bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2024‒02‒18
six papers selected by
José Carlos de Lima-Júnior, Washington University
  1. Connexin43 in mesenchymal lineage cells regulates body adiposity and energy metabolism in mice.
  2. Insulin at the intersection of thermoregulation and glucose homeostasis.
  3. Adipocyte p53 coordinates the response to intermittent fasting by regulating adipose tissue immune cell landscape.
  4. Heat stress reduces brown adipose tissue activity by exacerbating mitochondrial damage in type 2 diabetic mice.
  5. SLC25A51 decouples the mitochondrial NAD+/NADH ratio to control proliferation of AML cells.
  6. Phospholipids with two polyunsaturated fatty acyl tails promote ferroptosis.
  1. JCI Insight. 2024 Feb 13. pii: e170016. [Epub ahead of print]
    Connexin43 in mesenchymal lineage cells regulates body adiposity and energy metabolism in mice.
    Seung-Yon Lee, Francesca Fontana, Toshifumi Sugatani, Ignacio Portales Castillo, Giulia Leanza, Ariella Coler-Reilly, Roberto Civitelli.
      Connexin43 (Cx43) is the most abundant gap junction protein present in the mesenchymal lineage. In mature adipocytes, Cx43 mediates white adipose tissue (WAT) "beiging" in response to cold exposure and maintains the mitochondrial integrity of brown adipose tissue (BAT). We found that genetic deletion of Gja1 (Cx43 gene) in cells that give rise to chondro-osteogenic and adipogenic precursors driven by the Dermo1/Twist2 promoter led to lower body adiposity and partial protection against the weight gain and metabolic syndrome induced by a high fat diet (HFD) in both sexes. These protective effects from obesogenic diet were related to increased locomotion, fuel utilization, energy expenditure, non-shivering thermogenesis, and better glucose tolerance in conditionally Gja1 ablated mice. Accordingly, Gja1 mutant mice exhibited reduced adipocyte hypertrophy, partially preserved insulin sensitivity, increased BAT lipolysis and decreased whitening under HFD. This metabolic phenotype was not reproduced with more restricted Gja1 ablation in differentiated adipocytes, suggesting that Cx43 in adipocyte progenitors or other targeted cells restrains energy expenditures and promotes fat accumulation. These results disclose an hitherto unknown action of Cx43 in adiposity, and offer a promising new pharmacologic target for improving metabolic balance in diabetes and obesity.
    Keywords:  Adipose tissue; Adult stem cells; Metabolism; Obesity
    DOI:  https://doi.org/10.1172/jci.insight.170016
  2. Mol Metab. 2024 Feb 13. pii: S2212-8778(24)00032-2. [Epub ahead of print] 101901
    Insulin at the intersection of thermoregulation and glucose homeostasis.
    Nathan C Winn, Michael W Schleh, Jamie N Garcia, Louise Lantier, Owen P McGuinness, Joslin A Blair, Alyssa H Hasty, David H Wasserman.
      Mammals are protected from changes in environmental temperature by altering energetic processes that modify heat production. Insulin is the dominant stimulus of glucose uptake and metabolism, which are fundamental for thermogenic processes. The purpose of this work was to determine the interaction of ambient temperature induced changes in energy expenditure (EE) on the insulin sensitivity of glucose fluxes. Short-term and adaptive responses to thermoneutral temperature (TN, ∼28 °C) and room (laboratory) temperature (RT, ∼22 °C) were studied in mice. This range of temperature does not cause detectable changes in circulating catecholamines or shivering and postabsorptive glucose homeostasis is maintained. We tested the hypothesis that a decrease in EE that occurs with TN causes insulin resistance and that this reduction in insulin action and EE is reversed upon short term (<12h) transition to RT. Insulin-stimulated glucose disposal (Rd) and tissue-specific glucose metabolic index were assessed combining isotopic tracers with hyperinsulinemic-euglycemic clamps. EE and insulin-stimulated Rd are both decreased (∼50%) in TN-adapted vs RT-adapted mice. When RT-adapted mice are switched to TN, EE rapidly decreases and Rd is reduced by ∼50%. TN-adapted mice switched to RT exhibit a rapid increase in EE, but whole-body insulin-stimulated Rd remains at the low rates of TN-adapted mice. In contrast, whole body glycolytic flux rose with EE. This higher EE occurs without increasing glucose uptake from the blood, but rather by diverting glucose from glucose storage to glycolysis. In addition to adaptations in insulin action, 'insulin-independent' glucose uptake in brown fat is exquisitely sensitive to thermoregulation. These results show that insulin action adjusts to non-stressful changes in ambient temperature to contribute to the support of body temperature homeostasis without compromising glucose homeostasis.
    DOI:  https://doi.org/10.1016/j.molmet.2024.101901
  3. Nat Commun. 2024 Feb 15. 15(1): 1391
    Adipocyte p53 coordinates the response to intermittent fasting by regulating adipose tissue immune cell landscape.
    Isabel Reinisch, Helene Michenthaler, Alba Sulaj, Elisabeth Moyschewitz, Jelena Krstic, Markus Galhuber, Ruonan Xu, Zina Riahi, Tongtong Wang, Nemanja Vujic, Melina Amor, Riccardo Zenezini Chiozzi, Martin Wabitsch, Dagmar Kolb, Anastasia Georgiadi, Lisa Glawitsch, Ellen Heitzer, Tim J Schulz, Michael Schupp, Wenfei Sun, Hua Dong, Adhideb Ghosh, Anne Hoffmann, Dagmar Kratky, Laura C Hinte, Ferdinand von Meyenn, Albert J R Heck, Matthias Blüher, Stephan Herzig, Christian Wolfrum, Andreas Prokesch.
      In obesity, sustained adipose tissue (AT) inflammation constitutes a cellular memory that limits the effectiveness of weight loss interventions. Yet, the impact of fasting regimens on the regulation of AT immune infiltration is still elusive. Here we show that intermittent fasting (IF) exacerbates the lipid-associated macrophage (LAM) inflammatory phenotype of visceral AT in obese mice. Importantly, this increase in LAM abundance is strongly p53 dependent and partly mediated by p53-driven adipocyte apoptosis. Adipocyte-specific deletion of p53 prevents LAM accumulation during IF, increases the catabolic state of adipocytes, and enhances systemic metabolic flexibility and insulin sensitivity. Finally, in cohorts of obese/diabetic patients, we describe a p53 polymorphism that links to efficacy of a fasting-mimicking diet and that the expression of p53 and TREM2 in AT negatively correlates with maintaining weight loss after bariatric surgery. Overall, our results demonstrate that p53 signalling in adipocytes dictates LAM accumulation in AT under IF and modulates fasting effectiveness in mice and humans.
    DOI:  https://doi.org/10.1038/s41467-024-45724-y
  4. J Therm Biol. 2024 Feb 08. pii: S0306-4565(24)00017-2. [Epub ahead of print]119 103799
    Heat stress reduces brown adipose tissue activity by exacerbating mitochondrial damage in type 2 diabetic mice.
    Penghua Lai, Linlin Zhang, Yan Qiu, Jie Ren, Xue Sun, Ting Zhang, Liuyi Wang, Sijie Cheng, Sijia Liu, Hongli Zhuang, Daiwei Lu, Shaoliang Zhang, Huiqing Liang, Shaodong Chen.
      Epidemiological evidence shows that diabetic patients are susceptible to high temperature weather, and brown adipose tissue (BAT) activity is closely related to type 2 diabetes (T2DM). Activation of BAT under cold stress helps improve T2DM. However, the impact of high temperature on the activity of BAT is still unclear. The study aimed to investigate the impact of heat stress on glucose and lipid metabolism in T2DM mice by influencing BAT activity. High-fat feeding and injecting streptozotocin (STZ) induced model of T2DM mice. All mice were randomly divided into three groups: a normal(N) group, a diabetes (DM) group and a heat stress diabetes (DMHS) group. The DMHS group received heat stress intervention for 3 days. Fasting blood glucose, fasting serum insulin and blood lipids were measured in all three groups. The activity of BAT was assessed by using quantitative real-time PCR (qRT-PCR), electron microscopy, and PET CT. Furthermore, the UHPLC-Q-TOF MS technique was employed to perform metabolomics analysis of BAT on both DM group and DMHS group. The results of this study indicated that heat stress aggravated the dysregulation of glucose and lipid metabolism, exacerbated mitochondrial dysfunction in BAT and reduced the activity of BAT in T2DM mice. This may be related to the abnormal accumulation of branched-chain amino acids (BCAAs) in the mitochondria of BAT.
    Keywords:  Branched-chain amino acids; Brown adipose tissue; Heat stress; Type 2 diabetes
    DOI:  https://doi.org/10.1016/j.jtherbio.2024.103799
  5. Cell Metab. 2024 Feb 13. pii: S1550-4131(24)00013-5. [Epub ahead of print]
    SLC25A51 decouples the mitochondrial NAD+/NADH ratio to control proliferation of AML cells.
    Mu-Jie Lu, Jonathan Busquets, Valeria Impedovo, Crystal N Wilson, Hsin-Ru Chan, Yu-Tai Chang, William Matsui, Stefano Tiziani, Xiaolu A Cambronne.
      SLC25A51 selectively imports oxidized NAD+ into the mitochondrial matrix and is required for sustaining cell respiration. We observed elevated expression of SLC25A51 that correlated with poorer outcomes in patients with acute myeloid leukemia (AML), and we sought to determine the role SLC25A51 may serve in this disease. We found that lowering SLC25A51 levels led to increased apoptosis and prolonged survival in orthotopic xenograft models. Metabolic flux analyses indicated that depletion of SLC25A51 shunted flux away from mitochondrial oxidative pathways, notably without increased glycolytic flux. Depletion of SLC25A51 combined with 5-azacytidine treatment limits expansion of AML cells in vivo. Together, the data indicate that AML cells upregulate SLC25A51 to decouple mitochondrial NAD+/NADH for a proliferative advantage by supporting oxidative reactions from a variety of fuels. Thus, SLC25A51 represents a critical regulator that can be exploited by cancer cells and may be a vulnerability for refractory AML.
    Keywords:  AML; MCART1; SLC25A51; glutamine utilization; oxidative mitochondria; tumor metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2024.01.013
  6. Cell. 2024 Feb 08. pii: S0092-8674(24)00067-9. [Epub ahead of print]
    Phospholipids with two polyunsaturated fatty acyl tails promote ferroptosis.
    Baiyu Qiu, Fereshteh Zandkarimi, Carla T Bezjian, Eduard Reznik, Rajesh Kumar Soni, Wei Gu, Xuejun Jiang, Brent R Stockwell.
      Phospholipids containing a single polyunsaturated fatty acyl tail (PL-PUFA1s) are considered the driving force behind ferroptosis, whereas phospholipids with diacyl-PUFA tails (PL-PUFA2s) have been rarely characterized. Dietary lipids modulate ferroptosis, but the mechanisms governing lipid metabolism and ferroptosis sensitivity are not well understood. Our research revealed a significant accumulation of diacyl-PUFA phosphatidylcholines (PC-PUFA2s) following fatty acid or phospholipid treatments, correlating with cancer cell sensitivity to ferroptosis. Depletion of PC-PUFA2s occurred in aging and Huntington's disease brain tissue, linking it to ferroptosis. Notably, PC-PUFA2s interacted with the mitochondrial electron transport chain, generating reactive oxygen species (ROS) for initiating lipid peroxidation. Mitochondria-targeted antioxidants protected cells from PC-PUFA2-induced mitochondrial ROS (mtROS), lipid peroxidation, and cell death. These findings reveal a critical role for PC-PUFA2s in controlling mitochondria homeostasis and ferroptosis in various contexts and explain the ferroptosis-modulating mechanisms of free fatty acids. PC-PUFA2s may serve as diagnostic and therapeutic targets for modulating ferroptosis.
    Keywords:  PUFA; ROS; complex I; diacyl-PUFA phosphatidylcholine; electron transport chain; ferroptosis; lipids; mitochondria; phospholipid; polyunsaturated fatty acid
    DOI:  https://doi.org/10.1016/j.cell.2024.01.030
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