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 (EE).
A drug that increases EE 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 EE 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, PPARα and 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. Importantly, additional mechanisms for activating thermogenesis beyond UCP1 have been identified and characterized to varying extents, and several regulatory factors have been uncovered in recent years. Putative futile cycles include, creatine-dependent substrate cycling, calcium-dependent ATP hydrolysis and triacylglycerol/fatty acid (TAG/FA) cycling. Whether O304 promotes one or several of these futile cycles to increase energy expenditure will require further work.
O304 increases energy expenditure in dog
Moreover, in 9 month tox study in dogs O304 reduced body weight gain in a potent and dose-dependent manner in dogs that were fed regular diet. Under these conditions O304 increased food intake. Thus, long term treatment with O304 increased energy expenditure in dog without causing any adverse effects.
In summary: By potently increasing energy exposure in both mouse and dog, O304 may be developed into a first-in-class anti-obesity drug.