Disclosures: Gyongyi Szabo – Consulting: Idenix; Grant/Research Support: BMS, LDK378 mouse GSK, Cona-tus, Idera, Johnson&Johnson, Novartis, Ocera, Roche, Shering – Plough, Wyeth, Integrated Therapeutics, Idera The following people have nothing to disclose: Michal Ganz, Timea Csak, Shashi Bala, Banishree Saha Background: Them1 is a long-chain fatty acyl-CoA thioesterase that is highly expressed in brown adipose tissue (BAT) and is strongly upregulated by decreasing ambient temperature. At room temperature, Them1 −/− mice exhibit increased energy expenditure and resistance to diet-induced obesity and hepatic steatosis despite increased food consumption (Zhang et al, PNAS, 2012;109:5417). Aim: The

objective of this study was to elucidate the regulatory role of Them1 in energy metabolism, which may contribute in part to the pathogenesis of NAFLD. Methods: Using a temperature controlled Comprehensive Laboratory

Animal Monitoring System (Columbus Tamoxifen solubility dmso Instruments), Them1−/− and Them1+/+ control mice (n = 6/group) were acclimated (48 h) to ambient temperatures ranging from thermoneutrality (30 °C), room temperature (22 °C) and cold (4 °C). This was followed by 48 h of data collection, which included rates of O2 consumption (VO2) and CO2 production (VCO2), physical activity and food intake. Core body temperatures were determined using a rectal probe. Lean body weights were determined by magnetic resonance spectroscopy. Energy expenditure (EE) was calculated using VO2 and VCO2 and adjusted for lean body weights by ANCOVA. Upon completion of experiments, BAT was harvested Axenfeld syndrome to analyze for mRNA expression

levels by qPCR and for ultrastructure analysis by transmission electron microscopy. Results: Cumulative (48 h) values of EE (kJ) were increased when the temperature was reduced from 30 °C to 22 °C, but there were no genotype dependent differences. By contrast, at 4 °C, EE values were higher in Them1 −/− mice (Them1+/+, 154±3; Them1 −/−, 165±2). At 4 °C, Them1 −/− mice were less active (activity counts/48 h; Them1+/+, 80,843±3,570; Them1−/−; 57,561 ±3,386), consumed the same amounts of food (g/g lean body mass; Them1 +/+, 0.73 ± 0.03; Them1 −/−, 0.69 ± 0.01), but tended to lose a greater percentage of their weight (Them1 +/+, 2.2 ± 0.7; Them1 −/−, 3.8 ± 1.2). Core body temperatures did not differ between the two genotypes. Expression of the thermogenic genes Ucp1 and Pgc1α were markedly upregulated in BAT by decreasing ambient temperature, but genotype dependent differences were not observed. In BAT from mice housed at 4 °C, the absence of Them1 was associated with smaller lipid droplets and larger mitochondria. Conclusions: Our data demonstrate that Them1 in BAT functions to suppress thermogenesis potentially by reducing the delivery of fatty acids from lipid droplets to mitochondria for oxidation. Inhibition of Them1 could provide a unique strategy for the management of the obesity and NAFLD. Disclosures: David E.