bims-mimbat 2022-03-27 papers

bims-mimbat

Biomed News

on Mitochondrial metabolism in brown adipose tissue

Issue of 2022–03–27
nine papers selected by
José Carlos de Lima-Júnior, University of California San Francisco

Ejection of damaged mitochondria and their removal by macrophages ensure efficient thermogenesis in brown adipose tissue.
Tanshinone 1 prevents high fat diet-induced obesity through activation of brown adipocytes and induction of browning in white adipocytes.
Mitophagy Mediates the Beige to White Transition of Human Primary Subcutaneous Adipocytes Ex Vivo.
Baicalin promotes the activation of brown and white adipose tissue through AMPK/PGC1α pathway.
Inactivity and the passive slowing effect of cold on resting metabolism as the primary drivers of energy savings in overwintering fishes.
C-type natriuretic peptide is a pivotal regulator of metabolic homeostasis.
Revisiting Mitochondrial Bioenergetics: Experimental Considerations for Biological Interpretation.
3-Hydroxyacyl-CoA dehydratase 2 deficiency confers resistance to diet-induced obesity and glucose intolerance.
Hexokinase 1 cellular localization regulates the metabolic fate of glucose.

Cell Metab. 2022 Mar 15. pii: S1550-4131(22)00088-2. [Epub ahead of print]

Ejection of damaged mitochondria and their removal by macrophages ensure efficient thermogenesis in brown adipose tissue.

Marco Rosina, Veronica Ceci, Riccardo Turchi, Li Chuan, Nicholas Borcherding, Francesca Sciarretta, María Sánchez-Díaz, Flavia Tortolici, Keaton Karlinsey, Valerio Chiurchiù, Claudia Fuoco, Rocky Giwa, Rachael L Field, Matteo Audano, Simona Arena, Alessandro Palma, Federica Riccio, Farnaz Shamsi, Giovanni Renzone, Martina Verri, Anna Crescenzi, Salvatore Rizza, Fiorella Faienza, Giuseppe Filomeni, Sander Kooijman, Stefano Rufini, Antoine A F de Vries, Andrea Scaloni, Nico Mitro, Yu-Hua Tseng, Andrés Hidalgo, Beiyan Zhou, Jonathan R Brestoff, Katia Aquilano, Daniele Lettieri-Barbato.

  Recent findings have demonstrated that mitochondria can be transferred between cells to control metabolic homeostasis. Although the mitochondria of brown adipocytes comprise a large component of the cell volume and undergo reorganization to sustain thermogenesis, it remains unclear whether an intercellular mitochondrial transfer occurs in brown adipose tissue (BAT) and regulates adaptive thermogenesis. Herein, we demonstrated that thermogenically stressed brown adipocytes release extracellular vesicles (EVs) that contain oxidatively damaged mitochondrial parts to avoid failure of the thermogenic program. When re-uptaken by parental brown adipocytes, mitochondria-derived EVs reduced peroxisome proliferator-activated receptor-γ signaling and the levels of mitochondrial proteins, including UCP1. Their removal via the phagocytic activity of BAT-resident macrophages is instrumental in preserving BAT physiology. Depletion of macrophages in vivo causes the abnormal accumulation of extracellular mitochondrial vesicles in BAT, impairing the thermogenic response to cold exposure. These findings reveal a homeostatic role of tissue-resident macrophages in the mitochondrial quality control of BAT.

Keywords:  adipose tissue; brown adipocytes; extracellular vesicles; homeostasis; immunometabolism; macrophages; mitochondria; mitochondrial quality control; thermogenesis

DOI:  https://doi.org/10.1016/j.cmet.2022.02.016
Life Sci. 2022 Mar 21. pii: S0024-3205(22)00188-6. [Epub ahead of print] 120488

Tanshinone 1 prevents high fat diet-induced obesity through activation of brown adipocytes and induction of browning in white adipocytes.

Dae Young Jung, Nanjoo Suh, Myeong Ho Jung.

   AIM: Increasing brown adipocytes activity and inducting browning of white adipocytes are potential therapeutic targets for the treatment of obesity. In the present study, we investigated the effects of Tanshinone 1 (Tan 1), a major compound from Salvia miltiorrhiza Bunge, on the activation of brown adipocytes and browning of white adipocytes in vivo and in vitro.
MATERIALS AND METHODS: Expression of genes associated with brown adipocyte function including thermogenesis, mitochondria biogenesis and fatty acid oxidation was examined in brown adipose tissue (BAT) and white adipose tissue (WAT) of high fat diet (HFD)-fed obese mice administrated with Tan 1 or in immortalized brown adipocytes (iBAs) and 3T3-L1 adipocytes treated with Tan 1. Mitochondria DNA (mtDNA) content, lipolysis and phosphorylated AMP-activated protein kinase (AMPK) were further assessed in Tan 1 treated-iBAs and 3T3-L1 adipocytes.
KEY FINDINGS: The administration of Tan 1 protected against HFD-induced obesity in mice, which was associated with enhanced expression of brown adipocyte function-related genes in BAT and WAT. Tan 1 treatment also upregulated brown adipocyte function-related genes in iBA and induced beige adipocytes genes in 3T3-L1 adipocytes, resulting in increased mtDNA content and lipolysis. Tan 1 activated AMPK in BAT and WAT of HFD-fed obese mice as well as in iBAs and 3T3-L1 adipocytes. Inhibition of AMPK by compound C prevented Tan 1-induced expression of beige adipocytes genes.
SIGNIFICANCE: These results indicate that Tan 1 activates brown adipocytes and induces browning of white adipocytes, which may contribute to anti-obesity activity of Tan 1.

Keywords:  AMP-activated protein kinase; Brown adipocytes; Browning; Energy expenditure; Fatty acid oxidation; Mitochondrial biogenesis; Obesity; Thermogenesis

DOI:  https://doi.org/10.1016/j.lfs.2022.120488
Pharmaceuticals (Basel). 2022 Mar 17. pii: 363. [Epub ahead of print]15(3):

Mitophagy Mediates the Beige to White Transition of Human Primary Subcutaneous Adipocytes Ex Vivo.

Attila Vámos, Abhirup Shaw, Klára Varga, István Csomós, Gábor Mocsár, Zoltán Balajthy, Cecília Lányi, Zsolt Bacso, Mária Szatmári-Tóth, Endre Kristóf.

  Brown and beige adipocytes have multilocular lipid droplets, express uncoupling protein (UCP) 1, and promote energy expenditure. In rodents, when the stimulus of browning subsides, parkin-dependent mitophagy is activated and dormant beige adipocytes persist. In humans, however, the molecular events during the beige to white transition have not been studied in detail. In this study, human primary subcutaneous abdominal preadipocytes were differentiated to beige for 14 days, then either the beige culture conditions were applied for an additional 14 days or it was replaced by a white medium. Control white adipocytes were differentiated by their specific cocktail for 28 days. Peroxisome proliferator-activated receptor γ-driven beige differentiation resulted in increased mitochondrial biogenesis, UCP1 expression, fragmentation, and respiration as compared to white. Morphology, UCP1 content, mitochondrial fragmentation, and basal respiration of the adipocytes that underwent transition, along with the induction of mitophagy, were similar to control white adipocytes. However, white converted beige adipocytes had a stronger responsiveness to dibutyril-cAMP, which mimics adrenergic stimulus, than the control white ones. Gene expression patterns showed that the removal of mitochondria in transitioning adipocytes may involve both parkin-dependent and -independent pathways. Preventing the entry of beige adipocytes into white transition can be a feasible way to maintain elevated thermogenesis and energy expenditure.

Keywords:  beige adipocytes; mitophagy; obesity; parkin; thermogenesis; uncoupling protein 1

DOI:  https://doi.org/10.3390/ph15030363
Eur J Pharmacol. 2022 Mar 22. pii: S0014-2999(22)00174-1. [Epub ahead of print] 174913

Baicalin promotes the activation of brown and white adipose tissue through AMPK/PGC1α pathway.

Yanqing Zhang, Zhenzhen Zhang, Yiwei Zhang, Leiming Wu, Lu Gao, Rui Yao, Yanzhou Zhang.

  Obesity occurs when energy intake overtops energy expenditure. Promoting activation of brown adipose tissue (BAT) and white adipose tissue (WAT) has been proven a promising therapeutic strategy for obesity. Baicalin (BAI) has been shown to be protective for various animal models of cardiovascular diseases, such as pulmonary hypertension, atherosclerosis and myocardial hypertrophy. However, whether BAI could stimulate activation of BAT or browning of WAT remains unknown. Here we show that BAI limits weight gaining, ameliorates glucose tolerance, improves cold tolerance and promotes brown-like tissue formation in diet induced obesity mice model. BAI increases the mitochondrial copy number as judged by mtDNA detection. BAI also increases the expression of UCP1 and other classical browning-specific genes in BAT and WAT and cultured C3H10T1/2 adipocytes through a mechanism involving AMPK/PGC1α pathway. Collectively, our study established a role for BAI in regulating energy metabolism, which will provide new idea and theoretical basis for the treatment of obesity.

Keywords:  AMPK; Baicalin; Browning; PGC1α

DOI:  https://doi.org/10.1016/j.ejphar.2022.174913
J Exp Biol. 2022 Mar 22. pii: jeb.243407. [Epub ahead of print]

Inactivity and the passive slowing effect of cold on resting metabolism as the primary drivers of energy savings in overwintering fishes.

Connor Reeve, Lauren E Rowsey, Ben Speers-Roesch.

  Winter dormancy is a seasonal survival strategy common among temperate ectotherms, characterized by inactivity, fasting, and low metabolic rates. Previous reports of metabolic rate depression (MRD) in winter-dormant ectotherms, including many fishes, may result from confounding influences of temperature-dependent variation in activity on metabolic rate measurements. We hypothesize that, as demonstrated recently in the winter-dormant cunner (Tautogolabrus adspersus), inactivity and the passive physicochemical (Arrhenius) effect of cold on standard metabolic rate (SMR) are the common primary mechanisms underlying the low metabolic rates among winter-dormant fishes. Using automated video tracking, we investigated threshold temperatures for winter dormancy onset (major reductions in activity, increased sheltering, and fasting) in four phylogenetically-diverse teleost species reported to be winter dormant: cunner, pumpkinseed sunfish (Lepomis gibbosus), American eel (Anguilla rostrata), and mummichog (Fundulus heteroclitus). All species showed large activity and feeding reductions, but the magnitude of change and dormancy threshold temperature was species-specific. We propose that a continuum of overwintering responses exists among fishes from dormant to lethargic to active. The relationship between activity and metabolic rate was then measured using video-recorded automated respirometry during acute cooling and following cold acclimation in pumpkinseed, mummichog, and eel. In all species, activity and metabolic rate were strongly correlated at all temperatures, and cooling caused reduced activity and metabolic rate. When variation in activity was controlled for across temperatures spanning the dormancy thresholds, the thermal sensitivity of metabolic rate including SMR indicated the predominance of passive physicochemical influences (mean Q10<3.5), rather than active MRD. Activity reductions and physicochemical slowing of metabolism due to cold appear to be the primary energy saving mechanisms in overwintering fishes.

Keywords:  Activity; Energy expenditure; Fish; Hibernation; Metabolic rate; Temperature

DOI:  https://doi.org/10.1242/jeb.243407
Proc Natl Acad Sci U S A. 2022 Mar 29. 119(13): e2116470119

C-type natriuretic peptide is a pivotal regulator of metabolic homeostasis.

Cristina Perez-Ternero, Aisah A Aubdool, Raj Makwana, Gareth J Sanger, Roland H Stimson, Li F Chan, Amie J Moyes, Adrian J Hobbs.

  SignificanceThe global mortality, morbidity, and healthcare costs associated with cardiometabolic disease, including obesity, diabetes, hypertension, and dyslipidemia, are substantial and represent an expanding unmet medical need. Herein, we have identified a physiological role for C-type natriuretic peptide (CNP) in regulating key processes, including thermogenesis and adipogenesis, which combine to coordinate metabolic function and prevent the development of cardiometabolic disorders. This protective mechanism, which is in part mediated via an autocrine action of CNP on adipocytes, is underpinned by activation of cognate natriuretic peptide receptors (NPR)-B and NPR-C. This mechanism advances the fundamental understanding of energy homeostasis and glucose handling and offers the promise of improving the treatment of cardiometabolic disease.

Keywords:  G protein–coupled receptor; adipogenesis; cardiometabolic disease; natriuretic peptide; thermogenesis

DOI:  https://doi.org/10.1073/pnas.2116470119
Function (Oxf). 2021 ;2(1): zqaa044

Revisiting Mitochondrial Bioenergetics: Experimental Considerations for Biological Interpretation.

Heather L Petrick, Graham P Holloway.

DOI: https://doi.org/10.1093/function/zqaa044
Biochem Biophys Res Commun. 2022 Mar 12. pii: S0006-291X(22)00381-3. [Epub ahead of print]605 134-140

3-Hydroxyacyl-CoA dehydratase 2 deficiency confers resistance to diet-induced obesity and glucose intolerance.

Lengyun Wei, Shengmei Weng, Xuyang Lu, Shenglong Zhu, Qin Yang, Yong Q Chen.

  Obesity and associated complications are becoming a pandemic. Inhibiting fatty acid synthesis and elongation is an important intervention for the treatment of obesity. Despite intensive investigations, many potential therapeutic targets have yet to be discovered. In this study, decreased expression of Hacd2 (a newly found enzyme in fatty acid elongation) was found in HFD induced mice and loss of Hacd2 expression in the liver protected mice against HFD induced obesity as well as associated fatty liver disease and diabetes. Additionally, further study indicated that hepatic HACD2 deficiency increased energy expenditure by upregulating the transcription of thermogenic programming genes. Our results suggest that HACD2 may be a promising therapeutic target for the management of obesity and associated metabolic diseases.

Keywords:  HACD2; Metabolic disorders; Obesity

DOI:  https://doi.org/10.1016/j.bbrc.2022.03.057
Mol Cell. 2022 Mar 14. pii: S1097-2765(22)00166-6. [Epub ahead of print]

Hexokinase 1 cellular localization regulates the metabolic fate of glucose.

Adam De Jesus, Farnaz Keyhani-Nejad, Carolina M Pusec, Lauren Goodman, Justin A Geier, Joshua S Stoolman, Paulina J Stanczyk, Tivoli Nguyen, Kai Xu, Krishna V Suresh, Yihan Chen, Arianne E Rodriguez, Jason S Shapiro, Hsiang-Chun Chang, Chunlei Chen, Kriti P Shah, Issam Ben-Sahra, Brian T Layden, Navdeep S Chandel, Samuel E Weinberg, Hossein Ardehali.

  The product of hexokinase (HK) enzymes, glucose-6-phosphate, can be metabolized through glycolysis or directed to alternative metabolic routes, such as the pentose phosphate pathway (PPP) to generate anabolic intermediates. HK1 contains an N-terminal mitochondrial binding domain (MBD), but its physiologic significance remains unclear. To elucidate the effect of HK1 mitochondrial dissociation on cellular metabolism, we generated mice lacking the HK1 MBD (ΔE1HK1). These mice produced a hyper-inflammatory response when challenged with lipopolysaccharide. Additionally, there was decreased glucose flux below the level of GAPDH and increased upstream flux through the PPP. The glycolytic block below GAPDH is mediated by the binding of cytosolic HK1 with S100A8/A9, resulting in GAPDH nitrosylation through iNOS. Additionally, human and mouse macrophages from conditions of low-grade inflammation, such as aging and diabetes, displayed increased cytosolic HK1 and reduced GAPDH activity. Our data indicate that HK1 mitochondrial binding alters glucose metabolism through regulation of GAPDH.

Keywords:  GAPDH; S-nitrosylation; hexokinase; inflammation; innate immunity; macrophage; metabolism; mitochondria; pentose phosphate pathway; subcellular localization

DOI:  https://doi.org/10.1016/j.molcel.2022.02.028