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Diabetes 54:3190-3197, 2005
© 2005 by the American Diabetes Association, Inc.

Adipocyte Lipases and Defect of Lipolysis in Human Obesity

Dominique Langin1, Andrea Dicker2, Geneviève Tavernier1, Johan Hoffstedt2, Aline Mairal1, Mikael Rydén2, Erik Arner3, Audrey Sicard1, Christopher M. Jenkins4, Nathalie Viguerie1, Vanessa van Harmelen2, Richard W. Gross4, Cecilia Holm5, and Peter Arner2

1 Obesity Research Unit, Institut National de la Santé et de la Recherche Médicale, Université Paul Sabatier (UPS) U586, Louis Bugnard Institute, Toulouse University Hospitals, Paul Sabatier University, Toulouse, France
2 Department of Medicine, Karolinska University Hospital–Huddinge, Stockholm, Sweden
3 Center of Genomics and Bioinformatics, Karolinska Institute, Stockholm, Sweden
4 Division of Bioorganic Chemistry and Molecular Pharmacology, Departments of Medicine, Chemistry, Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri
5 Department of Experimental Medical Science, Division for Diabetes, Metabolism and Endocrinology, Biomedical Center, Lund University, Lund, Sweden

The mobilization of fat stored in adipose tissue is mediated by hormone-sensitive lipase (HSL) and the recently characterized adipose triglyceride lipase (ATGL), yet their relative importance in lipolysis is unknown. We show that a novel potent inhibitor of HSL does not inhibit other lipases. The compound counteracted catecholamine-stimulated lipolysis in mouse adipocytes and had no effect on residual triglyceride hydrolysis and lipolysis in HSL-null mice. In human adipocytes, catecholamine- and natriuretic peptide–induced lipolysis were completely blunted by the HSL inhibitor. When fat cells were not stimulated, glycerol but not fatty acid release was inhibited. HSL and ATGL mRNA levels increased concomitantly during adipocyte differentiation. Abundance of the two transcripts in human adipose tissue was highly correlated in habitual dietary conditions and during a hypocaloric diet, suggesting common regulatory mechanisms for the two genes. Comparison of obese and nonobese subjects showed that obesity was associated with a decrease in catecholamine-induced lipolysis and HSL expression in mature fat cells and in differentiated preadipocytes. In conclusion, HSL is the major lipase for catecholamine- and natriuretic peptide–stimulated lipolysis, whereas ATGL mediates the hydrolysis of triglycerides during basal lipolysis. Decreased catecholamine-induced lipolysis and low HSL expression constitute a possibly primary defect in obesity.

Address correspondence and reprint requests to Dominique Langin, Unité de Recherches sur les Obésités INSERM UPS U586, Institut Louis Bugnard IFR31, BP 84225, 31432 Toulouse Cedex 4, France. E-mail: langin{at}toulouse.inserm.fr

Abbreviations: ATGL, adipose triglyceride lipase; BAY, 4-isopropyl-3-methyl-2-[1-(3-(S)-methyl-piperidin-1-yl)-methanoyl]-2H-isoxazol-5–1; FFA, free fatty acid; HSL, hormone-sensitive lipase; KRBA, Krebs-Ringer bicarbonate buffer containing albumin; MOME, 1(3)-monooleoyl-2-0-monooleyl glycerol


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