Key Publications

Key Publications

  1. Oguri Y, Shinoda K, Kim H, Alba D, Bolus WR, Brown Z, Pradhan RN, Tajima K, Yoneshiro T, Ikeda K, Chen C, Cheang RT, Tsujino KR, Greiner VJ, McManus MT, Koliwad S, Spiegelman BM, and Kajimura S. CD81 controls beige progenitor cell growth and energy balance through Integrin-FAK signaling. Cell 2020; Jun 26: S0092-8674(20)30753-4. PMID: 32615086. PMC7415677. [Comment in Cell 2020]
    Abstract
    Adipose tissues dynamically remodel their cellular composition in response to external cues by stimulating beige adipocyte biogenesis; however, the developmental origin and pathways regulating this process remain insufficiently understood owing to adipose tissue heterogeneity. Here, we employed single-cell RNA-seq and identified a unique subset of adipocyte progenitor cells (APCs) that possessed the cell-intrinsic plasticity to give rise to beige fat. This beige APC population is proliferative and marked by cell-surface proteins, including PDGFRα, Sca1, and CD81. Notably, CD81 is not only a beige APC marker but also required for de novo beige fat biogenesis following cold exposure. CD81 forms a complex with αV/β1 and αV/β5 integrins and mediates the activation of integrin-FAK signaling in response to irisin. Importantly, CD81 loss causes diet-induced obesity, insulin resistance, and adipose tissue inflammation. These results suggest that CD81 functions as a key sensor of external inputs and controls beige APC proliferation and whole-body energy homeostasis.
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  2. Yoneshiro, T., Wang, Q., Tajima, K., Matsushita, M., Maki, H., Igarashi, K., Dai, Z., White, P. J., McGarrah, R. W., Ilkayeva, O., Deleye, Y., Oguri, Y., Kuroda, M., Ikeda, K., Li, H., Ueno, A., Ohishi, M., Ishikawa, T., Kim, K., Chen, Y., Sponton, C. H., Pradhan, R. N., Majd, H., Greiner, V. J., Yoneshiro, M., Brown, Z., Chondronikola, M., Takahashi, H., Goto, T., Kawada, T., Sidossis, L., Szoka, F. C., McManus, M. T., Saito, M., Soga, T., & Kajimura S. (2019) BCAA catabolism in brown fat controls energy homeostasis through SLC25A44. Nature (Article) 572(7771):614-619. PMC6715529 [Research highlight in NEJM 2019, Nature Metabolism 2019, Nature Reviews Endocrinology 2019, TIME etc.]
    Abstract
    Branched-chain amino acid (BCAA; valine, leucine and isoleucine) supplementation is often beneficial to energy expenditure; however, increased circulating levels of BCAA are linked to obesity and diabetes. The mechanisms of this paradox remain unclear. Here we report that, on cold exposure, brown adipose tissue (BAT) actively utilizes BCAA in the mitochondria for thermogenesis and promotes systemic BCAA clearance in mice and humans. In turn, a BAT-specific defect in BCAA catabolism attenuates systemic BCAA clearance, BAT fuel oxidation and thermogenesis, leading to diet-induced obesity and glucose intolerance. Mechanistically, active BCAA catabolism in BAT is mediated by SLC25A44, which transports BCAAs into mitochondria. Our results suggest that BAT serves as a key metabolic filter that controls BCAA clearance via SLC25A44, thereby contributing to the improvement of metabolic health.
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  3. Chen Y., Ikeda K., Yoneshiro T., Scaramozza, A., Tajima, K., Wang, Q., Kim K., Shinoda K., Henrique- Sponton C., Brown Z., Brack A., & Kajimura S. (2019) Thermal stress induces glycolytic beige fat formation via a myogenic state. Nature (Article) 565(7738):180-185. PMC6328316 [Research highlight in Nature 2019, Nature Reviews Endocrinology 2019, Faculty1000]
    Abstract
    Environmental cues profoundly affect cellular plasticity in multicellular organisms. For instance, exercise promotes a glycolytic-to-oxidative fibre-type switch in skeletal muscle, and cold acclimation induces beige adipocyte biogenesis in adipose tissue. However, the molecular mechanisms by which physiological or pathological cues evoke developmental plasticity remain incompletely understood. Here we report a type of beige adipocyte that has a critical role in chronic cold adaptation in the absence of β-adrenergic receptor signalling. This beige fat is distinct from conventional beige fat with respect to developmental origin and regulation, and displays enhanced glucose oxidation. We therefore refer to it as glycolytic beige fat. Mechanistically, we identify GA-binding protein α as a regulator of glycolytic beige adipocyte differentiation through a myogenic intermediate. Our study reveals a non-canonical adaptive mechanism by which thermal stress induces progenitor cell plasticity and recruits a distinct form of thermogenic cell that is required for energy homeostasis and survival.
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  4. Tajima K., Ikeda K., Chang H.Y., Chang C.H., Yoneshiro T., Oguri Y., Jun H., Wu J., Ishihama Y., & Kajimura S. (2019). Mitochondrial lipoylation integrates age-associated decline in brown fat thermogenesis. Nature Metabolism 1, 886-898.
    Abstract
    Thermogenesis in brown adipose tissue (BAT) declines with age; however, what regulates this process is poorly understood. Here, we identify mitochondrial lipoylation as a previously unappreciated molecular hallmark of aged BAT in mice. Using mitochondrial proteomics, we show that mitochondrial lipoylation is disproportionally reduced in aged BAT through a post-transcriptional decrease in the iron–sulfur (Fe–S) cluster formation pathway. A defect in Fe–S cluster formation by the fat-specific deletion of Bola3 significantly reduces mitochondrial lipoylation and fuel oxidation in BAT, leading to glucose intolerance and obesity. In turn, enhanced mitochondrial lipoylation by α-lipoic acid supplementation effectively restores BAT function in old mice, thereby preventing age-associated obesity and glucose intolerance. The effect of α-lipoic acids requires mitochondrial lipoylation via the BOLA3 pathway and does not depend on the antioxidant activity of α-lipoic acid. These results open up the possibility of alleviating age-associated decline in energy expenditure by enhancing the mitochondrial lipoylation pathway.
    [Link]

  5. Hasegawa Y, Ikeda K, Chen Y, Alba D, Stifler D, Shinoda K, Hosono T, Maretich P, Yang Y, Ishigaki Y, Chi J, Cohen P, Koliwad S, & Kajimura S. (2018) Repression of adipose tissue fibrosis through a PRDM16-GTF2IRD1 complex improves systemic glucose homeostasis. Cell Metabolism 27(1), 180-194. PMC5727902 [Selected in Faculty1000]
    Abstract
    Adipose tissue fibrosis is a hallmark of malfunction that is linked to insulin resistance and type 2 diabetes; however, what regulates this process remains unclear. Here we show that the PRDM16 transcriptional complex, a dominant activator of brown/beige adipocyte development, potently represses adipose tissue fibrosis in an uncoupling protein 1 (UCP1)-independent manner. By purifying the PRDM16 complex, we identified GTF2IRD1, a member of the TFII-I family of DNA-binding proteins, as a cold-inducible transcription factor that mediates the repressive action of the PRDM16 complex on fibrosis. Adipocyte-selective expression of GTF2IRD1 represses adipose tissue fibrosis and improves systemic glucose homeostasis independent of body-weight loss, while deleting GTF2IRD1 promotes fibrosis in a cell-autonomous manner. GTF2IRD1 represses the transcription of transforming growth factor β-dependent pro-fibrosis genes by recruiting PRDM16 and EHMT1 onto their promoter/enhancer regions. These results suggest a mechanism by which repression of obesity-associated adipose tissue fibrosis through the PRDM16 complex leads to an improvement in systemic glucose homeostasis.
    [Link]

  6. Ikeda K, Kang Q, Yoneshiro T, CamporezJP, Maki H, Homma M, Shinoda K, Lu, X, Maretich P, Ajuwon KM, Soga T, & Kajimura S. (2017). UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis. Nature Medicine (12):1454-1465PMC5727902 [Research highlight in Nature Medicine 2017; Nature Reviews Endocrinology 2017; Cell Metabolism; 2017, Science Signaling 2017, TIME, Faculty1000]
    Abstract
    Uncoupling protein 1 (UCP1) plays a central role in nonshivering thermogenesis in brown fat; however, its role in beige fat remains unclear. Here we report a robust UCP1-independent thermogenic mechanism in beige fat that involves enhanced ATP-dependent Ca2+ cycling by sarco/endoplasmic reticulum Ca2+-ATPase 2b (SERCA2b) and ryanodine receptor 2 (RyR2). Inhibition of SERCA2b impairs UCP1-independent beige fat thermogenesis in humans and mice as well as in pigs, a species that lacks a functional UCP1 protein. Conversely, enhanced Ca2+ cycling by activation of α1- and/or β3-adrenergic receptors or the SERCA2b–RyR2 pathway stimulates UCP1-independent thermogenesis in beige adipocytes. In the absence of UCP1, beige fat dynamically expends glucose through enhanced glycolysis, tricarboxylic acid metabolism and pyruvate dehydrogenase activity for ATP-dependent thermogenesis through the SERCA2b pathway; beige fat thereby functions as a ‘glucose sink’ and improves glucose tolerance independently of body weight loss. Our study uncovers a noncanonical thermogenic mechanism through which beige fat controls whole-body energy homeostasis via Ca2+ cycling.
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  7. Altshuler-Keylin S, Shinoda K, Hong H, Hasegawa Y, Ikeda K, Yang Y, Perera RM, Debnath J, & Kajimura S. (2016) Beige adipocyte maintenance is regulated by autophagy-induced mitochondrial clearance. Cell Metabolism 24(3):402-19. PMC5023491 [Research highlight in Cell Metabolism 2016; Nature Reviews Endocrinology 2016]
    Abstract
    Beige adipocytes gained much attention as an alternative cellular target in anti-obesity therapy. While recent studies have identified a number of regulatory circuits that promote beige adipocyte differentiation, the molecular basis of beige adipocyte maintenance remains unknown. Here, we demonstrate that beige adipocytes progressively lose their morphological and molecular characteristics after withdrawing external stimuli, and directly acquire white-like characteristics bypassing an intermediate precursor stage. The beige-to-white adipocyte transition is tightly coupled to a decrease in mitochondria, increase in autophagy, and activation of MiT/TFE transcription factor-mediated lysosome biogenesis. The autophagy pathway is crucial for mitochondrial clearance during the transition; inhibiting autophagy by UCP1+-adipocyte-specific deletion of Atg5 or Atg12 prevents beige adipocyte loss after withdrawing external stimuli, maintenaning high thermogenic capacity and protecting against diet-induced obesity and insulin resistance. The present study uncovers a fundamental mechanism by which autophagy-mediated mitochondrial clearance controls beige adipocyte maintenance, thereby providing new opportunities to counteract obesity.
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  8. Shinoda K, Ohyama K, Hasegawa Y, Chang H-Y, Ogura M, Sato A, Hong H, Hosono T, Sharp LZ, Scheel DW, Graham M, Ishihama Y, & Kajimura S. (2015) Phosphoproteomics Identifies CK2 as a negative regulator of beige adipocyte thermogenesis and energy expenditure.  Cell Metabolism 22(6):997-1008. [Research highlight in Cell Metabolism 2015]
    Abstract
    Catecholamines promote lipolysis both in brown and white adipocytes, whereas the same stimuli preferentially activate thermogenesis in brown adipocytes. Molecular mechanisms for the adipose-selective activation of thermogenesis remain poorly understood. Here, we employed quantitative phosphoproteomics to map global and temporal phosphorylation profiles in brown, beige, and white adipocytes under β3-adrenenoceptor activation and identified kinases responsible for the adipose-selective phosphorylation profiles. We found that casein kinase2 (CK2) activity is preferentially higher in white adipocytes than brown/beige adipocytes. Genetic or pharmacological blockade of CK2 in white adipocytes activates the thermogenic program in response to cAMP stimuli. Such activation is largely through reduced CK2-mediated phosphorylation of class I HDACs. Notably, inhibition of CK2 promotes beige adipocyte biogenesis and leads to an increase in whole-body energy expenditure and ameliorates diet-induced obesity and insulin resistance. These results indicate that CK2 is a plausible target to rewire the β3-adrenenoceptor signaling cascade that promotes thermogenesis in adipocytes.
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  9. Shinoda K, Luijten IHN, Hasegawa Y, Hong H, Sonne SB, Xue R, Chondronikola M, Kim M, Cypess AM, Tseng Y, Nedergaard J, Sidossis LS, & Kajimura S. (2015). Genetic and functional characterization of clonally-derived adult human brown adipocytes. Nature Medicine 21(4):389-94. PMC4427356 [Research highlight in Nature Medicine 2015]
    Abstract
    Brown adipose tissue (BAT) acts in mammals as a natural defense system against hypothermia, and its activation to a state of increased energy expenditure is believed to protect against the development of obesity. Even though the existence of BAT in adult humans has been widely appreciated, its cellular origin and molecular identity remain elusive largely because of high cellular heterogeneity within various adipose tissue depots. To understand the nature of adult human brown adipocytes at single cell resolution, we isolated clonally derived adipocytes from stromal vascular fractions of adult human BAT from two individuals and globally analyzed their molecular signatures. We used RNA sequencing followed by unbiased genome-wide expression analyses and found that a population of uncoupling protein 1 (UCP1)-positive human adipocytes possessed molecular signatures resembling those of a recruitable form of thermogenic adipocytes (that is, beige adipocytes). In addition, we identified molecular markers that were highly enriched in UCP1-positive human adipocytes, a set that included potassium channel K3 (KCNK3) and mitochondrial tumor suppressor 1 (MTUS1). Further, we functionally characterized these two markers using a loss-of-function approach and found that KCNK3 and MTUS1 were required for beige adipocyte differentiation and thermogenic function. The results of this study present new opportunities for human BAT research, such as facilitating cell-based disease modeling and unbiased screens for thermogenic regulators.
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  10. Ohno H, Shinoda K, Ohyama K, Sharp LZ, & Kajimura S.  (2013) EHMT1 controls brown adipose cell fate and thermogenesis through the PRDM16 complex. Nature 504(7478):163-67. PMC3855638 [Research highlight in Cell Metabolism 2014, Selected in Faculty1000, NIH director’s blog]
    Abstract
    Brown adipose tissue (BAT) dissipates chemical energy in the form of heat as a defence against hypothermia and obesity. Current evidence indicates that brown adipocytes arise from Myf5+ dermotomal precursors through the action of PR domain containing protein 16 (PRDM16) transcriptional complex1,2. However, the enzymatic component of the molecular switch that determines lineage specification of brown adipocytes remains unknown. Here we show that euchromatic histone-lysine N-methyltransferase 1 (EHMT1) is an essential BAT-enriched lysine methyltransferase in the PRDM16 transcriptional complex and controls brown adipose cell fate. Loss of EHMT1 in brown adipocytes causes a severe loss of brown fat characteristics and induces muscle differentiation in vivo through demethylation of histone 3 lysine 9 (H3K9me2 and 3) of the muscle-selective gene promoters. Conversely, EHMT1 expression positively regulates the BAT-selective thermogenic program by stabilizing the PRDM16 protein. Notably, adipose-specific deletion of EHMT1 leads to a marked reduction of BAT-mediated adaptive thermogenesis, obesity and systemic insulin resistance. These data indicate that EHMT1 is an essential enzymatic switch that controls brown adipose cell fate and energy homeostasis.
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  11. Ohno H., Shinoda K., Spiegelman B.M. & Kajimura S.  (2012) PPARγ agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein. Cell Metabolism 15(3), 395-404.PMC3410936    
    Abstract
    Brown adipose tissue dissipates energy through heat and functions as a defense against cold and obesity. PPAR ligands have been shown to induce the browning of white adipocytes; however, the underlying mechanisms remain unclear. Here we show that PPAR ligands require full agonism to induce a brown fat gene program preferentially in subcutaneous white adipose. These effects require expression of PRDM16, a factor that controls the development of classical brown fat. Depletion of PRDM16 blunts the effects of the PPAR agonist rosiglitazone on the induced brown fat gene program. Conversely, PRDM16 and rosiglitazone synergistically activate the brown fat gene program in vivo. This synergy is tightly associated with an increased accumulation of PRDM16 protein, due in large measure to an increase in the half-life of the protein in agonist treated cells. Identifying compounds that stabilize PRDM16 protein may represent a plausible therapeutic pathway for the treatment of obesity and diabetes.
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