Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity

Abstract

Hormone-sensitive lipase (HSL) is known to mediate the hydrolysis not only of triacylglycerol stored in adipose tissue but also of cholesterol esters in the adrenals, ovaries, testes, and macrophages. To elucidate its precise role in the development of obesity and steroidogenesis, we generated HSL knockout mice by homologous recombination in embryonic stem cells. Mice homozygous for the mutant HSL allele (HSL؊͞؊) were superficially normal except that the males were sterile because of oligospermia. HSL؊͞؊ mice did not have hypogonadism or adrenal insufficiency. Instead, the testes completely lacked neutral cholesterol ester hydrolase (NCEH) activities and contained increased amounts of cholesterol ester. Many epithelial cells in the seminiferous tubules were vacuolated. NCEH activities were completely absent from both brown adipose tissue (BAT) and white adipose tissue (WAT) in HSL؊͞؊ mice. Consistently, adipocytes were significantly enlarged in the BAT (5-fold) and, to a lesser extent in the WAT (2-fold), supporting the concept that the hydrolysis of triacylglycerol was, at least in part, impaired in HSL؊͞؊ mice. The BAT mass was increased by 1.65-fold, but the WAT mass remained unchanged. Discrepancy of the size differences between cell and tissue suggests the heterogeneity of adipocytes. Despite these morphological changes, HSL؊͞؊ mice were neither obese nor cold sensitive. Furthermore, WAT from HSL؊͞؊ mice retained 40% of triacylglycerol lipase activities compared with the wild-type WAT. In conclusion, HSL is required for spermatogenesis but is not the only enzyme that mediates the hydrolysis of triacylglycerol stored in adipocytes.

Adipocyte Death and Chronic Inflammation in Obesity

“…Important findings were obtained from a study with hormone-sensitive lipase (HSL), a major lipase in adipocytes, knockout mice. Due to the disruption of the lipolysis process, HSL knockout mice showed an increased adipocyte cell size without obesity (19). Increased macrophage infiltration and inflammation in adipose tissue were also observed in the knockout mouse (10).…”

Carnitine is necessary to maintain the phenotype and function of brown adipose tissue

“…4,8,31,33,34 In contrast to these animals, HSL knockout mice are sensitive to cold and maintain a normal body temperature despite possessing similar changes in their BAT. 30,32 Therefore, an enlargement of lipid vacuoles in BAT has been shown to be independent of cold sensitivity. However, the results of the present study strongly suggest that enlarged lipid droplets in BAT reflect an impaired function or a loss of function of BAT, because the low body temperatures and BAT phenotypes were completely recovered following L-carnitine administration.…”

“…Enlarged lipid vacuoles in BAT have been detected in animals that are fasted, have undergone denervation of the sympathetic nerves, are obese (db/db), or carry a knockout mutation in UCP-1, dopamine b-hydroxylase, or hormonesensitive lipase (HSL). 4,8,[30][31][32][33][34] The morphological transition from BAT to WAT-like tissue has been thought to reflect impaired thermogenesis in the BAT, because fasting, denervated, obese (db/db), UCP-1 knockout, and dopamine bhydroxylase knockout animals display low body temperatures and/or increased cold sensitivity. 4,8,31,33,34 In contrast to these animals, HSL knockout mice are sensitive to cold and maintain a normal body temperature despite possessing similar changes in their BAT.…”

Human adipose triglyceride lipase (PNPLA2) is not regulated by obesity and exhibits low in vitro triglyceride hydrolase activity

“…This enzyme possesses tri-and diglyceride hydrolase activities and is regulated by the major lipolysis-regulating hormones, which in man are insulin, catecholamines and natriuretic peptides [3]. However, HSL knock-out mice have residual lipolytic activity [4,5], which may be attributed to an additional lipase with high affinity for triglycerides [6,7]. Accordingly, a novel adipocyte-specific lipase termed adipose triglyceride lipase (ATGL, now known as patatin-like phospholipase domain containing 2 [PNPLA2]), the product of Pnpla2, and alternatively designated iPLA 2 ζ or desnutrin, was recently identified using different strategies [8][9][10].…”