Adipocyte lipases and defect of lipolysis in human obesity.
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.
Langin
Dominique
D
Obesity Research Unit, Institut National de la Santé et de la Recherche Médicale, Université Paul Sabatier (UPS) U586, Louis Bugnard Institute, Toulouse University Hospitals, Toulouse, France. langin@toulouse.inserm.fr
Dicker
Andrea
A
Tavernier
Geneviève
G
Hoffstedt
Johan
J
Mairal
Aline
A
Rydén
Mikael
M
Arner
Erik
E
Sicard
Audrey
A
Jenkins
Christopher M
CM
Viguerie
Nathalie
N
van Harmelen
Vanessa
V
Gross
Richard W
RW
Holm
Cecilia
C
Arner
Peter
P
D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology*; D000273:Adipose Tissue / Q000187:drug effects / Q000201:enzymology*; D000328:Adult; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008049:Lipase / Q000378:metabolism*; D008066:Lipolysis; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000201:enzymology / Q000378:metabolism*; D002787:Sterol Esterase / Q000378:metabolism
D002787:Sterol Esterase; D008049:Lipase; D007545:Isoproterenol