Endocrinol Metab.  2024 Dec;39(6):839-846. 10.3803/EnM.2024.2121.

Brown Fat and Metabolic Health: The Diverse Functions of Dietary Components

• Brown Z
• Yoneshiro T

• KMID: 2562710
• DOI: http://doi.org/10.3803/EnM.2024.2121

Abstract

Brown and beige adipocytes utilize a variety of substrates for cold-induced thermogenesis, contributing to the clearance of metabolites in circulation and, consequently, metabolic health. Food-derived compounds that exhibit agonistic activity at temperature-sensitive transient receptor potential channels may serve as cold mimics to elicit thermogenesis and substrate utilization in brown adipose tissue (BAT). In addition to fatty acids and glucose, branched-chain amino acids (BCAAs), which are essential amino acids obtained from foods, are actively catabolized in BAT through mitochondrial BCAA carrier (MBC). The relative contribution of BCAAs to fueling the tricarboxylic acid cycle as a substrate (i.e., anaplerosis) is estimated to be relatively small, yet BCAA catabolism in BAT exerts a critical role in systemic insulin sensitivity. The nature of this apparent tension remained unclear until the recent discovery that active BCAA catabolism in BAT through MBC is critical for the synthesis of metabolites such as glutathione, which is delivered to the liver to improve hepatic insulin sensitivity through redox homeostasis. Novel mechanistic insights into the control of BAT function and systemic metabolism reveal the therapeutic potential of food-derived compounds for improving metabolic flexibility and insulin sensitivity.

Keyword

Thermogenesis; Branched-chain amino acids; Transporter; Nitrogen flux; Glucose homeostasis; Food ingredients

Figure

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  Fig. 1. Metabolic fate of branched-chain amino acids (BCAAs) in brown adipose tissue (BAT) and its relevance to systemic insulin sensitivity. Cold exposure activates temperature-sensitive transient receptor potential (TRP) channels in the peripheral tissues such as the skin, triggering non-shivering thermogenesis through the sympathetic nervous system, β-adrenergic receptor (β-AR), and uncoupling protein 1 (UCP1) axis. Orally ingested food ingredients with agonistic activity on TRP channels can mimic cold-induced BAT thermogenesis via activation of gastrointestinal (GI) TRP channels. The food-derived compounds includes menthol, capsaicin, capsinoids, 6-paradol, tea catenin, and n-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). The thermogenesis in BAT is primary dependent on oxidation of the main substrates including glucose and fatty acids. Besides, BCAAs are actively taken up into brown adipocytes from the circulation through plasma membrane transporters (L-type/large neutral amino acid transporter 1 [LAT1]), and catabolized through a mitochondrial BCAA carrier (MBC), which is encoded by solute carrier family 25 member 44 (Slc25a44). MBC transports BCAAs from the cytosol into mitochondria, thereby serving as a gatekeeper for BCAA catabolism. BCAA-derived metabolites (carbons) are used for synthesis of tricarboxylic acid (TCA) intermediates such as alpha-ketoglutarate and succinate, facilitating thermogenesis and the maintenance of systemic energy homeostasis. Cold exposure also drives the biosynthesis of non-essential amino acids and glutathione, which are secreted into the circulation and provided to the liver as nitrogen carriers. The impaired mitochondrial BCAA-nitrogen flux and BCAA-derived metabolites in BAT lead to elevated oxidative stress, reduced insulin signaling in the liver, and systemic insulin resistance. Together, BCAA catabolism in BAT is critical for the control of energy balance and glucose homeostasis through thermogenesis-dependent energy expenditure and thermogenesis-independent redox balance and insulin signaling.

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