Although it has been reported that HL mRNA levels in the liver ar

Although it has been reported that HL mRNA levels in the liver are decreased in ob/ob mice and restored with whole body leptin treatment,12 we now report that this is not associated with increased non-LPL lipase activity in the liver. However, in mice with a liver-specific loss or gain of leptin signaling, our data do support a role for leptin signaling specifically in the liver to positively regulate non-LPL activity. Further, we also report a novel finding that leptin resistance specifically in the liver leads to a marked increase in hepatic LPL activity.

Because an overexpression BMS-777607 molecular weight of LPL in tissues can cause increased lipid uptake and lipid accumulation,22 we speculate that the elevation of LPL activity in Leprflox/flox AlbCre+ mice contributes to their elevated hepatic triglycerides.13 LPL activity HM781-36B ic50 has a complex mechanism of regulation, including transcriptional, posttranscriptional, translational,

and/or posttranslational mechanisms depending on nutrient status and tissue.26 Adding to this complexity, our data show that in db/db mice, the loss of leptin signaling caused an elevation of hepatic LPL activity through transcriptional changes, but in Leprflox/flox AlbCre+ mice, the increased LPL activity was mediated through posttranscriptional mechanisms. Furthermore, because insulin can regulate LPL activity in adipose and muscle,26 leptin regulation of hepatic LPL

activity may be indirect through the effects of leptin on hepatic insulin signaling. Additionally, because leptin treatment in ob/ob mice was unable to fully normalize lipase activity in the liver, secondary extrahepatic effects of leptin signaling also appear to contribute to the regulation of lipase activity in the liver. Although it is clear that loss of hepatic leptin signaling can increase hepatic Tolmetin LPL mRNA, the exact mechanism by which leptin regulates lipase activity in the liver remains to be determined. Leprflox/flox AlbCre+ mice have increased hepatic insulin sensitivity,13 and insulin is an important regulator of lipid metabolism in the liver as evidenced by its role in decreasing plasma apoB levels.17 Consistent with this, our data show that in mice lacking hepatic leptin signaling, increased hepatic insulin sensitivity is associated with decreased plasma apoB levels even in the fasting state. Although it is possible that this effect on apoB is mediated directly by leptin signaling independent of insulin, we speculate that it is actually the effect of leptin on insulin signaling that mediates changes in apoB, since leptin itself does not affect plasma apoB levels.

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