Background

Obesity occurs when the body is in a positive energy balance: when energy intake exceeds energy expenditure. The currently available anti-obesity drugs focus on either inhibiting food intake or fat absorption; none of them enhance energy expenditure. HSG4112, a synthetic new chemical entity, improves leptin sensitivity and drives the body’s energy balance to a negative direction by inducing the selective reduction of fat and enhancing energy expenditure. The anti-obesity effects of HSG4112 were studied in a diet-induced obese (DIO) mouse model.

Methods

DIO mice received a once-daily oral dose of HSG4112 (100 mg/kg) for 6 weeks. The study consisted of normal control (normal diet), vehicle control (high fat diet), treatment (high fat diet), and pair-fed groups. Body weight, food intake, and adiposity were measured and terminal blood biochemistry was also assessed.

Results

HSG4112 induced a weight loss of 26% in DIO mice. Energy expenditure contributed to 62% of the weight loss while food intake reduction contributed to 38%. Enhanced energy expenditure was observed through the heightened O2 consumption and CO2 production rates. Compared to the vehicle, HSG4112 significantly reduced the plasma leptin and markedly reduced fat in white adipose tissues as peri-epididymal and perirenal fat mass were reduced by 77% and 87%, respectively. Also, HSG4112 promoted similar significant reduction in liver fat and reduced hepatic expressions of FGF21, CCL2, and plasma resistin.

Conclusions

In nonclinical studies, HSG4112 demonstrated selective reduction in body fat with improved leptin sensitivity. Based on the observation of enhanced energy expenditure, it can be interpreted that HSG4112 induces weight loss by burning fat through the acceleration of lipolysis and by using free fatty acids as an energy source. HSG4112 is currently in its Phase 1 study for obesity, but its anti-steatosis and anti-inflammatory effects justify the further clinical development as a potential novel drug for the treatment of NASH.