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0.845?��?0.023 for hl?/? ciHL mice, P?=?0.01 (Fig.?(Fig.4B).4B). These results suggest that hl?/? ciHL mice (lacking the catalytic function) preferentially burn calories from fat, consistent with their lean phenotype. We also found a trend toward reduced ambulatory activity levels in HL-deficient mice expressing active HL compared with mice expressing inactive ciHL, with the number of beam breaks being nonsignificantly lower in hl?/? hHL than hl?/? ciHL mice (19,607?��?6747 vs. 31,743?��?17,491; P?=?0.076) (Fig.?(Fig.44C). These results confirm previous evidence that HL deficiency increases energy expenditure and Selleckchem Idelalisib fat oxidation in mice, and demonstrates that the enzyme's catalytic function is required to reverse these effects. Genotype differences in plasma variables and glucose homeostasis Because plasma leptin levels reflect the degree of adiposity, we postulated that values would be reduced in lean hl?/? mice and that this effect would be reversed by transgenic expression of intact HL, but not the ciHL mutant. As expected, leptin levels were highest in mice with active HL and decreased in both genotypes of mice that lacked HL catalytic activity. Specifically, leptin levels in female hl?/? hHL mice on the HFD were 47.1?��?22?ng/mL compared to 37.1?��?3.7?ng/mL and 18.0?��?11.6?ng/mL in hl?/? and hl?/? ciHL mice, respectively (n?=?4�C8/group, P?Ficain substantial differences in body weight and fat mass (Table?(Table3).3). Nevertheless, plasma glucose levels were considerably higher in male mice expressing intact human HL (207?��?34?mg/dL) compared to either hl?/? ciHL mice (143?��?23?mg/dL), or hl?/? (161?��?25?mg/dL) (P?=?0.01 for both comparisons). In contrast, plasma glucose levels did not differ between genotypes in female mice (Table?(Table33). To explore the glucose metabolic phenotype Small molecule library price further, we challenged the mice with an intraperitoneal glucose tolerance test (ipgtt). Surprisingly, despite distinct differences in weight and fat mass in male mice the ipgtt was not different between the three genotypes (Fig.?(Fig.5A),5A), and area under the curve (AUC) analyses of blood glucoses of all three genotypes showed no difference in glucose tolerance [AUC: hl?/? HL 425?��?75 (n?=?4), hl?/? ciHL 418?��?99 (n?=?4), and hl?/?433?��?59 (n?=?4), P?=?NS]. Therefore, in male mice, despite distinct differences in weight and fat mass, there was no consistent difference in glucose tolerance between genotypes. Figure 5 Effect of rescue of hepatic lipase deficiency on glucose tolerance. Intraperitoneal glucose tolerance test (IPGTT) in HF-fed hl?/?, hl?/? hHL and hl?/? ciHL in male (A) and female (B) mice. Mice were fasted ...