Is thermogenesis really needed for brown adipose tissue–mediated metabolic benefit?

Brown adipose tissue (BAT) dissipates energy in the form of heat and functions as a metabolic sink for lipids, glucose, and branched-chain amino acids. Enhanced BAT thermogenesis is thought to tightly couple with beneficial energy metabolism. However, in this issue of the JCI, Huang et al. report a mouse model in which BAT thermogenesis was impaired, yet systemic glucose and lipid homeostasis were improved, on a high-fat diet compared with what occurred in control mice. The authors showed that BAT-specific deletion of mitochondrial thioredoxin-2 (TRX2) impaired adaptive thermogenesis through elevated mitochondrial reactive oxygen species (ROS) and cytosolic efflux of mitochondrial DNA. On the other hand, TRX2 loss enhanced lipid uptake in the BAT and protected mice from obesity, hypertriglyceridemia, and insulin resistance. This study provides a unique model in which BAT does not require thermogenesis per se to function as a lipid sink that leads to metabolic benefits in vivo.

Brown and beige adipocytes harbor multilocular lipid droplets, possess a high number of mitochondria, and dissipate energy in the form of heat (1). Along with the ability to burn calories, brown adipose tissue (BAT) functions as a substantial metabolic sink for lipids, glucose, and branched-chain amino acids (2–4). Following cold exposure and subsequent activation of the β-3 adrenergic receptor (β3-AR), lipolysis in white adipose tissue (WAT), including the liberation of triglycerides (TG) to glycerol and free fatty acids (FFAs), triggers the activation of BAT thermogenesis (5).

Accordingly, the long-standing consensus in the field has been that enhanced BAT thermogenesis is closely linked to improved glucose tolerance, insulin sensitivity, and lipid profiles. In support of this notion, genetic ablation of brown and beige fat, for example, by BAT-specific overexpression of the diphtheria toxin or deletion of the central transcription factor, such as euchromatic histone-lysine N-methyltransferase 1 (EHMT1), causes obesity, insulin resistance, glucose intolerance, and dyslipidemia (6, 7).

Uncoupling protein 1 (UCP1) is a proton carrier that is selectively expressed in brown adipocytes and localizes to the mitochondrial inner membrane. UCP1 is required for BAT thermogenesis, as determined by genetic deletion of UCP1, which disrupts mitochondrial proton uncoupling in brown adipocytes and causes severe thermogenic defects following cold exposure in mice (8). However, UCP1-KO mice are not obese unless kept under a thermoneutral condition, and the metabolic phenotype does not recapitulate that found in brown and beige fat-ablation mice (6, 7, 9).

Notably, UCP1-mediated thermogenic activity does not reflect the fuel uptake of brown and beige fat. For instance, genetic deletion of UCP1 did not affect glucose uptake rates in brown and beige fat following activation of the β3-AR pathway (10–12). Chronic treatment with a β3-AR agonist (CL316,243) was able to stimulate glucose uptake in the interscapular BAT depots and improve systemic glucose tolerance in UCP1-KO mice on a high-fat diet (11). Also, fatty acid uptake into brown and beige fat was further enhanced in UCP1-KO mice compared with wild-type mice in response to β3-AR agonist treatment (13). Importantly, enhanced brown and beige fat biogenesis leads to improved insulin sensitivity, glucose tolerance, and lipid homeostasis, even in the absence of UCP1 (12). These studies demonstrate that UCP1 is required for brown fat thermogenesis, but dispensable for fuel-uptake capacity in brown and beige fat. This conclusion is somewhat surprising, but suggests a possibility that BAT thermogenesis does not necessarily couple with metabolic improvement at the organismal level.

Mitochondria play a key role in oxidative stress and immune response through the regulation of mitochondrial reactive oxygen species (mtROS), mitochondrial DNA (mtDNA), and antioxidant systems (14). Whereas mtROS serve as a key signaling entity in the mitochondria, uncontrolled mtROS induce oxidative stress and mtDNA release to the cytosol. Excess mtROS production and cytosolic mtDNA are known to activate the NLRP3 inflammasome via cyclic GMP/AMP synthase/stimulator of IFN genes (cGAS/STING), leading to elevated production of proinflammatory cytokines and inflammation (14, 15).

As a defense mechanism to protect cells against mitochondrial oxidative stress, mtROS is rapidly neutralized by the mitochondrial thioredoxin system that is composed of thioredoxin-2 (TRX2), TRX2 reductase (TRXR2), and peroxiredoxin 3 (PRX3). Of these, TRX2 is an essential mitochondrial antioxidant that scavenges ROS via mitochondrial peroxidase PRX3 (16). It has been demonstrated that overexpression of TRX2 suppresses inflammatory pathways and apoptosis by reducing mtROS production (17). Conversely, TRX2 loss leads to the accumulation of intracellular ROS and apoptotic cell death (18).

In this issue of the JCI, Huang et al. asked how mitochondrial inflammation in BAT influenced systemic energy balance and glucose homeostasis in mice. To this end, the authors generated a mouse model in which TRX2 was deleted in a BAT-specific manner by using UCP1-Cre, herein called Trx2^BATKO mice (19). The authors found that BAT-specific TRX2 deletion increased mtROS production and cytosolic mtDNA, leading to disrupted mitochondrial integrity. These molecular changes in the BAT activated mitochondrial immune responses, including the cGAS/STING and NLRP3 inflammasome pathways. Furthermore, adaptive thermogenesis and fatty acid oxidation in the BAT were substantially impaired in Trx2^BATKO mice. However, the authors found that lipid uptake into BAT was enhanced in Trx2^BATKO mice relative to control mice. The enhanced lipid uptake into BAT was accompanied by reduced adiposity and plasma TG levels as well as improved glucose and insulin sensitivity on a high-fat diet (Figure 1).

Figure 1

BAT improves systemic metabolism by enhancing lipid clearance from the circulation, regardless of impaired thermogenic activity. Brown adipocytes harbor multilocular lipid droplets, possess a high number of mitochondria, and dissipate energy in the form of heat. Huang et al. (19) showed that BAT-specific TRX2 deficiency caused BAT inflammation through activation of the NLRP3 inflammasome pathway. A mitochondrial defect enhanced lipid uptake into brown adipocytes, leading to improved systemic glucose and lipid homeostasis even though BAT thermogenesis was impaired.

To probe the underlying mechanism, Huang et al. next asked whether enhanced inflammasome activation in the BAT of Trx2^BATKO mice was responsible for the metabolic phenotypes. To address this question, the authors treated Trx2^BATKO mice with MCC950, a pharmacological inhibitor of the NLRP3 inflammasome. MCC950 treatment effectively ameliorated BAT thermogenic function and reversed metabolic benefits, resulting in increased body weight and impaired glucose homeostasis. These data provide compelling evidence that mitochondrial inflammation in BAT profoundly influences thermogenesis and whole-body energy homeostasis (19).

How does a defect in BAT thermogenesis lead to metabolic benefits? One intriguing observation in the study by Huang et al. was enhanced beige fat biogenesis in the inguinal WAT of Trx2^BATKO mice (19). This result aligns with a previous study showing that impaired brown adipocyte development in the interscapular BAT induces compensatory browning of WAT, specifically, beige fat biogenesis in mice (20). Huang and colleagues demonstrated that Trx2^BATKO mice showed enhanced lipolysis, fatty acid oxidation, and glucose utilization in the inguinal WAT of Trx2^BATKO mice following β3-AR agonist CL316,243 treatment. Conversely, inhibition of NLRP3 inflammasome by MCC950 treatment reversed the biogenesis of beige fat in Trx2^BATKO mice, showing a tight association between enhanced beige fat biogenesis and improved glucose homeostasis (19).

Enhanced beige fat biogenesis in the inguinal WAT was insufficient to rescue the hypothermic phenotype of Trx2^BATKO mice (19). This result makes sense because the contribution of beige fat to whole-body heat production appears marginal compared with that of BAT and skeletal muscle (12). However, emerging evidence shows that beige fat biogenesis potently represses adipose tissue inflammation and fibrosis in a UCP1-independent manner (21, 22). Importantly, repression of adipose tissue fibrosis and inflammation is associated with improved insulin sensitivity (21, 22). It would be intriguing to determine the degree to which compensatory activation of beige fat biogenesis contributes to metabolic improvement in Trx2^BATKO mice.

A technical hurdle to exploring this question is the lack of genetic tools for targeting a selective adipose tissue depot in vivo. Adiponectin-Cre has been widely used to delete a gene of interest in all differentiated adipocytes, including brown, beige, and white adipocytes. In contrast, UCP1-Cre targets UCP1-expressing cells, primarily in brown adipocytes and to a much lesser extent in beige adipocytes. Of note, a recent paper reported that UCP1-Cre also targeted the hypothalamus, thymus, adrenal glands, and kidney, raising a possibility that UCP1-Cre might alter neuronal activity if a gene of interest was expressed in these UCP1-Cre⁺ nerves (23). Thus, developing tools that enable us to manipulate specific adipose cells and/or depots would open up opportunities to dissect the functional relationship between thermogenesis and metabolic benefit that is associated with enhanced brown and beige fat biogenesis.

We thank Jake Wong for his suggestions. This work was supported by grants from the NIH (DK127575, DK125281, DK125283) and the Howard Hughes Medical Institute (to SK).

Address correspondence to: Shingo Kajimura, Center for Life Sciences, 3 Blackfan Circle, Room CLS7-737, Boston, Massachusetts 02115, USA. Phone: 617.735.3289; Email: skajimur@bidmc.harvard.edu.

Conflict of interest: The authors have declared that no conflict of interest exists.

Copyright: © 2022, Yook et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

Reference information: J Clin Invest. 2022;132(9):e159296. https://doi.org/10.1172/JCI159296.

See the related article at Brown adipose TRX2 deficiency activates mtDNA-NLRP3 to impair thermogenesis and protect against diet-induced insulin resistance.

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