HSG4112’s main mode of action for weight loss is enhanced energy expenditure
Within the same set of animals in Figure 2 and 3 , we measured daily food intake of Vehicle and HSG4112 group to test whether weight reduction is mediated by reduced energy intake or enhanced energy expenditure. HSG4112 significantly reduced mean daily food intake (Figure 5A ). To examine the effect of this food reduction, we had a pair-feeding cohort, which is daily fed at maximum of the amount that HSG4112 group daily consumed (Figure 5A ). The terminal body weight of pair-feeding group was 40.9g, compared to Vehicle group’s weight of 48.1g and HSG4112 group’s weight of 29.2g (Figure 5B ). Assuming that pair-feeding group fully represents the reduction of energy intake in HSG4112 group, reduced energy intake was responsible for 37.8% of weight loss while enhanced energy expenditure was responsible for 62.2% of weight loss induced by HSG4112; energy expenditure represents a greater portion of HSG4112’s mode of action.
In order to further confirm energy expenditure enhancing effect of HSG4112, we placed HFD-mice treated with HSG4112 or vehicle for 4 weeks into open-circuit indirect calorimetry cages (Even and Nadkarni, 2012) to measure respiration, movement, and energy consumption. HSG4112 significantly increased overall oxygen consumption rate and carbon dioxide production rate, in both light and dark hours (Figure 5C, D ). The respiratory exchange ratio (RER) did not change significantly (Figure 5E ). HSG4112 significantly increased the overall energy expenditure (Figure 5F ) in both dark and light hours – physically active and inactive hours –without increasing mice’s physical activity (Figure 5G ). These results strongly suggest that HSG4112 increased basal metabolism rate of these animals.