BCAA catabolism in brown fat controls energy homeostasis through SLC25A44

Yoneshiro, Takeshi; Wang, Qiang; Tajima, Kazuki; Matsushita, Mami; Maki, Hiroko; Igarashi, Kaori; Dai, Zhipeng; White, Phillip J.; McGarrah, Robert W; Ilkayeva, Olga R.; Deleye, Yann; Oguri, Yasuo; Kuroda, Mito; Ikeda, Kenji; Li, Huixia; Ueno, Ayano; Ohishi, Maki; Ishikawa, Takamasa; Kim, Kyeongkyu; Chen, Yong; Sponton, Carlos Henrique; Pradhan, Rachana N.; Majd, Homa; Greiner, Vanille Juliette; Yoneshiro, Momoko; Brown, Zachary A; Chondronikola, Maria; Takahashi, Haruya; Goto, Tsuyoshi; Kawada, Teruo; Sidossis, Labros S; Szoka, Francis C.; McManus, Michael T.; Saito, Masayuki U.; Soga, Tomoyoshi; Kajimura, Shingo

doi:10.1038/s41586-019-1503-x

ScienceOpen: research and publishing network

For Publishers

For Researchers

Blog
About

Search
Advanced search

views

recommends

Record: found
Abstract: found
Article: not found

BCAA catabolism in brown fat controls energy homeostasis through SLC25A44

research-article

Author(s): Takeshi Yoneshiro ¹ ^, ² ^, ³ ^, ¹⁴ , Qiang Wang ¹ ^, ² ^, ³ ^, ¹⁴ , Kazuki Tajima ¹ ^, ² ^, ³ , Mami Matsushita ⁴ , Hiroko Maki ⁵ , Kaori Igarashi ⁵ , Zhipeng Dai ⁶ , Phillip J. White ⁷ , Robert W. McGarrah ⁷ , Olga R Ilkayeva ⁷ , Yann Deleye ⁷ , Yasuo Oguri ¹ ^, ² ^, ³ , Mito Kuroda ¹ ^, ² ^, ³ , Kenji Ikeda ¹ ^, ² ^, ³ ^, ⁸ , Huixia Li ¹ ^, ² ^, ³ , Ayano Ueno ⁵ , Maki Ohishi ⁵ , Takamasa Ishikawa ⁵ , Kyeongkyu Kim ¹ ^, ² ^, ³ , Yong Chen ¹ ^, ² ^, ³ , Carlos Henrique Sponton ¹ ^, ² ^, ³ , Rachana N. Pradhan ¹ ^, ² ^, ³ , Homa Majd ² , Vanille Juliette Greiner ¹ ^, ⁹ , Momoko Yoneshiro ¹ ^, ² ^, ³ , Zachary Brown ¹ ^, ² ^, ³ , Maria Chondronikola ¹⁰ , Haruya Takahashi ¹¹ , Tsuyoshi Goto ¹¹ , Teruo Kawada ¹¹ , Labros Sidossis ¹² , Francis C. Szoka ⁶ , Michael T. McManus ¹ ^, ⁹ , Masayuki Saito ¹³ , Tomoyoshi Soga ⁵ , Shingo Kajimura ¹ ^, ² ^, ³ ^, ¹⁵

Publication date (Electronic): 21 August 2019

Journal: Nature

Keywords: Brown adipose tissue, Thermogenesis, Branched-chain amino acids, mitochondrial transporter, SLC25A44

Read this article at

ScienceOpenPublisher PMC

Bookmark

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Branched-chain amino acid (BCAA; valine, leucine, and isoleucine) supplementation is often beneficial to energy expenditure; however, paradoxically increased circulating BCAA levels are linked to obesity and diabetes. The mechanisms of the paradox remain elusive. Here we report that, upon 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, a previously uncharacterized mitochondrial transporter for BCAA. The present study suggests that BAT serves as a significant metabolic-filter that controls BCAA clearance via SLC25A44, thereby contributing to the improvement of metabolic health.

Related collections

Most cited references 23

Record: found
Abstract: found
Article: not found

Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans.

Véronique Ouellet, Sébastien M. Labbé, Denis Blondin … (2012)

Brown adipose tissue (BAT) is vital for proper thermogenesis during cold exposure in rodents, but until recently its presence in adult humans and its contribution to human metabolism were thought to be minimal or insignificant. Recent studies using PET with 18F-fluorodeoxyglucose (18FDG) have shown the presence of BAT in adult humans. However, whether BAT contributes to cold-induced nonshivering thermogenesis in humans has not been proven. Using PET with 11C-acetate, 18FDG, and 18F-fluoro-thiaheptadecanoic acid (18FTHA), a fatty acid tracer, we have quantified BAT oxidative metabolism and glucose and nonesterified fatty acid (NEFA) turnover in 6 healthy men under controlled cold exposure conditions. All subjects displayed substantial NEFA and glucose uptake upon cold exposure. Furthermore, we demonstrated cold-induced activation of oxidative metabolism in BAT, but not in adjoining skeletal muscles and subcutaneous adipose tissue. This activation was associated with an increase in total energy expenditure. We found an inverse relationship between BAT activity and shivering. We also observed an increase in BAT radio density upon cold exposure, indicating reduced BAT triglyceride content. In sum, our study provides evidence that BAT acts as a nonshivering thermogenesis effector in humans.

0 comments Cited 352 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis

Kenji Ikeda, Qianqian Kang, Takeshi Yoneshiro … (2017)

Uncoupling Protein 1 (UCP1) plays a central role in non-shivering 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+-ATPase2b (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 the activation of α1/β3-adrenergic receptors or the SERCA2b-RyR2 pathway stimulates UCP1-independent thermogenesis. In the absence of UCP1, beige fat dynamically expends glucose through enhanced glycolysis, tricarboxylic acid metabolism, and pyruvate dehydrogenase activity for ATP-dependent thermogenesis by the SERCA2b pathway; beige fat thereby functions as a “glucose-sink” and improves glucose tolerance independent of body-weight loss. Our study uncovers a non-canonical thermogenic mechanism by which beige fat controls whole-body energy homeostasis through Ca2+ cycling.

0 comments Cited 249 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Differential metabolomics reveals ophthalmic acid as an oxidative stress biomarker indicating hepatic glutathione consumption.

Tomoyoshi Soga, Richard Baran, Makoto Suematsu … (2006)

Metabolomics is an emerging tool that can be used to gain insights into cellular and physiological responses. Here we present a metabolome differential display method based on capillary electrophoresis time-of-flight mass spectrometry to profile liver metabolites following acetaminophen-induced hepatotoxicity. We globally detected 1,859 peaks in mouse liver extracts and highlighted multiple changes in metabolite levels, including an activation of the ophthalmate biosynthesis pathway. We confirmed that ophthalmate was synthesized from 2-aminobutyrate through consecutive reactions with gamma-glutamylcysteine and glutathione synthetase. Changes in ophthalmate level in mouse serum and liver extracts were closely correlated and ophthalmate levels increased significantly in conjunction with glutathione consumption. Overall, our results provide a broad picture of hepatic metabolite changes following acetaminophen treatment. In addition, we specifically found that serum ophthalmate is a sensitive indicator of hepatic GSH depletion, and may be a new biomarker for oxidative stress. Our method can thus pinpoint specific metabolite changes and provide insights into the perturbation of metabolic pathways on a large scale and serve as a powerful new tool for discovering low molecular weight biomarkers.

0 comments Cited 229 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-journal-id): 0410462

Journal ID (pubmed-jr-id): 6011

Journal ID (nlm-ta): Nature

Journal ID (iso-abbrev): Nature

Title: Nature

ISSN (Print): 0028-0836

ISSN (Electronic): 1476-4687

Publication date Nihms-submitted: 23 July 2019

Publication date (Electronic): 21 August 2019

Publication date (Print): August 2019

Publication date PMC-release: 21 February 2020

Volume: 572

Issue: 7771

Pages: 614-619

Affiliations

[1 ]UCSF Diabetes Center, San Francisco, CA, USA

[2 ]Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, CA, USA

[3 ]Department of Cell and Tissue Biology, University of California, San Francisco, CA, USA

[4 ]Department of Nutrition, Tenshi College, Sapporo, Japan

[5 ]Institute for Advanced Biosciences, Keio University, Yamagata, Japan

[6 ]Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA

[7 ]Duke Molecular Physiology Institute, Duke University, Durham, NC USA

[8 ]Department of Molecular Endocrinology and Metabolism, Tokyo Medical and Dental University, Tokyo, Japan

[9 ]Department of Microbiology and Immunology, University of California, San Francisco, CA, USA

[10 ]Center for Human Nutrition, Washington University in St. Louis, MO, USA

[11 ]Laboratory of Molecular Function of Food, Graduate School of Agriculture, Kyoto University, Uji, Japan

[12 ]Department of Kinesiology and Health, School of Arts and Sciences, Rutgers University, New Brunswick, NJ, USA

[13 ]Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan

[14 ]Contributed equally

Author notes

Author contributions T.Y. designed, carried out overall experiments, and analyzed data. Q.W. performed cellular experiments and liposome assays, and analyzed data. K.T. and C.H.S. performed animal experiments. M.M. and M.C. carried out human studies and analyzed the data with M.S. and L.S. H.M. (Maki), K.I., A.U., and M.O. performed BCAA tracing studies and analyzed the data with T.S. Z.D., M.K., H.L., and H.M. (Majd) performed liposome assays and analyzed the data with F.C.S. P.J.W., R.W.N., O.R.I., and Y.D., measured amino acids in mice and BCKDH activity. Y.O., K.I., K.K., Y.C., M.Y., and Z.B. assisted animal experiments and cultured cell studies. R.N.P conducted RNA-sequencing analysis. V.J.G. and M.T.M developed dCas9-KRAB mice. H.T., T.G., and T.K. assisted quantification of metabolites in human sera. S.K. conceived the project and directed the research. S.K. and T.Y wrote the paper with inputs from all the authors.

[15 ]Correspondence and requests for materials should be addressed to S.K. ( Shingo.Kajimura@ 123456ucsf.edu ).

Article

Manuscript ID: NIHMS1535499

DOI: 10.1038/s41586-019-1503-x

PMC ID: 6715529

PubMed ID: 31435015

SO-VID: 40d658d8-23d9-4e9b-a017-21248b615db9

License:

Reprints and permissions information is available at www.nature.com/reprints.

Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

BCAA catabolism in brown fat controls energy homeostasis through SLC25A44

Read this article at

Abstract

Related collections

Renewable Energy - Geothermal

Most cited references 23

Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans.

UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis

Differential metabolomics reveals ophthalmic acid as an oxidative stress biomarker indicating hepatic glutathione consumption.

Author and article information

Journal

Affiliations

Author notes

Article

History

Categories

Comments

Comment on this article

Similar content 422

Cited by 188

Most referenced authors 836