Brown adipose tissue and PET
Brown adipose tissue (BAT) is characterized by rich vasculature and innervation, required for its thermogenic function and control by sympathetic nervous system. Brown adipocytes contain numerous large mitochondria, surrounded by small lipid droplets. Brown adipocytes are smaller (15-60 µm) than the white adipocytes (25-200 µm) in white adipose tissue (WAT).
Cold environment sensed in the hypothalamus activates the sympathetic nervous system. Sympathetic nerve terminals release norepinephrine (NE, noradrenaline), which binds to the β2- and β3-adrenergic receptors (mainly β2ARs in humans and β3ARs in rodents) on BAT and WAT cells, and start a signalling cascade that leads to the hydrolysis of intracellular triglycerides. Released free fatty acids (FFAs), or other factors, can activate the uncoupling protein 1 (UCP1) in the mitochondrial inner membrane; UCP1 increases the permeability of the inner membrane to protons, thus uncoupling the ATP synthesis from substrate oxidation. PPARγ regulates BAT function and maintains the inducibility by β-adrenergic stimuli (Lasar et al., 2018). Neuropeptide secretin, released from the gut during a meal, binds to secretin receptors on brown adipocytes, activating BAT, which induces satiation and mediates meal-associated thermogenesis (Li et al., 2018; Laurila et al., 2021). Glucagon increases heat production in BAT and BAT mass in rats, and cold-exposure increases glucagon levels in the blood (Habegger et al., 2010). Cold exposure increases human BAT thermogenesis rapidly, in 20 min, while BAT deactivation after exposure is a slow process (Leitner et al., 2018). Adenosine and A2AR agonists activate BAT and induce browning of WAT (Gnad et al., 2014). Adenosine administration increases perfusion in BAT even more than cold exposure (Lahesmaa et al., 2018b). Opioid receptor agonist fentanyl increases BAT sympathetic nerve activity and thermogenesis in rats (Cao & Morrison, 2005), and photoperiod affects μ opioid receptor availability in BAT (Sun et al., 2023).
In addition to using intracellular triglycerides, activated brown adipocytes also take up and use more FFAs, glucose, and acylcarnitines from the plasma. Liver produces acylcarnitines in response to the cold and increased FFA concentration in the plasma (Simcox et al., 2017). Inhibition of lipolysis blunts cold-induced increase in oxidative activity, as shown with [1-11C]acetate PET in rats (Labbé et al., 2015) and in humans (Blondin et al., 2017). BAT has high activity of glutaminase, suggesting that it may use also glutamine (Cooney et al., 1986). BAT expresses much higher levels of monocarboxylate transporter MCT1 than WAT (Iwanaga & Kishimoto, 2015).
BAT releases brown adipokines, including factors with endocrine action, such as fibroblast growth factor (FGF21), neuregulin 4 (NRG4), IGF-1, and IL-6. During cold exposure BAT may be a major source of circulating T3 hormone (Villarroya et al., 2017), and BAT is also activated by thyroid hormones. In hypothyroid mice BAT is not active, as shown by reduced [18F]FDG uptake, and in hyperthyroid mice both BAT mass and [18F]FDG uptake were increased (Weiner et al., 2016). Intravenously administered TRH increases the activity (FDG uptake) of cold-stimulated BAT in humans (Heinen et al., 2018). The effect of T3 on BAT function is dependent on NE. Adipokines, including adiponectin, leptin, and resistin, affect BAT function via the central nervous system (Virtanen, 2016). BAT in adult humans may support brain metabolism during cold stress (U Din et al., 2023a). Inactive BAT can secrete myostatin which inhibits muscle function (Kong et al., 2018).
In adults, white adipose tissue (WAT) can contain thermogenic "brite" or "beige" adipocytes (BeAT) with UCP1 expression. In resting state BeATs resemble white adipocytes, but when activated transdifferentiate themselves to resemble brown adipocytes (Virtanen, 2016). Browning of white adipocytes is induced for example by FGF21, which is released from brown adipocytes in response to cold. Several other inducers of browning have been suggested, including prostaglandins, BMP7, BMP8b, and ANP/BNPs (Virtanen, 2016). PDE5 inhibitor sildenafil increases UCP1 expression and induces browning of WAT in mice and men (Mitschke et al., 2013; Li et al., 2018). Fat grafting can induce the browning of the graft (Hoppela et al., 2018).
BAT contains myoglobin, although less than is found in myocytes in skeletal and myocardial muscle. Myoglobin expression increases during brown adipogenesis and cold exposure in mice, rats, and humans (Watanabe et al., 2008; Fournier et al., 2012; Bal et al., 2017; Christen et al., 2022), and in humans its expression differs in subcutaneous and visceral adipose tissue depending on adipose tissue browning (Christen et al., 2022). Myoglobin has a role in linking oxygen and lipid metabolism in thermogenesis (Aboouf et al., 2021, 2023; Christen et al., 2022).
Localization of BAT
PET studies with [18F]FDG, and PET guided biopsies, have confirmed the presence of brown and beige adipose tissue (BAT and BeAT, respectively) in adults. Hypermetabolic adipose depots have been identified in the cervical (neck), supraclavicular (above collarbone), axial (close to armpits), paravertebral (beside the spine), mediastinal (between lungs), para-aortic (close to aorta), suprarenal (above kidneys), and possibly in interscapular (between shoulder blades) regions. In humans, high BAT activity correlates with low cardiovascular risk factors both cross-sectionally and longitudinally, and may indicate lower levels of subclinical atherosclerosis (Raiko et al., 2020).
[18F]FDG PET cannot separate BAT and BeAT. Based on gene expression, [18F]FDG uptake is caused by BeAT in supraclavicular fat, and by BAT in deeper neck fat. Beige adipocytes are interspersed within white adipose tissue (WAT) depots (therefore also called brite adipocytes, as brown-in-white), and, based on UCP1 protein levels BaAT can attain only 10% of the thermogenic capacity of the BAT (Nedergaard & Cannon, 2013); thus some or even most BeAT may be non-visible with PET imaging (Ong et al., 2018). Also BAT is dispersed in WAT and muscle. Additionally, detection of BAT or BeAT with [18F]FDG PET is more difficult in obese individuals than in lean ones, because BAT is often metabolically inactive in obese subjects. Biopsies have confirmed that BAT or BaAT is present in all adults, and only its metabolic activity (not necessarily thermogenesis) and abundance determines whether it is detected with [18F]FDG PET. Variability of cold-activated BAT mass in humans may partially be caused by different sensitivities of interoceptive cortical brain areas to changed skin temperature (Muzik et al., 2017).
Due to the high number of mitochondria in BAT, radiopharmaceuticals targeting mitochondria have been studied as a mean to detect BAT depots. TSPO is a promising mitochondrial target for detecting BAT in thermoneutral conditions (Ran et al., 2018; Hartimath et al., 2020; Oh et al., 2020); however, it is not yet known whether the variable binding affinity of TSPO ligands to the three identified human sub-populations would impair the imaging of BAT.
BAT has lower fat content than WAT, leading to increased CT radiodensity (U Din et al., 2017). Cold stimulation further increases CT radiodensity, probably due to increased vascular volume fraction (U Din et al., 2017). MRI can be used to assess water-fat fractions. Fat content is variable, and inversely correlated with glucose consumption in cervical-supraclavicular fat tissue (Lundström et al., 2021). No validated method for assessment of BAT volume currently exists (Virtanen & Nuutila, 2021).
UCP1 mRNA measurements do not represent well the activity of BAT or the metabolic significance of BeAT, but measurement of UCP1 protein amounts should be used instead (Nedergaard & Cannon, 2013), or metabolic imaging. Based on BAT, WAT, and BeAT transcriptome data, algorithm for calculating BAT content in human and mouse biopsies has been developed (Perdikari et al, 2018).
PET methods for BAT
PET can be used used to measure perfusion, glucose uptake, FFA uptake, oxygen consumption, and oxidative metabolism in brown adipose tissue (Virtanen et al., 2009; Orava et al., 2011; Muzik et al., 2012, 2013, and 2017; Ouellet et al., 2012; Lahesmaa et al., 2014; van der Lans AAJJ et al, 2014; Labbé et al., 2015; Blondin et al., 2014, 2015, and 2017; U Din et al., 2017, 2018 and 2023b; Dadson et al., 2018; Lundström et al., 2021).
During active thermogenesis the demand for blood flow in BAT is very high, suggesting that perfusion measurement using PET may be a good indicator of BAT activity (Virtanen, 2016). Perfusion increased from baseline 13±9 mL/(dL*min) to 18±6 during cold, and stayed at high level (22±12) after reheating; arterial vascular volume fraction (based on [15O]H2O PET) increased from 3±2% to 7±4%, and decreased to 2±2% after reheating (Lundström et al., 2021). In obese subjects the effect of cold exposure on BAT perfusion was much smaller than in lean subjects (Saari et al., 2020). In cold-acclimated rats, up to 1/3 of total cardiac output may be directed to BAT (Foster & Frydman, 1979), that is, perfusion in rat BAT may be 50 fold higher than in human BAT.
Fatty acid uptake in BAT is increased in cold exposure (Saari et al., 2020; Raiko et al., 2021a). In obesity, fatty acid uptake in BAT is impaired in both basal conditions and during cold exposure (Saari et al., 2020). Independent of visceral obesity and insulin sensitivity, fatty acid uptake in BAT is associated positively with brain grey matter volumes (Raiko et al., 2021b).
Glucose uptake does not represent well the activity of BAT and BeAT, because BAT prefers endogenously derived and circulating fatty acids and triglycerides over glucose as substrate for heat production. Insulin can increase glucose uptake (for storage) in BAT without increase in thermogenesis. Mitochondrial membrane potential can be studied using [18F]FBnTP. In rat studies by Madar et al. (2011, 2015), [18F]FBnTP enabled detection and localization of unstimulated BAT and quantification of mitochondrial thermogenic activity.
The density of noradrenaline transporters (NATs) has been quantified in the BAT using [11C]MRB (Lin et al., 2012; Hwang et al., 2015), and the radiopharmaceutical could be used to localize BAT in thermoneutral conditions. NAT activity and the density of sympathetic innervation in human BAT has also been studied using [11C]HED; [ 11C]HED uptake predicts the amount of functional BAT (Muzik et al., 2017). BAT also shows increased uptake of 6-[18F]fluorodopamine (Hadi et al., 2007). In rats, ephedrine and nicotine, and especially those together, increase [18F]FDG SUV (Baba et al., 2007).
Endocannabinoid system plays a role in activation of BAT, regulation of BAT mass, and browning of WAT. Availability of CB1 receptors in BAT and WAT has been studied in rats and humans using [18F]FMPEP-d2 (Eriksson et al., 2015; Lahesmaa et al., 2018a).
Radioligand [11C]TMSX binds selectively to adenosine receptor subtype A2AR. Cold-induced decrease in the VT of [11C]TMSX, calculated using Logan plot, suggests that endogenous adenosine was increased and reduced the density of available A2ARs in BAT (Lahesmaa et al., 2018b).
Cold-induced activation of BAT may be higher during winter than summer (Yoneshiro et al., 2016), which should be taken into account in plans of long-term studies.
Bartelt A, Heeren J. Adipose tissue browning and metabolic health. Nat Rev Endocrinol. 2014; 10: 24-36. doi: 10.1038/nrendo.2013.204.
Bauwens M, Wierts R, van Royen B, Bucerius J, Backes W, Mottaghy F, Brans B. Molecular imaging of brown adipose tissue in health and disease. Eur J Nucl Med Mol Imaging 2014; 41(4): 776-791. doi: 10.1007/s00259-013-2611-8.
Blondin DP, Labbé SM, Tingelstad HC, Noll C, Kunach M, Phoenix S, Guérin B, Turcotte ÉE, Carpentier AC, Richard D, Haman F. Increased brown adipose tissue oxidative capacity in cold-acclimated humans. J Clin Endocrinol Metab. 2014; 99(3), E438-E446. doi: 10.1210/jc.2013-3901.
Blondin DP, Labbé SM, Phoenix S, Guérin B, Turcotte ÉE, Richard D, Carpentier AC, Haman F. Contributions of white and brown adipose tissues and skeletal muscles to acute cold-induced metabolic responses in healthy men. J Physiol. 2015; 593(3): 701-714. doi: 10.1113/jphysiol.2014.283598.
Blondin DP, Labbé SM, Noll C, Kunach M, Phoenix S, Guérin B, Turcotte ÉE, Haman F, Richard D, Carpentier AC. Selective impairment of glucose, but not fatty acid or oxidative metabolism in brown adipose tissue of subjects with type 2 diabetes. Diabetes 2015; 64: 2388-2397. doi: 10.2337/db14-1651.
Blondin DP, Carpentier AC. The role of BAT in cardiometabolic disorders and aging. Best Pract Res Clin Endocrinol Metab. 2016; 30(4): 497-513. doi: 10.1016/j.beem.2016.09.002.
Carpentier AC, Blondin DP, Virtanen KA, Richard D, Haman F, Turcotte ÉE. Brown adipose tissue energy metabolism in humans. Front Endocrinol. 2018; 9: 447. doi: 10.3389/fendo.2018.00447.
Chechi K, van Marken Lichtenbelt W, Richard D. Brown and beige adipose tissues: phenotype and metabolic potential in mice and men. J Appl Physiol. 2018; 124: 482-496. doi: 10.1152/japplphysiol.00021.2017.
Chondronikola M, Beeman SC, Wahl RL. Non-invasive methods for the assessment of brown adipose tissue in humans. J Physiol. 2018; 596(3): 363-378. doi: 10.1113/JP274255.
Chondronikola M, Sidossis LS. Brown and beige fat: from molecules to physiology. Biochim Biophys Acta Mol Cell Biol Lipids 2019; 1864(1): 91-103. doi: 10.1016/j.bbalip.2018.05.014.
Cypess AM, Haft CR, Laughlin MR, Hu HH. Brown fat in humans: consensus points and experimental guidelines. Cell Metab. 2014; 20(3): 408-415. doi: 10.1016/j.cmet.2014.07.025.
Cypess AM, Weiner LS, Roberts-Toler C, Elia EF, Kessler SH, Kahn PA, English J, Chatman K, Trauger SA, Doria A, Kolodny GM. Activation of human brown adipose tissue by a β3-adrenergic receptor agonist. Cell Metab. 2015; 21: 33-38. doi: 10.1016/j.cmet.2014.12.009.
Himms-Hagen J. Brown adipose tissue thermogenesis and obesity. Prog Lipid Res. 1989; 28: 67-115. doi: 10.1016/0163-7827(89)90009-X.
Holstila M. Multimodality imaging of brown adipose tissue. Annales Universitatis Turkuensis, D1342, 2018.
Hwang JJ, Yeckel CW, Gallezot J-D, Belfort-De Aguiar R, Ersahin D, Gao H, Kapinos M, Nabulsi N, Huang Y, Cheng D, Carson RE, Sherwin R, Ding Y-S. Imaging human brown adipose tissue under room temperature conditions with 11C-MRB, a selective norepinephrine transporter PET ligand. Metabolism 2015; 64: 747-755. doi: 10.1016/j.metabol.2015.03.001.
Kolonin MG. How brown is brown fat that we can see? Adipocyte 2014; 3(2): 155-159. doi: 10.4161/adip.27747.
Kwok TC, Stimson RH. Human brown adipose tissue function: insights from current in vivo techniques. J Endocrinol. 2023; 259(1): e230017. doi: 10.1530/JOE-23-0017.
van der Lans AAJJ, Wierts R, Vosselman MJ, Schrauwen P, Brans B, van Marken Lichtenbelt WD. Cold-activated brown adipose tissue in human adults: methodological issues. Am J Physiol Regul Integr Comp Physiol. 2014; 307(2): R103-R113. doi: 10.1152/ajpregu.00021.2014
Lee P, Greenfield JR. Non-pharmacological and pharmacological strategies of brown adipose tissue recruitment in humans. Mol Cell Endocrinol. 2015; 418(2): 184-190. doi: 10.1016/j.mce.2015.05.025.
Lee P, Werner CD, Kebebew E, Celi FS. Functional thermogenic beige adipogenesis is inducible in human neck fat. Int J Obes. 2014; 38(2): 170-176. doi: 10.1038/ijo.2013.82.
Lee P, Zhao JT, Swarbrick MM, Gracie G, Bova R, Greenfield JR, Freund J, Ho KK. High prevalence of brown adipose tissue in adult humans. J Clin Endocrinol Metab. 2011; 96(8): 2450-2455. doi: 10.1210/jc.2011-0487.
Leitner BP, Huang S, Brychta RJ, Duckworth CJ, Baskin AS, McGehee S, Tal I, Dieckmann W, Gupta G, Kolodny GM, Pacak K, Herscovitch P, Cypess AM, Chen KY. Mapping of human brown adipose tissue in lean and obese young men. Proc Natl Acad Sci USA 2017; 114(32): 8649-8654. doi: 10.1073/pnas.1705287114.
Lidell ME, Betz MJ, Dahlqvist Leinhard O, Heglind M, Elander L, Slawik M, Mussack T, Nilsson D, Romu T, Nuutila P, Virtanen KA, Beuschlein F, Persson A, Borga M, Enerbäck S. Evidence for two types of brown adipose tissue in humans. Nat Med. 2013; 19(5): 631-634. doi: 10.1038/nm.3017.
Lidell ME, Betz MJ, Enerbäck S. Two types of brown adipose tissue in humans. Adipocyte 2014; 3(1): 63-66. doi: 10.4161/adip.26896.
Marlatt KL, Ravussin E. Brown adipose tissue: an update on recent findings. Curr Obes Rep. 2017; 6(4): 389-396. doi: 10.1007/s13679-017-0283-6.
Motiani P. Exercise training-induced effects on brown and white adipose tissue metabolism in humans. Annales Universitatis Turkuensis, D1429, 2019.
Muzik O, Mangner TJ, Granneman JG. Assessment of oxidative metabolism in brown fat using PET imaging. Front Endocrinol (Lausanne). 2012; 3:15. doi: 10.3389/fendo.2012.00015.
Muzik O, Mangner TJ, Leonard WR, Kumar A, Janisse J, Granneman JG. 15O PET measurement of blood flow and oxygen consumption in cold-activated human brown fat. J Nucl Med. 2013; 54(4): 523-531. doi: 10.2967/jnumed.112.111336
Muzik O, Mangner TJ, Leonard WR, Kumar A, Granneman JG. Sympathetic innervation of cold-activated brown and white fat in lean young adults. J Nucl Med. 2017; 58(5): 799-806. doi: 10.2967/jnumed.116.180992.
Orava J, Nuutila P, Lidell ME, Oikonen V, Noponen T, Viljanen T, Scheinin M, Taittonen M, Niemi T, Enerbäck S, Virtanen K. Different metabolic responses of human brown adipose tissue to activation by cold and insulin. Cell Metabolism 2011; 14: 272-279. doi: 10.1016/j.cmet.2011.06.012.
Orava J. Characterisation of functional brown adipose tissue in adult humans. Annales Universitatis Turkuensis, D1108, 2014.
Ouellet V, Labbé SM, Blondin DP, Phoenix S, Guérin B, Haman F, Turcotte EE, Richard D, Carpentier AC. Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans. J Clin Invest. 2012; 122(2): 545-552. doi: 10.1172/JCI60433.
Sampath SC, Sampath SC, Bredella MA, Cypess AM, Torriani M. Imaging brown adipose tissue: state of the art. Radiology 2016; 280(1): 4-19. doi: 10.1148/radiol.2016150390.
Sidossis L, Kajimura S. Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis. J Clin Invest. 2015; 125(2): 478-486. doi: 10.1172/JCI78362.
Takeda Y, Harada Y, Yoshikawa T, Dai P. Mitochondrial energy metabolism in the regulation of thermogenic brown fats and human metabolic diseases. Int J Mol Sci. 2023; 24(2): 1352. doi: 10.3390/ijms24021352.
Townsend K, Tseng Y-H. Brown adipose tissue. Recent insights into development, metabolic function and therapeutic potential. Adipocyte 2012; 1(1): 13-24. doi: 10.4161/adip.18951.
U Din M: Oxidative metabolism and non-invasive characterization of brown adipose tissue in adult humans. Annales Universitatis Turkuensis, D1348, 2018.
Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, Taittonen M, Laine J, Savisto N-J, Enerbäck S, Nuutila P. Functional brown adipose tissue in healthy adults. N Engl J Med. 2009; 360: 1418-1525. doi: 10.1056/NEJMoa0808949.
Virtanen KA. Adipose tissue: structure and function of brown adipose tissue. Encyclopedia of Food and Health, 2016. pp 30-34. doi: 10.1016/B978-0-12-384947-2.00007-6.
Wang GX, Zhao XY, Lin JD. The brown fat secretome: metabolic functions beyond thermogenesis. Trends Endocrinol Metab. 2015; 26(5): 231-237. doi: 10.1016/j.tem.2015.03.002.
Wei H, Chiba S, Moriwaki C, Kitamura H, Ina K, Aosa T, Tomonari K, Gotoh K, Masaki T, Katsuragi I, Noguchi H, Kakuma T, Hamaguchi K, Shimada T, Fujikura Y, Shibata H. A clinical approach to brown adipose tissue in the para-aortic area of the human thorax. PLoS One 2015; 10(4): e0122594. doi: 10.1371/journal.pone.0122594.
Yoneshiro T, Aita S, Matsushita M, Kameya T, Nakada K, Kawai Y, Saito M. Brown adipose tissue, whole-body energy expenditure, and thermogenesis in healthy adult men. Obesity 2011; 19(1): 13-16. doi: 10.1038/oby.2010.105.
Yoneshiro T, Matsushita M, Nakae S, Kameya T, Sugie H, Tanaka S, Saito M. Brown adipose tissue is involved in the seasonal variation of cold-induced thermogenesis in humans. Am J Physiol Regul Integr Comp Physiol. 2016; 310: R999-R1009. doi: 10.1152/ajpregu.00057.2015.
Updated at: 2023-10-19
Created at: 2015-05-14
Written by: Vesa Oikonen