bims-mimeim Biomed News
on Mitochondria, metabolism and immunity
Issue of 2021‒04‒18
nine papers selected by
Matthew C. Sinton
University of Glasgow


  1. Front Endocrinol (Lausanne). 2021 ;12 595020
      Obesity, an excess accumulation of white adipose tissue (WAT), has become a global epidemic and is associated with complex diseases, such as type 2 diabetes and cardiovascular diseases. Presently, there are no safe and effective therapeutic agents to treat obesity. In contrast to white adipocytes that store energy as triglycerides in unilocular lipid droplet, brown and brown-like or beige adipocytes utilize fatty acids (FAs) and glucose at a high rate mainly by uncoupling protein 1 (UCP1) action to uncouple mitochondrial proton gradient from ATP synthesis, dissipating energy as heat. Recent studies on the presence of brown or brown-like adipocytes in adult humans have revealed their potential as therapeutic targets in combating obesity. Classically, the main signaling pathway known to activate thermogenesis in adipocytes is β3-adrenergic signaling, which is activated by norepinephrine in response to cold, leading to activation of the thermogenic program and browning. In addition to the β3-adrenergic signaling, numerous other hormones and secreted factors have been reported to affect thermogenesis. In this review, we discuss several major pathways, β3-adrenergic, insulin/IGF1, thyroid hormone and TGFβ family, which regulate thermogenesis and browning of WAT.
    Keywords:  TGFβ superfamily; UCP1; b3-adrenergic signaling; brown adipose tissue; browning/beiging; insulin/IGF1 signaling; thermogenesis; thyroid hormone
    DOI:  https://doi.org/10.3389/fendo.2021.595020
  2. Diabetes. 2021 Apr 16. pii: db201210. [Epub ahead of print]
      L-Theanine is a nonprotein amino acid with much beneficial efficacy. We found that intraperitoneal treatment of the mice with L-Theanine(100mg/kg/day) enhanced adaptive thermogenesis and induced the browning of inguinal white adipose tissue (iWAT) with elevated expression of Prdm16, Ucp1 and other thermogenic genes. Meanwhile, administration of the mice with L-Theanine increased energy expenditure. In vitro studies indicated that L-Theanine induced the development of brown-like features in adipocytes. The shRNA-mediated depletion of Prdm16 blunted the role of L-Theanine in promoting the brown-like phenotypes in adipocytes and in the iWAT of mice. L-Theanine treatment enhanced AMPKα phosphorylation both in adipocytes and in iWAT. Knockdown of AMPKα ablolished L-Theanine-induced upregulation of Prdm16 and adipocytes browning. L-Theanine increased the α-ketoglutarate (α-KG) level in adipocytes, which may increase the transcription of Prdm16 by inducing active DNA demethylation on its promoter. AMPK activation was required for L-Theanine-induced increase of α-KG and DNA demethylation on Prdm16 promoter. Moreover, intraperitoneal administration with L-Theanine ameliorated obesity, improved glucose tolerance and insulin sensitivity, and reduced plasma triglyceride, total cholesterol and free fatty acid in the high fat diet-fed mice. Our results suggest a potential role of L-Theanine in combating diet-induced obesity in mice, which may involve L-Theanine-induced browning of white adipose tissue.
    DOI:  https://doi.org/10.2337/db20-1210
  3. Cell Metab. 2021 Apr 10. pii: S1550-4131(21)00130-3. [Epub ahead of print]
      NK cells are central to anti-tumor immunity and recently showed efficacy for treating hematologic malignancies. However, their dysfunction in the hostile tumor microenvironment remains a pivotal barrier for cancer immunotherapies against solid tumors. Using cancer patient samples and proteomics, we found that human NK cell dysfunction in the tumor microenvironment is due to suppression of glucose metabolism via lipid peroxidation-associated oxidative stress. Activation of the Nrf2 antioxidant pathway restored NK cell metabolism and function and resulted in greater anti-tumor activity in vivo. Strikingly, expanded NK cells reprogrammed with complete metabolic substrate flexibility not only sustained metabolic fitness but paradoxically augmented their tumor killing in the tumor microenvironment and in response to nutrient deprivation. Our results uncover that metabolic flexibility enables a cytotoxic immune cell to exploit the metabolic hostility of tumors for their advantage, addressing a critical hurdle for cancer immunotherapy.
    Keywords:  NK cell metabolism; NK cells; Warburg effect; adoptive cell therapy; cancer immunotherapy; glucose metabolism; immunometabolism; metabolic flexibility; oxidative stress; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cmet.2021.03.023
  4. Nat Metab. 2021 Apr 15.
      Overnutrition causes obesity, a global health problem without any effective therapy. Obesity is characterized by low-grade inflammation, which predisposes individuals to metabolic syndrome via unknown mechanisms. Here, we demonstrate that abolishing the interleukin-17A (IL-17A) axis in mice by inhibition of RORγt-mediated IL-17A production by digoxin, or by ubiquitous deletion of IL-17 receptor A (Il17ra), suppresses diet-induced obesity (DIO) and metabolic disorders, and promotes adipose-tissue browning, thermogenesis and energy expenditure. Genetic ablation of Il17ra specifically in adipocytes is sufficient to completely prevent DIO and metabolic dysfunction in mice. IL-17A produced in response to DIO induces PPARγ phosphorylation at Ser273 in adipocytes in a CDK5-dependent manner, thereby modifying expression of diabetogenic and obesity genes, which correlates with IL-17A signalling in white adipose tissues of individuals with morbid obesity. These findings reveal an unanticipated role for IL-17A in adipocyte biology, in which its direct action pathogenically reprograms adipocytes, promoting DIO and metabolic syndrome. Targeting the IL-17A axis could be an efficient antiobesity strategy.
    DOI:  https://doi.org/10.1038/s42255-021-00371-1
  5. Trends Immunol. 2021 Apr 10. pii: S1471-4906(21)00049-1. [Epub ahead of print]
      The mammalian immune system has crucial homeostatic functions in different adipose depots. However, white adipose tissue (WAT) inflammation is a hallmark of obesity and can contribute to type 2 diabetes mellitus (T2DM). Recently, mesenchymal cells were identified as highly heterogenous populations displaying specialized immune functions in immune cell migration, activation, survival, and overall lymphoid tissue organization in several tissues. How they regulate the inflammatory milieu within different adipose depots remains unknown. Using recently published single-cell RNA-sequencing (scRNAseq) data sets, we analyze cytokine and chemokine expression of mouse WAT mesenchymal cell subpopulations to highlight potential immunological heterogeneity and specialization, hypothesizing on their immunological functions. This new perspective on immune-mesenchymal cell interactions in adipose tissue may promote studies that heighten our understanding of immune cell processes within WAT during health and obesity. We hope that these studies redefine our knowledge of the roles of mesenchymal cells in regulating adipose tissue inflammation and physiology.
    DOI:  https://doi.org/10.1016/j.it.2021.03.001
  6. Pharmacol Res. 2021 Apr 07. pii: S1043-6618(21)00187-0. [Epub ahead of print] 105603
      Mitochondrial unfolded protein response (mitoUPR) is a mitochondria stress response to maintain mitochondrial proteostasis during stress. Increasing evidence suggests that mitoUPR participates in diverse physiological processes especially metabolism and immunity. Although mitoUPR regulates metabolism in many aspects, it is mainly reflected in the regulation of energy metabolism. During stress, mitoUPR alters energy metabolism via suppressing oxidative phosphorylation (OXPHOS) or increasing glycolysis. MitoUPR also alters energy metabolism and regulates diverse metabolic diseases such as diabetes, cancers, fatty liver and obesity. In addition, mitoUPR also participates in immune process during stress. MitoUPR can induce innate immune response during various infections and may regulate inflammatory response during diverse inflammations. Considering the pleiotropic actions of mitoUPR, mitoUPR may supply diverse therapeutic targets for metabolic diseases and immune diseases.
    Keywords:  diseases; immunity; metabolism; mitoUPR
    DOI:  https://doi.org/10.1016/j.phrs.2021.105603
  7. J Leukoc Biol. 2021 Apr 13.
      Obesity is an independent risk factor for morbidity and mortality in response to influenza infection. However, the underlying mechanisms by which obesity impairs immunity are unclear. Herein, we investigated the effects of diet-induced obesity on pulmonary CD8+ T cell metabolism, cytokine production, and transcriptome as a potential mechanism of impairment during influenza virus infection in mice. Male C57BL/6J lean and obese mice were infected with sub-lethal mouse-adapted A/PR/8/34 influenza virus, generating a pulmonary anti-viral and inflammatory response. Extracellular metabolic flux analyses revealed pulmonary CD8+ T cells from obese mice, compared with lean controls, had suppressed oxidative and glycolytic metabolism at day 10 post-infection. Flow cytometry showed the impairment in pulmonary CD8+ T cell metabolism with obesity was independent of changes in glucose or fatty acid uptake, but concomitant with decreased CD8+ GrB+ IFNγ+ populations. Notably, the percent of pulmonary effector CD8+ GrB+ IFNγ+ T cells at day 10 post-infection correlated positively with total CD8+ basal extracellular acidification rate and basal oxygen consumption rate. Finally, next-generation RNA sequencing revealed complex and unique transcriptional regulation of sorted effector pulmonary CD8+ CD44+ T cells from obese mice compared to lean mice following influenza infection. Collectively, the data suggest diet-induced obesity increases influenza virus pathogenesis, in part, through CD8+ T cell-mediated metabolic reprogramming and impaired effector CD8+ T cell function.
    Keywords:  Effector; Immunity; Pulmonary
    DOI:  https://doi.org/10.1002/JLB.4A0120-075RR
  8. Nat Metab. 2021 Apr 12.
      Brown adipose tissue can expend large amounts of energy, and therefore increasing its size or activity is a promising therapeutic approach to combat metabolic disease. In humans, major deposits of brown fat cells are found intimately associated with large blood vessels, corresponding to perivascular adipose tissue (PVAT). However, the cellular origins of PVAT are poorly understood. Here, we determine the identity of perivascular adipocyte progenitors in mice and humans. In mice, thoracic PVAT develops from a fibroblastic lineage, consisting of progenitor cells (Pdgfra+, Ly6a+ and Pparg-) and preadipocytes (Pdgfra+, Ly6a+ and Pparg+), which share transcriptional similarity with analogous cell types in white adipose tissue. Interestingly, the aortic adventitia of adult animals contains a population of adipogenic smooth muscle cells (Myh11+, Pdgfra- and Pparg+) that contribute to perivascular adipocyte formation. Similarly, human PVAT contains presumptive fibroblastic and smooth muscle-like adipocyte progenitor cells, as revealed by single-nucleus RNA sequencing. Together, these studies define distinct populations of progenitor cells for thermogenic PVAT, providing a foundation for developing strategies to augment brown fat activity.
    DOI:  https://doi.org/10.1038/s42255-021-00380-0
  9. Biochimie. 2021 Apr 12. pii: S0300-9084(21)00098-5. [Epub ahead of print]
      Glycogen storage disease type IV (GSD IV) is caused by mutations in the glycogen branching enzyme gene (GBE1) that lead to the accumulation of aberrant glycogen in affected tissues, mostly in the liver. To determine whether dysfunctional glycogen metabolism in GSD IV affects other components of cellular bioenergetics, we studied mitochondrial function in heterozygous Gbe1 knockout (Gbe1+/-) mice. Mitochondria isolated from the livers of Gbe1+/- mice showed elevated respiratory complex I activity and increased reactive oxygen species production, particularly by respiratory chain complex III. These observations indicate that GBE1 deficiency leads to broader rearrangements in energy metabolism and that the mechanisms underlying GSD IV pathogenesis may include more than merely mechanical cell damage caused by the presence of glycogen aggregates.
    Keywords:  Glycogen; Glycogen storage disease type IV; Mitochondria; Reactive oxygen species; Respiratory chain
    DOI:  https://doi.org/10.1016/j.biochi.2021.04.001