title: Insulin and leptin acutely regulate cholesterol ester metabolism in macrophages by novel signaling pathways.
abstract: Leptin is produced in adipose tissue and acts in the hypothalamus to regulate food intake. However, recent evidence also indicates a potential for direct roles for leptin in peripheral tissues, including those of the immune system. In this study, we provide direct evidence that macrophages are a target tissue for leptin. We found that J774.2 macrophages express the functional long form of the leptin receptor (ObRb) and that this becomes tyrosine-phosphorylated after stimulation with low doses of leptin. Leptin also stimulates both phosphoinositide 3-kinase (PI 3-kinase) activity and tyrosine phosphorylation of JAK2 and STAT3 in these cells. We investigated the effects of leptin on hormone-sensitive lipase (HSL), which acts as a neutral cholesterol esterase in macrophages and is a rate-limiting step in cholesterol ester breakdown. Leptin significantly increased HSL activity in J774.2 macrophages, and these effects were additive with the effects of cAMP and were blocked by PI 3-kinase inhibitors. Conversely, insulin inhibited HSL in macrophages, but unlike adipocytes, this effect did not require PI 3-kinase. These results indicate that leptin and insulin regulate cholesterol-ester homeostasis in macrophages and, therefore, defects in this process caused by leptin and/or insulin resistance could contribute to the increased incidence of atherosclerosis found associated with obesity and type 2 diabetes.
authors.affiliation: Department of Biochemistry and Molecular Biology, University College London, UK.
authors.forename: L
authors.initials: L
authors.lastname: O'Rourke
authors.forename: S J
authors.initials: SJ
authors.lastname: Yeaman
authors.forename: P R
authors.initials: PR
authors.lastname: Shepherd
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002788:Cholesterol Esters / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology*; D053614:Janus Kinase 2; D007700:Kinetics; D020738:Leptin / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D002787:Sterol Esterase / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D002788:Cholesterol Esters; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007328:Insulin; D020738:Leptin; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; C515447:leptin receptor, mouse; D019000:Phosphotyrosine; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D002787:Sterol Esterase