Chronic leptin administration increases serum NEFA in the pig and differentially regulates PPAR expression in adipose

Two in vivo studies were conducted with pigs to determine the effects of exogenous leptin on the expression of peroxisome proliferator activated receptors (PPAR), and on serum concentrations of selected metabolites and hormones. Initially, leptin was administered i.m. to young pigs for 15 days at 0 (control), 0.003 (low), 0.01 (medium) and 0.03 (high) mg · kg-1 · day-1. There was no leptin effect on serum glucose (P > 0.84), triglycerides (P > 0.69), non-esterified fatty acids (NEFA, P > 0.53), or glycerol (P > 0.33). Leptin at the intermediate and high doses depressed adipose expression of both PPARγ1 (P < 0.06) and PPARγ2 (P < 0.01). In a second study, we used a paired-feeding experimental design to determine the effects of a higher dose of leptin (0.05 mg · kg-1 · day-1) on serum metabolites and PPAR expression in selected tissues. At this dose, leptin increased (P < 0 .0001) serum NEFA concentrations relative to both the ad libitum and pair-fed control groups. However, in this study, there was no difference in the expression of PPARγ1 in adipose tissue, but PPARγ2 mRNA was upregulated by leptin (P < 0.08). In contrast, leptin had no impact on the expression of PPARα in liver, skeletal muscle or adipose tissue. Adipose tissue explants were also incubated with leptin to assess the effect on PPARγ expression, in vitro. The abundance of PPARγ1 mRNA (P < 0.05) was increased after 24 hr of exposure, but the effect of leptin on γ2 was not significant (P > 0.24). The lipolytic effect of leptin was also evaluated in vitro using isolated adipocytes. In keeping with the increase in serum NEFA concentrations in vivo, leptin stimulated lipolysis in vitro, increasing glycerol concentrations in the medium to about 219% of that in basal (non-treated) culture medium after 8 hr of incubation. Collectively, the data presented herein indicate that leptin modulates lipid metabolism in the pig, but that PPARα expression is not a parallel target of leptin as it is in rodent models. The regulation of PPARγ by leptin seems complex in that it varied in relation to dose in vivo, and may be impacted by in vitro vs. in vivo circumstances.