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 β3-adrenergic receptors (β3ARs) 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). 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). 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 and rats (Watanabe et al., 2008; Fournier et al., 2012; Bal et al., 2017), 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; 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 and 2018; 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.
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Updated at: 2023-01-28
Created at: 2015-05-14
Written by: Vesa Oikonen