ThermoMouse: an in vivo model to identify modulators of UCP1 expression in brown adipose tissue.

Obesity develops when energy intake chronically exceeds energy expenditure. Because brown adipose tissue (BAT) dissipates energy in the form of heat, increasing energy expenditure by augmenting BAT-mediated thermogenesis may represent an approach to counter obesity and its complications. The ability of BAT to dissipate energy is dependent on expression of mitochondrial uncoupling protein 1 (UCP1). To facilitate the identification of pharmacological modulators of BAT UCP1 levels, which may have potential as antiobesity medications, we developed a transgenic model in which luciferase activity faithfully mimics endogenous UCP1 expression and its response to physiologic stimuli. Phenotypic screening of a library using cells derived from this model yielded a small molecule that increases UCP1 expression in brown fat cells and mice. Upon adrenergic stimulation, compound-treated mice showed increased energy expenditure. These tools offer an opportunity to identify pharmacologic modulators of UCP1 expression and uncover regulatory pathways that impact BAT-mediated thermogenesis.

High-glycemic index carbohydrates abrogate the antiobesity effect of fish oil in mice.

Fish oil rich in n-3 polyunsaturated fatty acids is known to attenuate diet-induced obesity and adipose tissue inflammation in rodents. Here we aimed to investigate whether different carbohydrate sources modulated the antiobesity effects of fish oil. By feeding C57BL/6J mice isocaloric high-fat diets enriched with fish oil for 6 wk, we show that increasing amounts of sucrose in the diets dose-dependently increased energy efficiency and white adipose tissue (WAT) mass. Mice receiving fructose had about 50% less WAT mass than mice fed a high fish oil diet supplemented with either glucose or sucrose, indicating that the glucose moiety of sucrose was responsible for the obesity-promoting effect of sucrose. To investigate whether the obesogenic effect of sucrose and glucose was related to stimulation of insulin secretion, we combined fish oil with high and low glycemic index (GI) starches. Mice receiving the fish oil diet containing the low-GI starch had significantly less WAT than mice fed high-GI starch. Moreover, inhibition of insulin secretion by administration of nifedipine significantly reduced WAT mass in mice fed a high-fish oil diet in combination with sucrose. Our data show that the macronutrient composition of the diet modulates the effects of fish oil. Fish oil combined with sucrose, glucose, or high-GI starch promotes obesity, and the reported anti-inflammatory actions of fish oil are abrogated. In conclusion, our data indicate that glycemic control of insulin secretion modulates metabolic effects of fish oil by demonstrating that high-GI carbohydrates attenuate the antiobesity effects of fish oil.