bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2022‒05‒01
ten papers selected by
José Carlos de Lima-Júnior
University of California San Francisco

  1. Mol Metab. 2022 Apr 22. pii: S2212-8778(22)00068-0. [Epub ahead of print] 101499
      OBJECTIVE: Classical ATP-independent non-shivering thermogenesis enabled by uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) is activated, but not essential for survival, in the cold. It has long been suspected that futile ATP-consuming substrate cycles also contribute to thermogenesis and can partially compensate for the genetic ablation of UCP1 in mouse models. Futile ATP-dependent thermogenesis could thereby enable survival in the cold even when brown fat is less abundant or missing.METHODS: In this study, we explore different potential sources of UCP1-independent thermogenesis and identify a futile ATP-consuming triglyceride/fatty acid cycle as the main contributor to cellular heat production in brown adipocytes lacking UCP1. We uncover the mechanism on a molecular level and pinpoint the key enzymes involved using pharmacological and genetic interference.
    RESULTS: ATGL is the most important lipase in terms of releasing fatty acids from lipid droplets, while DGAT1 accounts for the majority of fatty acid re-esterification in UCP1-ablated brown adipocytes. Furthermore, we demonstrate that chronic cold exposure causes a pronounced remodeling of adipose tissues and leads to the recruitment of lipid cycling capacity specifically in BAT of UCP1-knockout mice, possibly fueled by fatty acids from white fat. Quantification of triglyceride/fatty acid cycling clearly shows that UCP1-ablated animals significantly increase turnover rates at room temperature and below.
    CONCLUSION: Our results suggest an important role for futile lipid cycling in adaptive thermogenesis and total energy expenditure.
    Keywords:  Brown adipose tissue; Fatty acids; Futile substrate cycle; Lipolysis; Re-esterification; UCP1-independent thermogenesis
  2. Am J Physiol Regul Integr Comp Physiol. 2022 Apr 26.
      Complexes of the electron transport system can associate with each other to form supercomplexes (SCs) within mitochondrial membranes, perhaps increasing respiratory capacity or reducing reactive oxygen species production. In this study, we determined the abundance, composition, and stability of SCs in a mammalian hibernator, in which both whole-animal and mitochondria metabolism change greatly throughout winter. We isolated mitochondria from thirteen-lined ground squirrels (Ictidomys tridecemlineatus) in different hibernation states, as well as from rats (Rattus norvegicus). We extracted mitochondrial proteins using two non-ionic detergents of different strengths, and quantified SC abundance using two-dimensional gel electrophoresis and immunoblotting. Rat heart and liver had fewer SCs than ground squirrels. Within ground squirrels, SCs are dynamic, changing among hibernation states within a matter of hours. In brown adipose tissue, Complex III composition in different SCs differed between the torpid and interbout euthermic phase of a hibernation bout. In heart and liver, complex III composition changed between winter and summer. We also evaluated the stability of liver SCs using a stronger detergent and found that the stability of SCs differed: torpor SCs were more stable than the SCs of ground squirrels in other states and rats. This study is the first report of SC changes during hibernation, and the first to demonstrate their dynamics on a short timescale.
    Keywords:  Heterothermy; Hibernation; Mitochondria; Supercomplexes; Thermoregulation
  3. Nat Chem Biol. 2022 May;18(5): 461-469
      Metabolites once considered solely in catabolism or anabolism turn out to have key regulatory functions. Among these, the citric acid cycle intermediate succinate stands out owing to its multiple roles in disparate pathways, its dramatic concentration changes and its selective cell release. Here we propose that succinate has evolved as a signaling modality because its concentration reflects the coenzyme Q (CoQ) pool redox state, a central redox couple confined to the mitochondrial inner membrane. This connection is of general importance because CoQ redox state integrates three bioenergetic parameters: mitochondrial electron supply, oxygen tension and ATP demand. Succinate, by equilibrating with the CoQ pool, enables the status of this central bioenergetic parameter to be communicated from mitochondria to the rest of the cell, into the circulation and to other cells. The logic of this form of regulation explains many emerging roles of succinate in biology, and suggests future research questions.
  4. Front Cell Dev Biol. 2022 ;10 836741
      Brown adipose tissue (BAT) has emerged as an appealing therapeutic target for cardio metabolic diseases. BAT is a heat-producing organ and upon activation substantially lowers hyperlipidemia. In response to cold exposure, not only the uptake of lipids into BAT is increased but also the Cyp7b1-mediated synthesis of bile acids (BA) from cholesterol in the liver is triggered. In addition to their role for intestinal lipid digestion, BA act as endocrine signals that can activate thermogenesis in BAT. When exposed to cold temperatures, Cyp7b1 -/- mice have compromised BAT function along with reduced fecal bile acid levels. Here, we aim to evaluate the role of Cyp7b1 for BAT-dependent lipid clearance. Using metabolic studies with radioactive tracers, we show that in response to a cold stimulus, BAT-mediated clearance of fatty acids derived from triglyceride-rich lipoproteins (TRL), and their remnants are reduced in Cyp7b1 -/- mice. The impaired lipid uptake can be explained by reduced BAT lipoprotein lipase (LPL) levels and compromised organ activity in Cyp7b1 -/- mice, which may be linked to impaired insulin signaling. Overall, our findings reveal that alterations of systemic lipoprotein metabolism mediated by cold-activated BAT are dependent, at least in part, on CYP7Β1.
    Keywords:  CYP7B1; bile acids; brown adipose tissue; lipoproteins; postprandial metabolism
  5. Nat Immunol. 2022 Apr 28.
      The NLRP3 inflammasome is linked to sterile and pathogen-dependent inflammation, and its dysregulation underlies many chronic diseases. Mitochondria have been implicated as regulators of the NLRP3 inflammasome through several mechanisms including generation of mitochondrial reactive oxygen species (ROS). Here, we report that mitochondrial electron transport chain (ETC) complex I, II, III and V inhibitors all prevent NLRP3 inflammasome activation. Ectopic expression of Saccharomyces cerevisiae NADH dehydrogenase (NDI1) or Ciona intestinalis alternative oxidase, which can complement the functional loss of mitochondrial complex I or III, respectively, without generation of ROS, rescued NLRP3 inflammasome activation in the absence of endogenous mitochondrial complex I or complex III function. Metabolomics revealed phosphocreatine (PCr), which can sustain ATP levels, as a common metabolite that is diminished by mitochondrial ETC inhibitors. PCr depletion decreased ATP levels and NLRP3 inflammasome activation. Thus, the mitochondrial ETC sustains NLRP3 inflammasome activation through PCr-dependent generation of ATP, but via a ROS-independent mechanism.
  6. Proc Biol Sci. 2022 Apr 27. 289(1973): 20220456
      Hibernation is a natural state of suspended animation that many mammals experience and has been interpreted as an adaptive strategy for saving energy. However, the actual amount of savings that hibernation represents, and particularly its dependence on body mass (the 'scaling') has not been calculated properly. Here, we estimated the scaling of daily energy expenditure of hibernation (DEEH), covering a range of five orders of magnitude in mass. We found that DEEH scales isometrically with mass, which means that a gram of hibernating bat has a similar metabolism to that of a gram of bear, 20 000 times larger. Given that metabolic rate of active animals scales allometrically, the point where these scaling curves intersect with DEEH represents the mass where energy savings by hibernation are zero. For BMR, these zero savings are attained for a relatively small bear (approx. 75 kg). Calculated on a per cell basis, the cellular metabolic power of hibernation was estimated to be 1.3 × 10-12 ± 2.6 × 10-13 W cell-1, which is lower than the minimum metabolism of isolated mammalian cells. This supports the idea of the existence of a minimum metabolism that permits cells to survive under a combination of cold and hypoxia.
    Keywords:  allometry; dormancy; endothermy; hibernation; mammals; metabolism
  7. Front Endocrinol (Lausanne). 2022 ;13 812802
      STATs (Signal Transducers and Activators of Transcription) 5A and 5B are induced during adipocyte differentiation and are primarily activated by growth hormone (GH) and prolactin in fat cells. Previous studies in mice lacking adipocyte GH receptor or STAT5 support their roles in lipolysis-mediated reduction of adipose tissue mass. Male and female mice harboring adipocyte-specific deletion of both STAT5 genes (STAT5AKO) exhibit increased subcutaneous or inguinal adipose tissue mass, but no changes in visceral or gonadal fat mass. Both depots display substantial increases in adipocyte size with no changes in lipolysis in adipose tissue explants. RNA sequencing analysis of subcutaneous adipose tissue and indirect calorimetry experiments reveal sex-dependent differences in adipose gene expression and whole-body energy expenditure, respectively, resulting from the loss of adipocyte STAT5.
    Keywords:  STATs; adipose; growth hormone; sexual dimorphism; transcription
  8. Sci Adv. 2022 Apr 29. 8(17): eabm7012
      The immune checkpoint B7-H3 (CD276) is a member of the B7 family that has been studied in the tumor microenvironment and immunotherapy, but its potential role in metabolism remains largely unknown. Here, we show that B7-H3 is highly expressed in mouse and human adipose tissue at steady state, with the highest levels in adipocyte progenitor cells. B7-H3 is rapidly down-regulated upon the initiation of adipocyte differentiation. Combined RNA sequencing and metabolic studies reveal that B7-H3 stimulates glycolytic and mitochondrial activity of adipocyte progenitors. Loss of B7-H3 in progenitors results in impaired oxidative metabolism program and increased lipid accumulation in derived adipocytes. Consistent with these observations, mice knocked out for B7-H3 develop spontaneous obesity, metabolic dysfunction, and adipose tissue inflammation. Our results reveal an unexpected metabolic role for B7-H3 in adipose tissue and open potential new avenues for the treatment of metabolic diseases by targeting the B7-H3 pathway.
  9. FASEB J. 2022 Jun;36(6): e22333
      There is increasing evidence that aquatic ectotherms are especially vulnerable to global warming since their metabolic demands increase with ambient temperature while water-oxygen content decreases. The possible role of shrinking aerobic scope in limiting performance has been much discussed; however, less attention has been given to whether tissue-level changes in the efficiency of oxygen usage occur at elevated temperatures. Here, we show that this varies widely among individuals, with consequences for performance. We examined the inter-individual variation in growth rate and mitochondrial function from white muscle and liver of brown trout (Salmo trutta) acclimated to either high (19.5°C) or near-optimal temperature (12°C). Liver (but not muscle) mitochondria showed a positive relationship between growth rate and maximal oxidative phosphorylation at both temperatures, and a negative relationship between growth rate and ROS release. There was a positive correlation in both tissues between individual mitochondrial phosphorylation efficiency and growth rate, but only at 19.5°C. In this representative of aquatic ectotherms, an individual's liver mitochondrial efficiency thus seems to dictate its capacity to grow at elevated temperatures. This suggests that individual heterogeneity in cellular function may cause variation in the thermal limits of aquatic ectotherms and could adversely affect wild populations in warming environments.
    Keywords:  ATP/O; brown trout; climate change; global warming; liver; muscle
  10. Cell Death Dis. 2022 Apr 27. 13(4): 407
      Wnt5a, a prototypic non-canonical Wnt, is an inflammatory factor elevated in the sera of obese humans and mice. In the present study, fat-specific knockout of Wnt5a (Wnt5a-FKO) prevented HFD-induced increases in serum Wnt5a levels in male C57BL/6 J mice, which suggested adipocytes are primarily responsible for obesity-induced increases in Wnt5a levels. Mouse subcutaneous white adipose tissues (WATs) more sensitively responded to HFD, in terms of cell size increases and Wnt5a levels than epididymal WATs. Furthermore, adipocyte sizes were positively correlated with Wnt5a levels in vitro and in vivo. In hypertrophic adipocytes, enlarged lipid droplets increased cell stiffness and rearranged the f-actin stress fibers from the cytoplasm to the cortical region. The activities of YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) increased in response to these mechanical changes in hypertrophic adipocytes, and inhibition or knock-down of YAP and TAZ reduced Wnt5a expression. ChIP (chromatin immunoprecipitation) analyses revealed that YAP was recruited by Wnt5a-1 gene promoter and increased Wnt5a expression. These results suggested that YAP responds to mechanical stress in hypertrophic adipocytes to induce the expression Wnt5a. When 8-week-old Wnt5a-FKO mice were fed an HFD for 20 weeks, the fat mass increased, especially in subcutaneous WATs, as compared with that observed in floxed mice, without significant changes in food intake or activity. Furthermore, Wnt5a-FKO mice showed impaired glucose tolerance regardless of diet type. Our findings show that hypertrophy/YAP/Wnt5a signaling constitutes a negative-feedback loop that retrains adipose tissue hypertrophy.