Obesity is a global epidemic that is strongly associated with the global increase in type 2 diabetes and associated macro- and microvascular complications. Obesity occurs when assimilated energy exceeds energy expenditure and can only be reduced by affecting either side of the energy balance equation. Currently, there are no effective medical treatments for obesity, and current treatments reduce food intake and do not increase energy expenditure. A drug that increases energy expenditure for a significant fraction of obese patients, may therefore have profound effects on a myriad of metabolic and cardiovascular complications, and represent a ‘‘first in class’’ pharmaceutical breakthrough.
O304 and Obesity: In DIO mice, O304 both prevents and reduces white adipose tissue (WAT) weight but not lean weight, also at thermoneutrality. Under these conditions O304 increases food intake providing evidence that O304 increases energy expenditure. Consistently, in DIO mice O304 significantly increased oxygen consumption (VO2) during both light and dark period, and decreased significantly respiratory exchange ratio (RER) at day 2 during the light period, and throughout a 3-day measurements during the dark period, providing evidence that mice fed O304-HFD switched their main energy source from carbohydrates to fatty acids. Accordingly, O304 significantly increased energy expenditure during both light and dark periods.
To reduce WAT depots, lipolysis needs to be enhanced. Desnutrin/Atgl, which encodes the rate-limiting enzyme catalyzing basal triglyceride (TG) hydrolysis is a direct target of AMPK, and phosphorylation of S406 by AMPK increases ATGL activity, which should increase lipolysis. Accordingly, O304 increased both Atgl mRNA levels and p-S406 ATGL levels inguinal (i)WAT. Moreover, Cpt1 b that increases mitochondrial FA uptake, and PGC-1α, PPARαand Cox8b, which would increase mitochondrial activity/FA oxidation, were also increased by O304. Under these conditions, O304 reduced the low-level UCP1 expression in iWAT, arguing against ectopic expression of UCP1 in WAT as a mechanism for the anti-obesity effect of O304, which mimics the effects of systemic genetic activation of AMPK, which protects against diet induced obesity through Ucp1-independent thermogenesis in WAT. Importantly, additional mechanisms for activating thermogenesis beyond UCP1 have been identified and characterized to varying extents. Among other putative futile cycles, mitochondrial H+ permeability through the ADP/ATP carrier mediates UCP-1 independent uncoupling and requires free fatty acids. Whether O304 promotes one or several of these futile cycles to increase energy expenditure will require further work.
Accordingly, in a 9 months tox study when dogs were fed regular diet O304 reduced body weight gain (not body weight) in a potent and dose-dependent manner, which was fully reversible after washout and mitigated by additional food. Under these conditions O304 increased food intake and thus energy expenditure. Thus, long term treatment with O304 increased energy expenditure in dog without causing any adverse effects. In summary: O304 potently increases energy exposure in both mouse and dog and may be developed into a first-in-class anti-obesity drug.