BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis

Anthony R P Verkerke; Dandan Wang; Naofumi Yoshida; Zachary H Taxin; Xu Shi; Shuning Zheng; Yuka Li; Christopher Auger; Satoshi Oikawa; Jin-Seon Yook; Melia Granath-Panelo; Wentao He; Guo-Fang Zhang; Mami Matsushita; Masayuki Saito; Robert E Gerszten; Evanna L Mills; Alexander S Banks; Yasushi Ishihama; Phillip J White; Robert W McGarrah; Takeshi Yoneshiro; Shingo Kajimura

doi:10.1016/j.cell.2024.03.030

BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis

Cell. 2024 Apr 17:S0092-8674(24)00346-5. doi: 10.1016/j.cell.2024.03.030. Online ahead of print.

Authors

Anthony R P Verkerke¹, Dandan Wang¹, Naofumi Yoshida¹, Zachary H Taxin¹, Xu Shi², Shuning Zheng², Yuka Li³, Christopher Auger¹, Satoshi Oikawa¹, Jin-Seon Yook¹, Melia Granath-Panelo¹, Wentao He⁴, Guo-Fang Zhang⁴, Mami Matsushita⁵, Masayuki Saito⁶, Robert E Gerszten², Evanna L Mills⁷, Alexander S Banks⁸, Yasushi Ishihama³, Phillip J White⁹, Robert W McGarrah¹⁰, Takeshi Yoneshiro¹¹, Shingo Kajimura¹²

Affiliations

¹ Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, and Howard Hughes Medical Institute, Boston, MA, USA.
² Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
³ Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
⁴ Duke Molecular Physiology Institute, Duke School of Medicine, Department of Medicine, Division of Endocrinology, Metabolism and Nutrition, Duke University, Durham, NC, USA.
⁵ Department of Nutrition, School of Nursing and Nutrition, Tenshi College, Sapporo, Japan.
⁶ Laboratory of Biochemistry, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
⁷ Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute and Department of Immunology, Harvard Medical School, Boston, MA, USA.
⁸ Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
⁹ Duke Molecular Physiology Institute, Duke School of Medicine, Department of Medicine, Division of Endocrinology, Metabolism and Nutrition, Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA.
¹⁰ Duke Molecular Physiology Institute, Duke School of Medicine, Sarah W. Stedman Nutrition and Metabolism Center, Department of Medicine, Division of Cardiology, Duke University, Durham, NC, USA.
¹¹ Division of Metabolic Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan; Division of Molecular Physiology and Metabolism, Tohoku University Graduate School of Medicine, Sendai, Japan.
¹² Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, and Howard Hughes Medical Institute, Boston, MA, USA. Electronic address: skajimur@bidmc.harvard.edu.

PMID: 38653240
DOI: 10.1016/j.cell.2024.03.030

Abstract

Brown adipose tissue (BAT) is best known for thermogenesis. Rodent studies demonstrated that enhanced BAT thermogenesis is tightly associated with increased energy expenditure, reduced body weight, and improved glucose homeostasis. However, human BAT is protective against type 2 diabetes, independent of body weight. The mechanism underlying this dissociation remains unclear. Here, we report that impaired mitochondrial catabolism of branched-chain amino acids (BCAAs) in BAT, by deleting mitochondrial BCAA carriers (MBCs), caused systemic insulin resistance without affecting energy expenditure and body weight. Brown adipocytes catabolized BCAA in the mitochondria as nitrogen donors for the biosynthesis of non-essential amino acids and glutathione. Impaired mitochondrial BCAA-nitrogen flux in BAT resulted in increased oxidative stress, decreased hepatic insulin signaling, and decreased circulating BCAA-derived metabolites. A high-fat diet attenuated BCAA-nitrogen flux and metabolite synthesis in BAT, whereas cold-activated BAT enhanced the synthesis. This work uncovers a metabolite-mediated pathway through which BAT controls metabolic health beyond thermogenesis.

Keywords: amino acid metabolism; bioenergetics; brown adipose tissue; diabetes; glucose homeostasis; insulin resistance; inter-organ communication; mitochondria; thermogenesis.