Human hormone-sensitive lipase (HSL): expression in white fat corrects the white adipose phenotype of HSL-deficient mice.
In white adipose tissue (WAT), hormone-sensitive lipase (HSL) can mediate lipolysis, a central pathway in obesity and diabetes. Gene-targeted HSL-deficient (HSL-/-) mice with no detectable HSL peptide or activity (measured as cholesteryl esterase) have WAT abnormalities, including low mass, marked heterogeneity of cell diameter, increased diacylglycerol content, and low beta-adrenergic stimulation of adipocyte lipolysis. Three transgenic mouse strains preferentially expressing human HSL in WAT were bred to a HSL-/- background. One, HSL-/- N, expresses normal human HSL (41.3 +/- 9.1% of normal activity); two express a serine-to-alanine mutant (S554A) initially hypothesized to be constitutively active: HSL-/- ML, 50.3 +/- 12.3% of normal, and HSL-/- MH, 69.8 +/- 15.8% of normal. In WAT, HSL-/- N mice resembled HSL+/+ controls in WAT mass, histology, diacylglyceride content, and lipolytic response to beta-adrenergic agents. In contrast, HSL-/- ML and HSL-/- MH mice resembled nontransgenic HSL-/- mice, except that diacylglycerol content and perirenal and inguinal WAT masses approached normal in HSL-/- MH mice. Therefore, 1) WAT expression of normal human HSL markedly improves HSL-/- WAT biochemically, physiologically, and morphologically; 2) similar levels of S554A HSL have a low physiological effect despite being active in vitro; and 3) diacylglycerol accumulation is not essential for the development of the characteristic WAT pathology of HSL-/- mice.
Fortier
Mélanie
M
Division of Medical Genetics, Research Centre, Sainte-Justine Hospital, Montréal, Québec, Canada.
Soni
Krishnakant
K
Laurin
Nancy
N
Wang
Shu Pei
SP
Mauriège
Pascale
P
Jirik
Frank R
FR
Mitchell
Grant A
GA
D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D004075:Diglycerides / Q000032:analysis; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D020738:Leptin / Q000097:blood; D008066:Lipolysis; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009929:Organ Size; D010641:Phenotype; D002787:Sterol Esterase / Q000172:deficiency* / Q000235:genetics*; D014280:Triglycerides / Q000032:analysis
D004075:Diglycerides; D020738:Leptin; D014280:Triglycerides; D002787:Sterol Esterase