyle S Cavagnini, Han-Byeol Kim, Chan Hyun Na, Michael J Wolfgang.
      Pyruvate has two major fates upon entry into mitochondria, the oxidative decarboxylation to acetyl-CoA via the pyruvate decarboxylase complex or the biotin-dependent carboxylation to oxaloacetate via pyruvate carboxylase (Pcx). Here, we have generated mice with a liver-specific KO of pyruvate carboxylase (PcxL-/-) to understand the role of Pcx in hepatic mitochondrial metabolism under disparate physiological states. PcxL-/- mice exhibited a deficit in hepatic gluconeogenesis and enhanced ketogenesis as expected but were able to maintain systemic euglycemia following a 24 h fast. Feeding a high-fat diet to PcxL-/- mice resulted in animals that were resistant to glucose intolerance without affecting body weight. However, we found that PcxL-/- mice fed a ketogenic diet for 1 week became severely hypoglycemic, demonstrating a requirement for hepatic Pcx for long-term glycemia under carbohydrate-limited diets. Additionally, we determined that loss of Pcx was associated with an induction in the abundance of lysine-acetylated proteins in PcxL-/- mice regardless of physiologic state. Furthermore, liver acetyl-proteomics revealed a biased induction in mitochondrial lysine-acetylated proteins. These data show that Pcx is important for maintaining the proper balance of pyruvate metabolism between oxidative and anaplerotic pathways.
    Keywords:  Pyruvate Carboxylase; acetylation; fasting; gluconeogenesis; mitochondria
    DOI:  https://doi.org/10.1016/j.jbc.2022.102648
  3. Nat Commun. 2022 Nov 26. 13(1): 7303
    Epigenetic regulation of white adipose tissue plasticity and energy metabolism by nucleosome binding HMGN proteins.
    Ravikanth Nanduri, Takashi Furusawa, Alexei Lobanov, Bing He, Carol Xie, Kimia Dadkhah, Michael C Kelly, Oksana Gavrilova, Frank J Gonzalez, Michael Bustin.
      White adipose tissue browning is a key metabolic process controlled by epigenetic factors that facilitate changes in gene expression leading to altered cell identity. We find that male mice lacking the nucleosome binding proteins HMGN1 and HMGN2 (DKO mice), show decreased body weight and inguinal WAT mass, but elevated food intake, WAT browning and energy expenditure. DKO white preadipocytes show reduced chromatin accessibility and lower FRA2 and JUN binding at Pparγ and Pparα promoters. White preadipocytes and mouse embryonic fibroblasts from DKO mice show enhanced rate of differentiation into brown-like adipocytes. Differentiating DKO adipocytes show reduced H3K27ac levels at white adipocyte-specific enhancers but elevated H3K27ac levels at brown adipocyte-specific enhancers, suggesting a faster rate of change in cell identity, from white to brown-like adipocytes. Thus, HMGN proteins function as epigenetic factors that stabilize white adipocyte cell identity, thereby modulating the rate of white adipose tissue browning and affecting energy metabolism in mice.
    DOI:  https://doi.org/10.1038/s41467-022-34964-5
  4. Cell Rep. 2022 Nov 29. pii: S2211-1247(22)01617-5. [Epub ahead of print]41(9): 111739
    Neuronal IRE-1 coordinates an organism-wide cold stress response by regulating fat metabolism.
    Reut Dudkevich, Jhee Hong Koh, Caroline Beaudoin-Chabot, Cenk Celik, Ilana Lebenthal-Loinger, Sarit Karako-Lampert, Syed Ahmad-Albukhari, Guillaume Thibault, Sivan Henis-Korenblit.
      Cold affects many aspects of biology, medicine, agriculture, and industry. Here, we identify a conserved endoplasmic reticulum (ER) stress response, distinct from the canonical unfolded protein response, that maintains lipid homeostasis during extreme cold. We establish that the ER stress sensor IRE-1 is critical for resistance to extreme cold and activated by cold temperature. Specifically, neuronal IRE-1 signals through JNK-1 and neuropeptide signaling to regulate lipid composition within the animal. This cold-response pathway can be bypassed by dietary supplementation with unsaturated fatty acids. Altogether, our findings define an ER-centric conserved organism-wide cold stress response, consisting of molecular neuronal sensors, effectors, and signaling moieties, which control adaptation to cold conditions in the organism. Better understanding of the molecular basis of this stress response is crucial for the optimal use of cold conditions on live organisms and manipulation of lipid saturation homeostasis, which is perturbed in human pathologies.
    Keywords:  C. elegans; CP: Metabolism; IRE-1; IRE1; JNK; cell non-autonomous stress response; cold stress; endoplasmic reticulum; fat metabolism; lipids; unfolded protein response
    DOI:  https://doi.org/10.1016/j.celrep.2022.111739
  5. Commun Biol. 2022 Nov 29. 5(1): 1310
    Temperature-robust rapid eye movement and slow wave sleep in the lizard Laudakia vulgaris.
    Nitzan Albeck, Daniel I Udi, Regev Eyal, Arik Shvartsman, Mark Shein-Idelson.
      During sleep our brain switches between two starkly different brain states - slow wave sleep (SWS) and rapid eye movement (REM) sleep. While this two-state sleep pattern is abundant across birds and mammals, its existence in other vertebrates is not universally accepted, its evolutionary emergence is unclear and it is undetermined whether it is a fundamental property of vertebrate brains or an adaptation specific to homeotherms. To address these questions, we conducted electrophysiological recordings in the Agamid lizard, Laudakia vulgaris during sleep. We found clear signatures of two-state sleep that resemble the mammalian and avian sleep patterns. These states switched periodically throughout the night with a cycle of ~90 seconds and were remarkably similar to the states previously reported in Pogona vitticeps. Interestingly, in contrast to the high temperature sensitivity of mammalian states, state switches were robust to large variations in temperature. We also found that breathing rate, micro-movements and eye movements were locked to the REM state as they are in mammals. Collectively, these findings suggest that two-state sleep is abundant across the agamid family, shares physiological similarity to mammalian sleep, and can be maintain in poikilothems, increasing the probability that it existed in the cold-blooded ancestor of amniotes.
    DOI:  https://doi.org/10.1038/s42003-022-04261-4
  6. Proc Natl Acad Sci U S A. 2022 Dec 06. 119(49): e2212220119
    Acetyl-CoA-mediated autoacetylation of fatty acid synthase as a metabolic switch of de novo lipogenesis in Drosophila.
    Ting Miao, Jinoh Kim, Ping Kang, Hideji Fujiwara, Fong-Fu Hsu, Hua Bai.
      De novo lipogenesis is a highly regulated metabolic process, which is known to be activated through transcriptional regulation of lipogenic genes, including fatty acid synthase (FASN). Unexpectedly, we find that the expression of FASN protein remains unchanged during Drosophila larval development from the second to the third instar larval stages (L2 to L3) when lipogenesis is hyperactive. Instead, acetylation of FASN is significantly upregulated in fast-growing larvae. We further show that lysine K813 residue is highly acetylated in developing larvae, and its acetylation is required for elevated FASN activity, body fat accumulation, and normal development. Intriguingly, K813 is autoacetylated by acetyl-CoA (AcCoA) in a dosage-dependent manner independent of acetyltransferases. Mechanistically, the autoacetylation of K813 is mediated by a novel P-loop-like motif (N-xx-G-x-A). Lastly, we find that K813 is deacetylated by Sirt1, which brings FASN activity to baseline level. In summary, this work uncovers a previously unappreciated role of FASN acetylation in developmental lipogenesis and a novel mechanism for protein autoacetylation, through which Drosophila larvae control metabolic homeostasis by linking AcCoA, lysine acetylation, and de novo lipogenesis.
    Keywords:  FASN; acetyl-CoA; animal development; autoacetylation; de novo lipogenesis
    DOI:  https://doi.org/10.1073/pnas.2212220119
  7. Nat Metab. 2022 Nov 28.
    Metabolon formation regulates branched-chain amino acid oxidation and homeostasis.
    McKenzie Patrick, Zhimin Gu, Gen Zhang, R Max Wynn, Pranita Kaphle, Hui Cao, Hieu Vu, Feng Cai, Xiaofei Gao, Yuannyu Zhang, Mingyi Chen, Min Ni, David T Chuang, Ralph J DeBerardinis, Jian Xu.
      The branched-chain aminotransferase isozymes BCAT1 and BCAT2, segregated into distinct subcellular compartments and tissues, initiate the catabolism of branched-chain amino acids (BCAAs). However, whether and how BCAT isozymes cooperate with downstream enzymes to control BCAA homeostasis in an intact organism remains largely unknown. Here, we analyse system-wide metabolomic changes in BCAT1- and BCAT2-deficient mouse models. Loss of BCAT2 but not BCAT1 leads to accumulation of BCAAs and branched-chain α-keto acids (BCKAs), causing morbidity and mortality that can be ameliorated by dietary BCAA restriction. Through proximity labelling, isotope tracing and enzymatic assays, we provide evidence for the formation of a mitochondrial BCAA metabolon involving BCAT2 and branched-chain α-keto acid dehydrogenase. Disabling the metabolon contributes to BCAT2 deficiency-induced phenotypes, which can be reversed by BCAT1-mediated BCKA reamination. These findings establish a role for metabolon formation in BCAA metabolism in vivo and suggest a new strategy to modulate this pathway in diseases involving dysfunctional BCAA metabolism.
    DOI:  https://doi.org/10.1038/s42255-022-00689-4
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