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

Article information

Endocrinol Metab. 2024;39(6):839-846

Publication date (electronic) : 2024 November 20

doi : https://doi.org/10.3803/EnM.2024.2121

¹Department of Anesthesia and Perioperative Care, University of California, San Francisco, School of Medicine, San Francisco, CA, USA

²Division of Molecular Physiology and Metabolism, Tohoku University Graduate School of Medicine, Sendai, Japan

³Division of Metabolic Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan

Corresponding author: Takeshi Yoneshiro. Division of Molecular Physiology and Metabolism, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8575, Japan Tel: +81-22-717-8117, Fax: +81-22-717-8118, E-mail: takeshi.yoneshiro.a8@tohoku.ac.jp

Received 2024 August 1; Revised 2024 August 19; Accepted 2024 August 28.

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.

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

INTRODUCTION

Obesity and type 2 diabetes mellitus are associated with serious and prevalent health problems, such as insulin resistance, diabetic nephropathy, cardiovascular disease, diabetic retinopathy, neuropathy, and tumor growth. The rediscovery of metabolically active brown adipose tissue (BAT) in healthy adult humans sparked interest in BAT as a promising target for increasing energy expenditure (EE) in the treatment of obesity and type 2 diabetes [1]. BAT has a unique ability to dissipate vast amounts of chemical energy into heat in response to environmental cues such as cold exposure. Brown adipocytes in BAT rapidly respond to cold exposure through significant uptake of circulating metabolites, including glucose, triglyceride-rich lipoproteins, and fatty acids [1]. Thermogenic activity and substrate oxidation of brown adipocytes are primarily dependent on the presence of mitochondrial thermogenic molecule uncoupling protein 1 (UCP1). Beige adipocytes—another type of UCP1-expressing adipocytes—are dramatically induced in certain depots of white adipose tissue (WAT) by long-term cold exposure, facilitating thermoregulation and energy homeostasis [2]. Beige adipocytes have some distinct thermogenic pathways, such as dissipation of the proton (H+) energy gradient through UCP1 in the mitochondria, futile calcium cycling through sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase 2 b (SERCA2b) in the endoplasmic reticulum [2,3], and a futile creatine cycle through tissue-nonspecific alkaline phosphatase (TNAP) in the mitochondria [4-7]. Environmental or genetic activation of brown and beige fat thermogenesis increases EE and improves systemic metabolic disorders in mice [1,2,4-7].

Although it has long been speculated that BAT degenerates in healthy adults, metabolically active BAT was rediscovered in healthy adults via advanced imaging techniques, substantiating the notion that BAT might serve as a modifiable target for the prevention and treatment of obesity and type 2 diabetes [8-11]. This notion was further supported by findings that BAT activity inversely correlates with insulin resistance and obesity in adult humans [12-14]. Experimental investigations in healthy volunteers demonstrated that chronic activation of BAT through repeated cold exposure or administration of β-adrenergic receptor agonists is coupled with body fat reduction and improvement of insulin sensitivity [15-18]. Despite these advances, interventions aimed at activating BAT in patients with obesity and type 2 diabetes have been limited due to the potential unfavorable side effects of increased sympathetic tone on cardiovascular function [15].

There have been substantial efforts—largely limited to animal models—to establish both naturally-occurring and chemically engineered agents that are capable of stimulating BAT thermogenesis [19]. A promising avenue for the stimulation of BAT activity without cold exposure has emerged through the discovery of temperature-sensitive transient receptor potential (TRP) channels [19]. These TRP channels are activated by various physical and chemical signals and play crucial roles in thermoregulation, hormone secretion, and systemic energy homeostasis, serving as a therapeutic target for activating BAT thermogenesis and improving metabolic health [20-22]. Moreover, preclinical studies have shown that mitochondrial oxidation of branched-chain amino acids (BCAAs; valine, leucine, and isoleucine), which are essential amino acids, are required for BAT thermogenesis. It is well-known that fatty acids and glucose fuel the tricarboxylic acid (TCA) cycle and thermogenesis as major substrates [1]. Besides fatty acids and glucose, it was recently revealed that BAT oxidizes BCAA through a series of anaplerotic reactions that drive thermogenesis via the mitochondrial BCAA carrier (MBC) in brown adipocytes [23,24]. Importantly, BCAA catabolism in BAT not only fuels the TCA cycle and thermogenesis, but also promotes the biosynthesis of glutathione and related amino acids as nitrogen donors to regulate systemic insulin sensitivity [25].

Here we describe recent advances in our understanding of the pathophysiological significance of adipose tissue thermogenesis triggered by food-derived substances and summarize current progress in research on substrate preference in thermogenesis, focusing on the underlying mechanisms through which BAT controls energy metabolism and insulin sensitivity.

TRP AGONISTS AS COLD MIMICS

Temperature-sensitive TRP channels are categorized into seven subfamilies including TRPV (vanilloid), TRPM (melastatin), and TRPA (ankyrin) [20-22]. Most temperature-sensitive TRP channels constitute a major class of calcium-permeable ion channels that exert a wide variety of physiological functions, including the detection of physical and chemical stimuli in vision, taste, pain, and temperature. For instance, the cold-induced activation of BAT is initiated by the activation of temperature-sensitive TRP channels located in peripheral tissues such as the skin. This, in turn, causes the activation of sympathetic efferent nerves innervating the BAT to release norepinephrine (NE) and trigger a cascade of β-adrenergic receptor-mediated intracellular signaling pathways in brown adipocytes, culminating in cold-induced activation of UCP1 [26-28].

In addition to temperature, certain naturally-occurring compounds that act as TRP agonists can activate the TRP-sympathetic nervous system (SNS)-UCP1 axis [19,29]. A classic example of a food-derived TRP agonist is capsaicin, which is found in red pepper. Capsaicin is a potent activator of TRPV1, a thermoreceptor that senses temperatures greater than 42°C [19]. Capsinoids, non-pungent capsaicin derivatives found in nonpungent red pepper CH-19 sweet, can activate not only TRPV1 but TRPA1, which senses temperatures below 17°C. In experimental animals, oral administration of both capsaicin and capsinoids can activate TRPV1 expressed in sensory nerves within the gastrointestinal (GI) tract and increase BAT sympathetic tone to induce thermogenesis [30]. Furthermore, chronic administration of capsinoids has been demonstrated to upregulate UCP1 expression in BAT and subcutaneous WAT, decrease body fat, and improve glucose homeostasis [31,32], suggesting that TRP agonism promotes the recruitment of brown and beige adipocytes. In humans, single oral ingestion of capsinoids increases EE in a BAT activity-dependent manner [33,34]. Chronic stimulation with capsinoids is sufficient to reactivate BAT in individuals who have lost active BAT; the daily ingestion of capsinoids for 6 weeks led to BAT recruitment and augmented non-shivering cold-induced thermogenesis (CIT) in individuals whose BAT was undetectable at baseline [16,35]. While it remains unknown if capsinoid treatment can improve insulin sensitivity in patients with type 2 diabetes, as cold exposure does [36], chronic treatment with capsinoids for 12 weeks generates a significant decrease in abdominal fat in the obese population [37,38]. Like capsinoids, 6-paradol, a compound found in several types of ginger, is also known to act as an agonist of TRPV1 and TRPA1 (Fig. 1). Animal studies have demonstrated that the oral ingestion of 6-paradol activates sympathetic nerve discharge connected to BAT [39]. Moreover, the oral ingestion of Guinea pepper seed extracts, a substance rich in 6-paradol, induces BAT thermogenesis and body fat reduction in humans [40-42].

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.

Another example of naturally-occurring TRP agonists are catechins, low molecular-weight polyphenols abundant in green teas, which have demonstrated agonistic TRPA1 activity [19,43]. It has been reported that oral ingestion of tea containing 615 mg of catechins in 350 mL (approximately 700 μM) significantly increased EE only in subjects with detectable BAT activity [44]. The catechin-induced increase in EE was positively correlated with BAT activity. Moreover, 5-week daily ingestion of catechin-rich tea (1,230 mg/day) resulted in a significant increase in BAT-dependent thermogenic capacity (i.e., CIT). Although catechins exert an inhibitory effect against the noradrenaline-degrading enzyme catechol-O-methyltransferase (COMT) [45], the circulating levels (approximately 0.1 μM) following oral ingestion of high doses of epigallocatechin gallate (EGCG) is much lower than the half-maximal inhibitory concentration for COMT activity (approximately 14 μM) [44]. Given that TRPA1 is activated by 20 to 100 μM EGCG [46,47], the tea with approximately 700 μM catechins, used in the investigation by Yoneshiro et al. [44], is likely to efficiently activate TRPA1 in the GI tract. Studies in mice have shown that several additional food ingredients can stimulate the TRPs-SNS-BAT axis, including menthol (a TRPM8 agonist) in mint, and docosahexaenoic acid and eicosapentaenoic acid (TRPV1 agonists) in fish oil [19]. Additionally, chronic administration of these TRP agonists has been shown to not only augment BAT thermogenic capacity, but also induce beige adipogenesis in WAT [32,48]. However, it remains to be investigated whether these thermogenic effects are UCP1-dependent or -independent. Together, these findings indicate that oral ingestion of TRP agonists can mimic the cold-induced activation of BAT and beigeing of WAT (Fig. 1).

BCAA CATABOLISM IN BAT AND INSULIN RESISTANCE

Early investigations into BAT have emphasized fatty acids and glucose as substrates for thermogenesis [49-51]. Cold exposure markedly induces the uptake and catabolism of these substrates, fueling the TCA cycle and thermogenesis. Accordingly, enzymes required for mitochondrial transport and metabolism of fatty acids and glucose, including carnitine palmitoyltransferase 1 (CPT1b), CPT2, glucose transporters (GLUT1, GLUT4), mitochondrial pyruvate carrier, and pyruvate dehydrogenase are expressed at elevated levels in brown adipocytes [23]. However, the apparent fact that BAT recruits circulating metabolites beyond these substrates for thermogenesis has been increasingly recognized [52]. For instance, uptake of succinate, a TCA intermediate, from the circulation is induced by cold exposure, driving thermogenesis through its oxidation and generation of reactive oxygen species [53,54].

Several studies have demonstrated that BAT activation is coupled with decreases in the circulating levels of BCAA, but not other amino acids, both in mice and humans [23,55]. Leucine uptake in BAT, determined by positron emission tomography/computed tomography with the leucine analog ¹⁸F-fluciclovine, is activated by cold acclimation specifically in BAT and subcutaneous WAT, but not liver, muscle, epididymal WAT and other tissues [23], suggesting that BCAAs are a key substrate for thermogenesis in brown and beige cells. In fact, enzymes crucial for BCAA catabolism, including branched-chain keto acid dehydrogenase E1 subunit alpha (BCKDHA), are abundantly expressed in brown and beige adipocytes compared to white adipocytes and further upregulated by cold exposure. Active BCAA oxidation in cultured mouse brown and beige adipocytes, as well as human brown adipocytes, was directly confirmed by using 14C-labeled BCAA. Quantitative analysis of whole-body BCAA oxidative capacity confirmed that BAT is the tissue with the highest BCAA oxidation flux [56]. Moreover, depletion of the MBC, which is encoded by solute carrier family 25 member 44 (Slc25a44), resulted in a significant decrease in mitochondrial BCAA uptake in brown adipocytes and NE-induced BAT thermogenesis. Metabolic tracing with 13C-labeled leucine revealed that NE stimulation significantly increased the production of BCAA-derived TCA intermediates, while the fractional contribution of leucine was relatively small. Importantly, a BAT-specific defect in BCAA catabolism through genetic ablation of Bckdha caused thermogenic dysfunction in BAT, body fat accumulation, and systemic insulin resistance in mice. It should be emphasized, however, that incomplete BCAA catabolism may have adverse effects on energy homeostasis. For example, accumulation of branched-chain keto acids (BCKAs) exacerbates macrophage oxidative stress in the liver and kidney, and inhibits insulin action in skeletal muscle [57,58], while BCKAs inhibit pyruvate import into the mitochondria and glucose production in hepatocytes [59]. Moreover, the accumulation of acetyl coenzyme A (acetyl-CoA) derived from BCAAs and BCKAs suppresses beigeing of WAT by acetylation of PR domain-containing protein 16 (PRDM16), whereas depletion of BCAA/BCKA-derived acetyl-CoA prompts WAT beigeing [60].

These findings indicate that MBC-mediated uptake and complete oxidation of BCAA in the brown fat mitochondria facilitate thermogenesis by fueling the TCA cycle, thereby preventing obesity-associated insulin resistance [23,24]. This was further supported by a human biopsy study showing that cold exposure upregulates BCAA catabolic enzymes and MBC in human BAT, but not in WAT [23]. Owing to the established role of BCAAs in the pathogenesis of cardiovascular and metabolic disease [61-63], the recent recognition of the role of BAT as a metabolic sink for BCAAs suggests that MBC may be a novel target for the treatment of obesity and related metabolic diseases.

BCAA-NITROGEN FLUX

Several independent groups have reported that the association of BAT activity with glucose homeostasis is partly independent of body-mass index, suggesting an insulin sensitizing effect of BAT beyond thermogenesis [64-66]. One potential mechanism is that increased circulating BCAA levels induce its cytosolic accumulation and constitutive activation of mammalian target of rapamycin complex 1 (mTORC1), inhibiting intracellular insulin signaling [67]. In addition, the association of BCAAs with insulin resistance is also partly independent of EE [67-69]. Consistently, tracing of the metabolic fate of BCAAs suggested that BCAAs are not a major carbon source for the production of TCA intermediates in brown adipocytes [70,71]. It is thus conceivable that BAT controls insulin sensitivity through BCAA catabolism independently of EE.

This possibility is supported by many observations focusing on the contribution of BAT to systemic BCAA metabolism and glucose homeostasis. An analysis of oxidative capacity for BCAAs in different tissues in mice demonstrated that skeletal muscle and BAT contributions comprise almost 80% of total BCAA oxidation across the entire body [41]. However, BCAA catabolism in muscle does not affect systemic insulin resistance [72]. In contrast, defects in BCAA catabolism in BAT through brown/beige-specific depletion of Bckdha induce BCAA accumulation in the circulation and systemic insulin resistance while body fat content is also elevated [23]. Notably, whole-body depletion of MBC by CRISPR interference (CRISPRi) led to the elevation of circulating BCAAs and systemic insulin resistance without affecting body weight in mice, clearly suggesting that BCAAs play a role other than as a fuel for thermogenesis [25].

Recently, Verkerke et al. [25] addressed the ambiguity regarding the apparent link between BCAA catabolism in BAT and glucose homeostasis. They first observed that BAT-specific knockout of MBC had insulin resistance, but thermogenesis and EE were unaffected [25]. Metabolic tracing with 15N-labeled BCAA isotopes demonstrated that brown adipocytes catabolize BCAAs for the biosynthesis of non-essential amino acids and glutathione and provide these metabolites to the liver through circulation as nitrogen donors [25]. Inhibition of mitochondrial BCAA-nitrogen flux in BAT resulted in elevated oxidative stress and impaired insulin signaling in the liver, suggesting metabolite-mediated inter-organ communication between BAT and the liver. Systemic insulin resistance induced by inhibiting mitochondrial BCAA-nitrogen flux was restored by glutathione supplementation in mice. In humans, cold exposure decreased circulating BCAA levels and increased circulating glutathione in a BAT activity-dependent fashion, suggesting that BCAA-derived glutathione synthesis takes place in human BAT. These findings imply that BAT controls systemic insulin sensitivity through redox homeostasis beyond thermogenesis (Fig. 1).

CONCLUSIONS

It is well recognized that BAT activity is associated with metabolic health, euglycemia, and lower cardiovascular risk in humans. In this review, we described the potential of dietary components to facilitate BAT metabolic functions, thereby improving obesity and insulin resistance. TRP agonists in foods can mimic cold-induced activation of thermogenesis and UCP1 induction in BAT and WAT. Mitochondrial catabolism of food-derived amino acids (i.e., BCAAs), partly fuels thermogenesis by providing TCA intermediates in BAT. Moreover, BCAA-derived nitrogen is actively utilized to synthesize glutathione, which is delivered to the liver to improve insulin sensitivity through redox homeostasis. These pathophysiological insights clearly highlight that modulating BCAA mitochondrial transport and catabolism via MBC and BAT thermogenesis affords therapeutic potential for the treatment of insulin resistance.

Notes

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

Acknowledgements

This study was funded by grants to Takeshi Yoneshiro from the Japan Society for the Promotion of Science (21K08548, 20K226 47), the Japan Science and Technology Agency (JPMJFR2014), and the Naito Foundation (Grant-in-Aid for Raising Next Generation).

References

1. Chouchani ET, Kajimura S. Metabolic adaptation and maladaptation in adipose tissue. Nat Metab 2019;1:189–200.

2. Ikeda K, Maretich P, Kajimura S. The common and distinct features of brown and beige adipocytes. Trends Endocrinol Metab 2018;29:191–200.

3. Ikeda K, Kang Q, Yoneshiro T, Camporez JP, Maki H, Homma M, et al. UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis. Nat Med 2017;23:1454–65.

4. Kazak L, Cohen P. Creatine metabolism: energy homeostasis, immunity and cancer biology. Nat Rev Endocrinol 2020;16:421–36.

5. Vargas-Castillo A, Sun Y, Smythers AL, Grauvogel L, Dumesic PA, Emont MP, et al. Development of a functional beige fat cell line uncovers independent subclasses of cells expressing UCP1 and the futile creatine cycle. Cell Metab 2024;36:2146–55.

6. Wang T, Sharma AK, Wu C, Maushart CI, Ghosh A, Yang W, et al. Single-nucleus transcriptomics identifies separate classes of UCP1 and futile cycle adipocytes. Cell Metab 2024;36:2130–45.

7. Sun Y, Rahbani JF, Jedrychowski MP, Riley CL, Vidoni S, Bogoslavski D, et al. Mitochondrial TNAP controls thermogenesis by hydrolysis of phosphocreatine. Nature 2021;593:580–5.

8. Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T, Nio-Kobayashi J, et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 2009;58:1526–31.

9. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med 2009;360:1500–8.

10. Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, et al. Functional brown adipose tissue in healthy adults. N Engl J Med 2009;360:1518–25.

11. Cypess AM. Reassessing human adipose tissue. N Engl J Med 2022;386:768–79.

12. Yoneshiro T, Aita S, Matsushita M, Okamatsu-Ogura Y, Kameya T, Kawai Y, et al. Age-related decrease in cold-activated brown adipose tissue and accumulation of body fat in healthy humans. Obesity (Silver Spring) 2011;19:1755–60.

13. Ouellet V, Routhier-Labadie A, Bellemare W, Lakhal-Chaieb L, Turcotte E, Carpentier AC, et al. Outdoor temperature, age, sex, body mass index, and diabetic status determine the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in humans. J Clin Endocrinol Metab 2011;96:192–9.

14. Matsushita M, Yoneshiro T, Aita S, Kameya T, Sugie H, Saito M. Impact of brown adipose tissue on body fatness and glucose metabolism in healthy humans. Int J Obes (Lond) 2014;38:812–7.

15. Cypess AM, Weiner LS, Roberts-Toler C, Franquet Elia E, Kessler SH, Kahn PA, et al. Activation of human brown adipose tissue by a β3-adrenergic receptor agonist. Cell Metab 2015;21:33–8.

16. Yoneshiro T, Aita S, Matsushita M, Kayahara T, Kameya T, Kawai Y, et al. Recruited brown adipose tissue as an antiobesity agent in humans. J Clin Invest 2013;123:3404–8.

17. O’Mara AE, Johnson JW, Linderman JD, Brychta RJ, McGehee S, Fletcher LA, et al. Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity. J Clin Invest 2020;130:2209–19.

18. Straat ME, Hoekx CA, van Velden FH, Pereira Arias-Bouda LM, Dumont L, Blondin DP, et al. Stimulation of the beta2-adrenergic receptor with salbutamol activates human brown adipose tissue. Cell Rep Med 2023;4:100942.

19. Yoneshiro T, Matsushita M, Saito M. Translational aspects of brown fat activation by food-derived stimulants. Handb Exp Pharmacol 2019;251:359–79.

20. Kashio M, Tominaga M. TRP channels in thermosensation. Curr Opin Neurobiol 2022;75:102591.

21. Uchida K, Dezaki K, Yoneshiro T, Watanabe T, Yamazaki J, Saito M, et al. Involvement of thermosensitive TRP channels in energy metabolism. J Physiol Sci 2017;67:549–60.

22. Suito T, Tominaga M. Functional relationship between peripheral thermosensation and behavioral thermoregulation. Front Neural Circuits 2024;18:1435757.

23. Yoneshiro T, Wang Q, Tajima K, Matsushita M, Maki H, Igarashi K, et al. BCAA catabolism in brown fat controls energy homeostasis through SLC25A44. Nature 2019;572:614–9.

24. Yoneshiro T, Kataoka N, Walejko JM, Ikeda K, Brown Z, Yoneshiro M, et al. Metabolic flexibility via mitochondrial BCAA carrier SLC25A44 is required for optimal fever. Elife 2021;10e66865.

25. Verkerke AR, Wang D, Yoshida N, Taxin ZH, Shi X, Zheng S, et al. BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis. Cell 2024;187:2359–74.

26. Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev 2004;84:277–359.

27. Nakamura K. Central circuitries for body temperature regulation and fever. Am J Physiol Regul Integr Comp Physiol 2011;301:R1207–28.

28. Choi JH, Kim MS. Homeostatic regulation of glucose metabolism by the central nervous system. Endocrinol Metab (Seoul) 2022;37:9–25.

29. Hachemi I, U-Din M. Brown adipose tissue: activation and metabolism in humans. Endocrinol Metab (Seoul) 2023;38:214–22.

30. Ono K, Tsukamoto-Yasui M, Hara-Kimura Y, Inoue N, Nogusa Y, Okabe Y, et al. Intragastric administration of capsiate, a transient receptor potential channel agonist, triggers thermogenic sympathetic responses. J Appl Physiol (1985) 2011;110:789–98.

31. Okamatsu-Ogura Y, Tsubota A, Ohyama K, Nogusa Y, Saito M, Kimura K. Capsinoids suppress diet-induced obesity through uncoupling protein 1-dependent mechanism in mice. J Funct Foods 2015;19:1–9.

32. Ohyama K, Nogusa Y, Shinoda K, Suzuki K, Bannai M, Kajimura S. A synergistic antiobesity effect by a combination of capsinoids and cold temperature through promoting beige adipocyte biogenesis. Diabetes 2016;65:1410–23.

33. Yoneshiro T, Aita S, Kawai Y, Iwanaga T, Saito M. Nonpungent capsaicin analogs (capsinoids) increase energy expenditure through the activation of brown adipose tissue in humans. Am J Clin Nutr 2012;95:845–50.

34. Sun L, Camps SG, Goh HJ, Govindharajulu P, Schaefferkoetter JD, Townsend DW, et al. Capsinoids activate brown adipose tissue (BAT) with increased energy expenditure associated with subthreshold 18-fluorine fluorodeoxyglucose uptake in BAT-positive humans confirmed by positron emission tomography scan. Am J Clin Nutr 2018;107:62–70.

35. Nirengi S, Homma T, Inoue N, Sato H, Yoneshiro T, Matsushita M, et al. Assessment of human brown adipose tissue density during daily ingestion of thermogenic capsinoids using near-infrared time-resolved spectroscopy. J Biomed Opt 2016;21:091305.

36. Hanssen MJ, Hoeks J, Brans B, van der Lans AA, Schaart G, van den Driessche JJ, et al. Short-term cold acclimation improves insulin sensitivity in patients with type 2 diabetes mellitus. Nat Med 2015;21:863–5.

37. Ludy MJ, Moore GE, Mattes RD. The effects of capsaicin and capsiate on energy balance: critical review and meta-analyses of studies in humans. Chem Senses 2012;37:103–21.

38. Snitker S, Fujishima Y, Shen H, Ott S, Pi-Sunyer X, Furuhata Y, et al. Effects of novel capsinoid treatment on fatness and energy metabolism in humans: possible pharmacogenetic implications. Am J Clin Nutr 2009;89:45–50.

39. Iwami M, Mahmoud FA, Shiina T, Hirayama H, Shima T, Sugita J, et al. Extract of grains of paradise and its active principle 6-paradol trigger thermogenesis of brown adipose tissue in rats. Auton Neurosci 2011;161:63–7.

40. Sugita J, Yoneshiro T, Hatano T, Aita S, Ikemoto T, Uchiwa H, et al. Grains of paradise (Aframomum melegueta) extract activates brown adipose tissue and increases whole-body energy expenditure in men. Br J Nutr 2013;110:733–8.

41. Sugita J, Yoneshiro T, Sugishima Y, Ikemoto T, Uchiwa H, Suzuki I, et al. Daily ingestion of grains of paradise (Aframomum melegueta) extract increases whole-body energy expenditure and decreases visceral fat in humans. J Nutr Sci Vitaminol (Tokyo) 2014;60:22–7.

42. Yoneshiro T, Matsushita M, Sugita J, Aita S, Kameya T, Sugie H, et al. Prolonged treatment with grains of paradise (Aframomum melegueta) extract recruits adaptive thermogenesis and reduces body fat in humans with low brown fat activity. J Nutr Sci Vitaminol (Tokyo) 2021;67:99–104.

43. Osuna-Prieto FJ, Martinez-Tellez B, Sanchez-Delgado G, Aguilera CM, Lozano-Sanchez J, Arraez-Roman D, et al. Activation of human brown adipose tissue by capsinoids, catechins, ephedrine, and other dietary components: a systematic review. Adv Nutr 2019;10:291–302.

44. Yoneshiro T, Matsushita M, Hibi M, Tone H, Takeshita M, Yasunaga K, et al. Tea catechin and caffeine activate brown adipose tissue and increase cold-induced thermogenic capacity in humans. Am J Clin Nutr 2017;105:873–81.

45. Dulloo AG. The search for compounds that stimulate thermogenesis in obesity management: from pharmaceuticals to functional food ingredients. Obes Rev 2011;12:866–83.

46. Kurogi M, Miyashita M, Emoto Y, Kubo Y, Saitoh O. Green tea polyphenol epigallocatechin gallate activates TRPA1 in an intestinal enteroendocrine cell line, STC-1. Chem Senses 2012;37:167–77.

47. Kurogi M, Kawai Y, Nagatomo K, Tateyama M, Kubo Y, Saitoh O. Auto-oxidation products of epigallocatechin gallate activate TRPA1 and TRPV1 in sensory neurons. Chem Senses 2015;40:27–46.

48. Baskaran P, Krishnan V, Ren J, Thyagarajan B. Capsaicin induces browning of white adipose tissue and counters obesity by activating TRPV1 channel-dependent mechanisms. Br J Pharmacol 2016;173:2369–89.

49. Ouellet V, Labbe SM, Blondin DP, Phoenix S, Guerin B, Haman F, et al. Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans. J Clin Invest 2012;122:545–52.

50. Chondronikola M, Volpi E, Borsheim E, Porter C, Annamalai P, Enerback S, et al. Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans. Diabetes 2014;63:4089–99.

51. Chondronikola M, Volpi E, Borsheim E, Porter C, Saraf MK, Annamalai P, et al. Brown adipose tissue activation is linked to distinct systemic effects on lipid metabolism in humans. Cell Metab 2016;23:1200–6.

52. Cai J, Wang F, Shao M. The emerging importance of mitochondria in white adipocytes: neither last nor least. Endocrinol Metab (Seoul) 2023;38:493–503.

53. Mills EL, Pierce KA, Jedrychowski MP, Garrity R, Winther S, Vidoni S, et al. Accumulation of succinate controls activation of adipose tissue thermogenesis. Nature 2018;560:102–6.

54. Reddy A, Winther S, Tran N, Xiao H, Jakob J, Garrity R, et al. Monocarboxylate transporters facilitate succinate uptake into brown adipocytes. Nat Metab 2024;6:567–77.

55. Baskin AS, Linderman JD, Brychta RJ, McGehee S, AnflickChames E, Cero C, et al. Regulation of human adipose tissue activation, gallbladder size, and bile acid metabolism by a β3-adrenergic receptor agonist. Diabetes 2018;67:2113–25.

56. Neinast MD, Jang C, Hui S, Murashige DS, Chu Q, Morscher RJ, et al. Quantitative analysis of the whole-body metabolic fate of branched-chain amino acids. Cell Metab 2019;29:417–29.

57. Liu S, Li L, Lou P, Zhao M, Wang Y, Tang M, et al. Elevated branched-chain α-keto acids exacerbate macrophage oxidative stress and chronic inflammatory damage in type 2 diabetes mellitus. Free Radic Biol Med 2021;175:141–54.

58. Biswas D, Dao KT, Mercer A, Cowie AM, Duffley L, El Hiani Y, et al. Branched-chain ketoacid overload inhibits insulin action in the muscle. J Biol Chem 2020;295:15597–621.

59. Nishi K, Yoshii A, Abell L, Zhou B, Frausto R, Ritterhoff J, et al. Branched-chain keto acids inhibit mitochondrial pyruvate carrier and suppress gluconeogenesis in hepatocytes. Cell Rep 2023;42:112641.

60. Ma QX, Zhu WY, Lu XC, Jiang D, Xu F, Li JT, et al. BCAA-BCKA axis regulates WAT browning through acetylation of PRDM16. Nat Metab 2022;4:106–22.

61. McGarrah RW, White PJ. Branched-chain amino acids in cardiovascular disease. Nat Rev Cardiol 2023;20:77–89.

62. Brown Z, Yoneshiro T. Brown fat thermogenesis and branchedchain amino acids in metabolic disease. Endocr J 2024;71:89–100.

63. Fine KS, Wilkins JT, Sawicki KT. Circulating branched chain amino acids and cardiometabolic disease. J Am Heart Assoc 2024;13e031617.

64. Becher T, Palanisamy S, Kramer DJ, Eljalby M, Marx SJ, Wibmer AG, et al. Brown adipose tissue is associated with cardiometabolic health. Nat Med 2021;27:58–65.

65. Raiko J, Orava J, Savisto N, Virtanen KA. High brown fat activity correlates with cardiovascular risk factor levels cross-sectionally and subclinical atherosclerosis at 5-year follow-up. Arterioscler Thromb Vasc Biol 2020;40:1289–95.

66. Herz CT, Kulterer OC, Prager M, Schmoltzer C, Langer FB, Prager G, et al. Active brown adipose tissue is associated with a healthier metabolic phenotype in obesity. Diabetes 2022;71:93–103.

67. White PJ, McGarrah RW, Herman MA, Bain JR, Shah SH, Newgard CB. Insulin action, type 2 diabetes, and branchedchain amino acids: a two-way street. Mol Metab 2021;52:101261.

68. Huffman KM, Shah SH, Stevens RD, Bain JR, Muehlbauer M, Slentz CA, et al. Relationships between circulating metabolic intermediates and insulin action in overweight to obese, inactive men and women. Diabetes Care 2009;32:1678–83.

69. Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF, et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab 2009;9:311–26.

70. Bornstein MR, Neinast MD, Zeng X, Chu Q, Axsom J, Thorsheim C, et al. Comprehensive quantification of metabolic flux during acute cold stress in mice. Cell Metab 2023;35:2077–92.

71. Park G, Haley JA, Le J, Jung SM, Fitzgibbons TP, Korobkina ED, et al. Quantitative analysis of metabolic fluxes in brown fat and skeletal muscle during thermogenesis. Nat Metab 2023;5:1204–20.

72. Blair MC, Neinast MD, Jang C, Chu Q, Jung JW, Axsom J, et al. Branched-chain amino acid catabolism in muscle affects systemic BCAA levels but not insulin resistance. Nat Metab 2023;5:589–606.

Article information Continued

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.