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Hormone-Sensitive Lipase Deficiency in Mouse Islets Abolishes Neutral Cholesterol Ester Hydrolase Activity but Leaves Lipolysis, Acylglycerides, Fat Oxidation, and Insulin Secretion Intact

Department of Cell and Molecular Biology (M.F., U.F., K.B., H.L., C.H., H.M.) and Departments of Medicine (M.S.-W.) and Physiological Sciences (C.S.O., P.R.) at Lund University, Biomedical Center, SE-221 84, Sweden; and The Oxford Center for Diabetes, Endocrinology and Metabolism (P.R.), Churchill Hospital, Oxford OX3 7LJ, United Kingdom

Address all correspondence and requests for reprints to: Hindrik Mulder, Section for Molecular Signaling, Department of Cell and Molecular Biology, Lund University, BMC C11, SE-221 84, Lund Sweden. E-mail: hindrik.mulder{at}medkem.lu.se.

Lipids are thought to serve as coupling factors in insulin secretion. Hormone-sensitive lipase (HSL) is expressed in pancreatic ß-cells and could potentially regulate insulin secretion via mobilization of stored triglycerides. Here, we examined the impact of HSL deficiency on fuel metabolism and insulin secretion in mouse islets. Lack of HSL resulted in abrogation of neutral cholesterol ester hydrolase activity, whereas diglyceride lipase activity remained intact. Although glucose stimulates lipolysis in rat islets, elevation of glucose with or without addition of cAMP failed to increase lipolysis in mouse islets regardless of genotype, as indicated by release of glycerol from islets. Storage of lipids, assayed as total acylglycerides, was unaltered in HSL null islets, and oxidation of fatty acids or glucose was not different. The intracellular rise in Ca²⁺ triggered by glucose and its subsequent oscillations was unaffected in HSL null islets. Accordingly, insulin secretion in static incubations of islets, in response to fuel- and nonfuel secretagogues, was in no instance significantly different between wild-type and HSL null mice. The lacking impact of HSL deficiency on insulin secretion may be attributed to the failure of insulin secretagogues to stimulate lipolysis. Consequently, a regulatory function of lipid mobilization in insulin secretion in the mouse appears unlikely.

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