Insulin and leptin acutely regulate cholesterol ester metabolism in macrophages by novel signaling pathways

Leptin is produced in adipose tissue and acts in the hypothalamus to regula te food intake. However, recent evidence also indicates a potential for dir ect roles for leptin in peripheral tissues, including those of the immune s ystem. In this study, me provide direct evidence that macrophages-are a tar get tissue for leptin. We found that J774.2 macrophages express the functio nal long form of the leptin receptor (ObRb) and that this becomes tyrosine- phosphorylated after stimulation with low doses of leptin. Leptin also stim ulates both phosphoinositide 3-kinase (PI 3-kinase) activity and tyrosine p hosphorylation of JAK2 and STAT3 in these cells. We investigated the effect s of leptin on hormone-sensitive lipase (HSL), which acts as a neutral chol esterol esterase in macrophages and is a rate-limiting Step in cholesterol ester breakdown. Leptin significantly increased HSL activity in J774.2 macr ophages, and these effects were additive with the effects of cAMP and mere blocked by PI 3-kinase inhibitors. Conversely, insulin inhibited HSL in mac rophages, but unlike adipocytes, this effect did not require PI 3-kinase. T hese results indicate that leptin and insulin regulate cholesterol-ester ho meostasis in macrophages and, therefore, defects in this process caused by leptin and/or insulin resistance could contribute to the increased incidenc e of atherosclerosis found associated with obesity and type 2 diabetes.