7). These data clearly reveal a role for hepatic leptin signaling in regulating lipase activity in the liver. Similar to mice that have a liver-specific loss

of leptin signaling, Ad-β-gal-treated db/db mice also had a ∼30% decrease in non-LPL activity in the liver compared with C57BL/6 controls (Fig. 6D), and this correlated with a decrease in hepatic HL mRNA (Fig. 5C). When functional leptin receptors were overexpressed in the livers of db/db mice, non-LPL activity increased even beyond levels seen in wild-type mice (Fig. 6D). Furthermore, control db/db mice had a two-fold increase in LPL activity levels, and when db/db mice were treated with Ad-Lepr-b, LPL activity returned to wild-type levels (Fig. 6E). We also observed that in the total lack of leptin signaling, hepatic LPL activity contributed to 60% of total triglyceride lipase

activity in the liver, and when PLX4032 leptin signaling was selectively restored to the liver, hepatic LPL activity contributed only 20% to total triglyceride lipase activity, which is similar to wild-type levels (Fig. 6F). These data from two complementary models reveal a novel role for hepatic leptin signaling in modulating lipase activity in the liver. However, the manner (transcriptional versus posttranscriptional) by which lipase activity in the liver is regulated in mice with a life-long loss of hepatic leptin signaling and mice with an induced gain of hepatic leptin signaling is different (Figs. 5 and 6). Nonetheless, the functional end result is that with

a loss of hepatic leptin signaling, selleck chemical non-LPL lipase activity is decreased and LPL activity is MCE increased. To determine whether these effects of leptin on apoB transcription and lipase activity in the liver are due to direct or indirect actions of leptin, we treated ob/ob mice with acute leptin injections as well as chronic leptin infusions, which restored leptin signaling to all tissues. Acute leptin injections increased apoB mRNA in the liver by nearly 60%, but chronic low-dose leptin treatment had no effect (Supporting Fig. 3A). Further, while liver-selective restoration of leptin signaling in db/db mice decreased hepatic LPL expression back toward wild-type levels (Fig. 5D), acute leptin injections into ob/ob mice increased hepatic LPL mRNA (Supporting Fig. 3C). Therefore, the increase in hepatic LPL mRNA in ob/ob mice after acute leptin treatment is likely a result of leptin action outside of the liver. Interestingly, we previously observed that a whole body loss of leptin signaling has distinct effects, in fact opposite, from a liver specific loss of leptin signaling with respect to glucose homeostasis.13 Notably, chronic low-dose leptin did not change hepatic LPL mRNA expression in ob/ob mice (Supporting Fig.