Brown Adipose Tissue-A Translational Perspective

Abstract

Brown adipose tissue (BAT) displays the unique capacity to generate heat through uncoupled oxidative phosphorylation that makes it a very attractive therapeutic target for cardiometabolic diseases. Here, we review BAT cellular metabolism, its regulation by the central nervous and endocrine systems and circulating metabolites, the plausible roles of this tissue in human thermoregulation, energy balance, and cardiometabolic disorders, and the current knowledge on its pharmacological stimulation in humans. The current definition and measurement of BAT in human studies relies almost exclusively on BAT glucose uptake from positron emission tomography with 18F-fluorodeoxiglucose, which can be dissociated from BAT thermogenic activity, as for example in insulin-resistant states. The most important energy substrate for BAT thermogenesis is its intracellular fatty acid content mobilized from sympathetic stimulation of intracellular triglyceride lipolysis. This lipolytic BAT response is intertwined with that of white adipose (WAT) and other metabolic tissues, and cannot be independently stimulated with the drugs tested thus far. BAT is an interesting and biologically plausible target that has yet to be fully and selectively activated to increase the body's thermogenic response and shift energy balance. The field of human BAT research is in need of methods able to directly, specifically, and reliably measure BAT thermogenic capacity while also tracking the related thermogenic responses in WAT and other tissues. Until this is achieved, uncertainty will remain about the role played by this fascinating tissue in human cardiometabolic diseases.

Keywords: adipose tissues; brown adipose tissue; diabetes; energy metabolism; glucose metabolism; insulin resistance; lipid metabolism; obesity; thermogenesis.

Graphical Abstract

Figure 1.

Brown adipocyte energy metabolism. Long-chain fatty acids (FA-CoA) activate uncoupling protein 1 (UCP1) and are the major energy source of the brown adipocyte thermogenesis. The main source of these FA-CoA is intracellular triglyceride (TG) lipolysis, but circulating nonesterified fatty acids (NEFA) and triglyceride-rich lipoproteins (TRL), through lipoprotein lipase (LPL)-mediated lipolysis, also contribute fatty acids to drive thermogenesis. Glucose, branched-chain amino acids (BCAA), glutamate, and other sources of energy contribute mainly to drive anaplerosis and cataplerotic processes such as de novo lipogenesis (DNL) and glycerol synthesis that are essential to replete intracellular triglycerides and to sustain the very high rate of TG/nonesterified fatty acid cycling necessary for brown adipose thermogenesis. In addition to UCP1, a phosphocreatine/creatine (PCr/Cr) futile cycle contributes to reduce the ATP/ADP ratio and drive mitochondrial thermogenesis. ADP, adenosine 5′-diphosphate; ATP, adenosine 5′-triphosphate; BCAA, branched-chain amino acids; Cr, creatine; DNL, de novo lipogenesis; FA-CoA, long-chain fatty acyl coenzyme A; LPL, lipoprotein lipase; NEFA, nonesterified fatty acids; TG, triglycerides; PCr, phosphocreatine; TCA, tricarboxylic acid cycle; TRL, triglyceride-rich lipoproteins; UCP1, uncoupling protein 1.

Figure 2.

Definition of brown adipose tissue through metabolic imaging. First, computed tomography (CT) or magnetic resonance imaging (MRI) is necessary for anatomic definition and quantification of tissue fat content. Second, metabolic function of the fat tissue needs to be measured. The standard procedure for the latter is positron emission tomography (PET) with intravenous administration of ¹⁸F-fluoro-deoxyglucose (¹⁸FDG) that measures glucose uptake. Other experimental approaches can provide measurement of other important characteristics of brown adipose tissue such as oxygen utilization or carbon dioxide production (thermogenesis), fatty acid uptake and/or oxidation, intracellular triglyceride (TG) mobilization, mitochondrial content, or sympathetic activity. CT, computed tomography; DFA, dietary fatty acids; ¹⁸FDG, ¹⁸F-fluoro-deoxyglucose; FSF, fat signal fraction; ¹⁸FTHA, ¹⁸F-fluoro-thia-heptadecanoic acid; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NEFA, nonesterified fatty acids; PET, positron emission tomography; TG, triglycerides; TSPO, translocator protein.

Figure 3.

Central nervous system (CNS) regulation of sympathetic outflow to brown and white adipose tissues. The classic thermoregulatory sympathetic nervous system afferent signal from skin thermal receptors to efferent signal to brown and white adipose tissues is displayed in black. Thermosensitive neurons connect to the spinal dorsal horn (DH) neurons that in turn connect to neurons of the lateral parabrachial nucleus (PBN). Glutamatergic neurons from this structure then connect to the preoptic area that in turn connect to the dorsomedial hypothalamus/dorsal hypothalamic area (DMH/DHyA). The sympathetic outflow signal is relayed directly to the spinal intermediolateral (IML) column neurons, or indirectly via the raphe pallidus nucleus (RPa). In the mouse, the sympathetic efferent signal to the interscapular brown fat transits through the stellate and T2 to T5 sympathetic ganglia, whereas that of inguinal white adipose depots transits through the T12 to L1 sympathetic ganglia. Afferent nerve signals from sensing of local lipolysis, blood flow, and/or temperature in white and brown adipose tissues and from visceral cues (eg, intestinal fat, arterial blood hypoxia) can be relayed to several CNS sympathetic regulatory areas (depicted in blue to red color phasing) such as the nucleus tractus solitarius (NTS), ventromedial hypothalamus (VMH), and lateral hypothalamus (LH), but also directly to primary sympathetic outflow nuclei such as the POA, DMH, and RPa. Likewise, peripheral cues of energy balance such as insulin and leptin can be detected by sympathetic regulatory areas (in blue to red color phasing) such as the arcuate nucleus (ARC), periventricular hypothalamus (PVH), LH, and VMH, but also in primary sympathetic outflow areas such as the DMH. ARC, arcuate nucleus; CNS, central nervous system; DH, dorsal horn; DMH/DHyA, dorsomedial hypothalamus/dorsal hypothalamic area; IML, intermediolateral column; LH, lateral hypothalamus; NTS, nucleus tractus solitarius; PBN, parabrachial nucleus; POA, preoptic area; RPa, raphe pallidus; VMH, ventromedial hypothalamus.

Figure 4.

Sympathetic regulation of brown adipocyte thermogenesis and triglyceride/nonesterified fatty acid (TG/NEFA) cycling. The β-adrenergic receptors (β-3 in mice, β-2, and β-1 in humans) drive the cAMP-mediated signal that stimulates intracellular triglyceride signaling to activate UCP1 and brown adipose thermogenesis. cAMP signal also leads to the activation of the p38 MAPK and mTORC1 pathways to increase brown adipogenesis and mitochondrial genesis to increase the thermogenic capacity of brown adipocytes. Sustained elevation of cAMP leads to the recruitment of Gi-mediated ERK signaling that also stimulates intracellular lipolysis, β-arrestin and β-adrenergic receptors desensitization. Alpha-1 adrenergic receptors lead to PI3K/DAC, ERK, and PKC activation, participating in brown thermogenesis. The latter also activate the AKT-mTORC2 pathway, leading to increase glucose uptake, de novo lipogenesis, and triglyceride repletion. Alpha-2 receptors on presynaptic neurons downregulate noradrenaline secretion, whereas those on the brown adipocytes reduce cAMP levels and brown thermogenesis. Adenosine, cosecreted with noradrenaline by sympathetic neurons, activates adenosine receptors to amplify the cAMP-driven thermogenic response. A_2A, adenosine receptor 2A; cAMP, cyclic adenosine 3’,5’-monophosphate; DAG, diacylglycerol; ERK, extracellular signal-regulated kinase; FA-CoA, fatty acyl-coenzyme A; mTOR, mechanistic target of rapamycin; NEFA, nonesterified fatty acids; p38 MAPK, phospho-38 mitogen-activated protein kinase; PI3K, phosphoinositide 3-kinase; PKA, protein kinase A; PKC, protein kinase C; TG, triglycerides.

Figure 5.

Regulation of brown adipocyte thermogenesis by metabolites. Extracellular adenosine 5′-triphosphate (ATP) can promote brown adipocyte thermogenesis through purinergic 2 receptors (P2X, P2Y). FABP4, secreted by white adipocytes during intracellular lipolysis, can form a complex with adenosine kinase and nucleotide diphosphate kinase to reduce ATP levels and therefore limit this effect. Lactate, produced from glycolysis in brown adipocytes or during skeletal muscle exertion, can inhibit brown adipocyte thermogenesis via the activation of GPR81, but could also promote adipose browning through alteration of cellular redox state and the production of reactive oxygen species (ROS). Acetate, propionate, and succinate from the gut microbiota or ischemic or inflammatory cells, and β-hydroxybutyrate from excessive hepatic lipid oxidation, can also reduce brown adipose thermogenesis via the activation of G protein-coupled receptors. ADK, adenosine kinase; ATP, adenosine 5′-triphosphate; cAMP, cyclic adenosine 3’,5’-monophosphate; FABP4, fatty acid binding protein 4; FA-CoA, fatty acyl-coenzyme A; GPR, G protein–coupled receptor; NDPK, nucleoside diphosphate kinase; NEFA, nonesterified fatty acids; P2X, purinergic receptor 2X; P2Y, purinergic receptor 2Y; ROS, reactive oxygen species; TG, triglycerides.

Figure 6.

Hormonal regulation of brown adipose tissue thermogenesis (T°) and metabolism in vivo. AT, adipose tissue; BAT, brown adipose tissue; EE, energy expenditure; FGF21, fibroblast growth factor 21; FSH, follicle-stimulating hormone; GIP, glucose-dependent insulinotropic polypeptide; GLP1, glucagon-like peptide 1; IS, insulin sensitivity; SNS, sympathetic nervous system; T°, thermogenesis; T3, 3,5,3′-triiodothyronine; TEE, total energy expenditure (whole body); TG, triglycerides; TSH, thyrotropin.

Figure 7.

The known physiological roles of brown adipose tissue in humans. Brown adipose tissue (BAT) contributes to nonshivering thermogenesis (NST) during cold exposure in humans. First, daily short and mild cold exposure bouts repeated during a few weeks have been shown to increase BAT volume and thermogenic capacity. Second, inhibition of BAT thermogenic activity during acute cold exposure leads to increased skeletal muscle shivering activity without change in whole-body energy expenditure. Third, prolonged cold exposure leads to reduced skeletal muscle uncoupled respiration, suggesting reduced muscle and increased BAT NST in this condition. BAT also contributes to diet-induced thermogenesis (DIT) in humans. However, the uncertainty about total thermogenically active BAT volume, which is based on BAT ¹⁸F-fluorodeoxyglucose uptake, makes imprecise the true contribution of BAT vs muscles and other organs to NST and diet-induced thermogenesis. Despite its high uptake rates of glucose, glutamate, nonesterified fatty acids (NEFA), and triglyceride-rich lipoproteins (TRL), the very small current estimates of BAT volume translate into very low (< 1%) BAT clearance rates of these blood substrates in humans. Likewise, the very small relative mass of BAT in humans and the fact that all batokines are also produced by other organs makes any purported endocrine function of BAT undetermined at the present time. BAT, brown adipose tissue; NEFA, nonesterified fatty acids; NST, nonshivering thermogenesis; TRL, triglyceride-rich lipoproteins.

Figure 8.

Proposed pathophysiological mechanisms of reduced brown adipose tissue glucose metabolism and thermogenic activity and capacity. In situ reduction of regulatory T cells, macrophage M1 activation, and infiltration by other immune cells such as mastocytes increase local production of proinflammatory cytokines that reduce brown adipocyte recruitment. Proinflammatory cytokines, nitric oxide, and serotonin produced by these cells have also all been shown to activate intracellular brown adipocyte inflammatory signaling pathways, including the nuclear factor-kappa B (NF-kB) and the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways. In turn, these pathways activate the intracellular degradation of cyclic adenosine 3’,5’-monophosphate (cAMP) that impairs beta adrenergic signaling and shuts down the thermogenic program. They also lead to adipocyte insulin resistance and reduced glucose uptake. Energy surfeit contributes to increase brown adipocyte triglyceride (TG) deposition, leading to whitening of brown adipose tissues. The ensuing lipotoxicity and glucotoxicity activate toll-like receptors (TLRs) and endoplasmic reticulum (ER) stress, also increasing intracellular inflammation. Aging has been shown to increase monoamine oxidase (MAOA) expression and activity in brown adipocytes, leading to local degradation of noradrenaline and reduced beta adrenergic signaling. β1/2/3, beta adrenergic receptors 1, 2, and 3; cAMP, cyclic adenosine 3’,5’-monophosphate; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; MAOA, monoamine oxidase; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-kappa B; TG, triglycerides; TLRs, toll-like receptors.