BCAA catabolism in brown fat controls energy homeostasis through SLC25A44,Nature

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BCAA catabolism in brown fat controls energy homeostasis through SLC25A44
Nature ( IF 50.5 ) Pub Date : 2019-08-21 , DOI: 10.1038/s41586-019-1503-x
Takeshi Yoneshiro _{1,

2,

3} , Qiang Wang _{1,

2,

3} , 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}

Affiliation

UCSF Diabetes Center, San Francisco, CA, USA.
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, San Francisco, CA, USA.
Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA.
Department of Nutrition, Tenshi College, Sapporo, Japan.
Institute for Advanced Biosciences, Keio University, Yamagata, Japan.
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
Department of Molecular Endocrinology and Metabolism, Tokyo Medical and Dental University, Tokyo, Japan.
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.
Center for Human Nutrition, Washington University in St Louis, St Louis, MO, USA.
Laboratory of Molecular Function of Food, Graduate School of Agriculture, Kyoto University, Uji, Japan.
Department of Kinesiology and Health, School of Arts and Sciences, Rutgers University, New Brunswick, NJ, USA.
Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.

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.The solute carrier transporter protein SLC25A44 regulates uptake of branched-chain amino acids in mitochondria of brown adipose tissue in which they are utilized for thermogenesis.

中文翻译：

棕色脂肪中的 BCAA 分解代谢通过 SLC25A44 控制能量稳态

支链氨基酸（BCAA；缬氨酸、亮氨酸和异亮氨酸）补充通常有利于能量消耗；然而，BCAA 循环水平升高与肥胖和糖尿病有关。这一悖论的机制仍不清楚。在这里，我们报告说，在冷暴露时，棕色脂肪组织 (BAT) 会积极利用线粒体中的 BCAA 进行产热，并促进小鼠和人类的全身 BCAA 清除。反过来，BCAA 分解代谢中 BAT 特异性缺陷会减弱全身 BCAA 清除、BAT 燃料氧化和生热作用，导致饮食引起的肥胖和葡萄糖不耐受。从机制上讲，BAT 中活跃的 BCAA 分解代谢是由 SLC25A44 介导的，SLC25A44 将 BCAA 转运到线粒体中。我们的结果表明，BAT 作为一个关键的代谢过滤器，通过 SLC25A44 控制 BCAA 清除，从而有助于改善代谢健康。溶质载体转运蛋白 SLC25A44 调节棕色脂肪组织线粒体中支链氨基酸的摄取。用于产热。

更新日期：2019-08-21

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