It should be noted, under certain circumstance the dynamic changes and adaptive response in EE during an intervention somehow adds to the difficulty in analyzing the metabolic effect of certain treatment. Specifically, even though certain treatment promotes weight reduction through enhancing energy expenditure at the beginning, the weight loss will probably lead to reduced EE in turn as an adaptive response to maintain the homeostasis of body weight, which is seen in most studies (Leibel et al., 1995; Keesey and Hirvonen, 1997; Wyatt et al., 1999; MacLean et al., 2004). In our current study, the mice were subjected to the CLAMS system for analysis of metabolic status at the end of the experiment, but the weight reduction effect was seen after the first drug injection and maintained throughout the experiment, rendering the possibility that we might have missed the best time window to quantify EE that significantly influences body weight gain. Nevertheless, our data that Supaglultide-treated mice demonstrated a concomitantly increased trend of EE both on per-whole-animal and BW-normalized basis suggested that supaglutide exerted a regulatory effect on the energy expenditure of the obese mice, which is in good agreement with previous studies in both preclinical and clinical obese subjects (Kanoski et al., 2011; Fukuda-Tsuru et al., 2014; Shah and Vella, 2014; Decara et al., 2016; Rondanelli et al., 2016; Xu et al., 2016). It is important to note, the tissue-specific modulation of lipid metabolism and WAT remodeling of GLP-1 represents a molecular mechanism in mediating GLP-1's anti-obesity actions (Decara et al., 2016; Xu et al., 2016).