28, 29 In contrast, the inflammatory and fibrotic responses in ATGLLKO www.selleckchem.com/products/Everolimus(RAD001).html liver were mild and less than those reported for similar degrees of steatosis in diet-induced obesity.28, 30-33 Insulin and glucose tolerances were normal in ATGLLKO mice, showing that overall body energy homeostasis is preserved despite hepatic ATGL deficiency. In contrast, constitutive ATGL-deficient mice have increased insulin sensitivity compared with controls.16 This finding has been attributed to enhanced insulin sensitivity in muscle.34 The lack of insulin sensitivity of ATGLLKO mice is consistent with this finding, suggesting that the insulin sensitivity of ATGL−/− mice is not of hepatic origin. Despite the marked

steatosis of ATGLLKO mice, the mainstreams of hepatocyte FA flux were preserved. The normal fasting oxygen consumption, RER, heat production, and fasting tolerance in ATGLLKO mice, and their normal level of 3-hydroxybutyrate after a 48-hour fast, demonstrate that substantial rates of mitochondrial beta oxidation and ketogenesis are possible in ATGLLKO mice. Furthermore, their hepatic mitochondrial ultrastructure is normal. In addition, gluconeogenesis, see more which is fueled by reducing equivalents from FA oxidation,35 was normal in ATGLLKO mice. This contrasts with the low levels of PPARα and CPT-1α mRNAs, which are predicted to reduce

FA oxidative capacity. Direct measurement of FA oxidation in liver slices showed 31% less carbon dioxide production in ATGLLKO than in normal liver (Fig. 6D), consistent with a reduced capacity for FA oxidation in ATGLLKO

liver. The residual oxidative capacity of ATGLLKO liver appears adequate to meet most physiological demands, including 48-hour fasting. VLDL production is the other main fate of FA in hepatocytes. It appeared to be normal in ATGLLKO mice (Fig. 5D). Plasma TG concentrations were normal in fed and fasted ATGLLKO mice (Tables 2 and 3). Levels of microsomal triglyceride transfer protein and TGH, two microsomal proteins implicated in VLDL production, were normal (Supporting Fig. 4). In addition, following injection of a lipoprotein lipase inhibitor, plasma TG levels increased at similar rates in ATGLLKO mice and controls (Fig. 5D). Of note, a similar dissociation of hepatic steatosis and metabolic abnormalities has also been observed in mice that overexpress DGAT2, which develop steatosis but are protected MCE from the metabolic changes associated with HFD-induced obesity.36 Our findings are highly complementary to and extend those of Ong et al.18 That group studied mice 7 days after adenoviral-mediated knockdown of ATGL, whereas we studied chronic genetic ATGL deficiency. In each model, increased liver TG content, decreased TG hydrolase activity, lower rates of FA oxidation, and similar VLDL secretion were found in ATGL-deficient mice compared with controls. The severity of steatosis varied six- to seven-fold from the level reported by Ong et al. (0.