A major advance in the understanding of adipose biology during the past decades is the identification of functionally active BAT in adult humans. The BAT activity in human is determined by multiple factors, including sex, age, BMI, and ambient temperature (ref. 4, 5, 13, 14). In this study, we observed BAT-positive participants are significantly younger and leaner than BAT-negative ones, consistent with other previous studies (ref. 4, 15). However, there was no significant difference in serum scEMC10 between the BAT-negative and -positive groups at room temperature. In BAT-positive participants, serum scEMC10 levels were significantly elevated by thermoneutrality, concomitant with suppression of active BAT determined by PET-CT scan, suggesting scEMC10 acts as a suppressor of BAT activity in humans which is congruent with its inhibitory role in BAT thermogenesis in mice (ref. 9). These findings also suggest scEMC10 a regulatory role in facultative thermogenesis, rather than a role in determining BAT mass in humans. Facultative thermogenesis, which cold exposure activates, while thermoneutrality inactivates, has been linked to human BAT (ref. 14, 16, 17). It has been shown that the regulation of facultative thermogenesis involves the SNS in both rodents and humans (ref. 18, 19). EMC10 has been implicated in the SNS-regulated BAT thermogenesis. Emc10 KO potentiated β3 adrenoceptor agonist-evoked UCP1 expression in brown adipocytes through PKA-CREB/p38 MAPK signaling in vitro and energy expenditure in mice in vivo (ref. 9). Collectively, these data suggest scEMC10 suppresses facultative thermogenesis via inhibition of SNS-PKA signaling in humans.
It is well established that facultative thermogenesis, a quick-response form of nonshivering thermogenesis emanating from BAT, is blunted in obesity, and even its small increases can significantly affect the long-term energy homeostasis, making BAT a promising therapeutic target to treat obesity and its associated metabolic diseases, such as type 2 diabetes (ref. 16, 20, 21). We have proven that a scEMC10-neutralizing antibody is effective in treating diet-induced obesity, impaired glucose tolerance, and fatty liver in mouse, which is mainly attributed to heightened BAT thermogenesis (ref. 9). Consistent with the inhibitory effect of scEMC10 on human BAT activity at thermoneutrality, Emc10 KO prevents diet-induced obesity in mouse under thermoneutral condition (30°C) (ref. 9). Taken together, these observations suggest inhibition of scEMC10 will be a therapeutic strategy to treat obesity and its associated cardiometabolic diseases via enhancing facultative thermogenesis.
PET-CT scanning analysis didn’t identify active BAT in patients with hyperthyroidism, which accounts for the observation that serum scEMC10 levels remained unchanged before and after ATD treatment. Of note, there was an apparent reduction in the uptake of 18F-FDG in whole body, especially in skeletal muscle, after ATD treatment, which coincides with a previous study showing patients with elevated levels of THs exhibited increased whole-body thermogenesis together with an increase in skeletal muscle mitochondrial uncoupling (ref. 22). This may be accounted for by the fact that deiodinase II, a key enzyme converting cellular T4 to more active T3 which in turn increases thermogenesis, is predominantly expressed in skeletal muscle in adult humans (ref. 16, 23). A larger cohort consisting of BAT-positive patients with hyperthyroidism is needed to investigate whether there is an association between serum scEMC10 and TH-regulated BAT activity.
It has been shown that both BAT and skeletal muscle contribute to nonshivering thermogenesis in humans (ref. 24). The findings of this study that serum scEMC10 is inversely associated with BAT activity, while doesn’t correlate with skeletal muscle thermogenesis suggest scEMC10-modulated facultative thermogenesis is BAT-specific and independent of skeletal muscle in humans. This may be explained by different subtypes of β adrenergic receptors present in BAT and skeletal muscle where β3 subtype predominates in BAT, while β2 receptor is the most subtype in skeletal muscle (ref. 7, 25). We have shown that scEMC10 is involved in the β3 adrenoceptor-modulated thermogenesis in BAT (ref. 9). Further experiments are needed to determine whether scEMC10 regulates β2-adrenoceptor signaling in skeletal muscle.
In conclusion, our data link scEMC10 to BAT facultative thermogenesis, but not to thyroid hormone-associated skeletal muscle thermogenesis in humans. This study renders inhibition of scEMC10 a translational significance in treating obesity and its associated cardiometabolic diseases via activation of BAT activity.