The Adipose Tissue Phenotype of Hormone‐Sensitive Lipase Deficiency in Mice

Abstract

Objective: To directly ascertain the physiological roles in adipocytes of hormone‐sensitive lipase (HSL; E.C. 3.1.1.3), a multifunctional hydrolase that can mediate triacylglycerol cleavage in adipocytes. Research Methods and Procedures: We performed constitutive gene targeting of the mouse HSL gene (Lipe), subsequently studied the adipose tissue phenotype clinically and histologically, and measured lipolysis in isolated adipocytes. Results: Homozygous HSL−/− mice have no detectable HSL peptide or cholesteryl esterase activity in adipose tissue, and heterozygous mice have intermediate levels with respect to wild‐type and deficient littermates. HSL‐deficient mice have normal body weight but reduced abdominal fat mass compared with normal littermates. Histologically, both white and brown adipose tissues in HSL−/− mice show marked heterogeneity in cell size, with markedly enlarged adipocytes juxtaposed to cells of normal morphology. In isolated HSL−/− adipocytes, lipolysis is not significantly increased by β3‐adrenergic stimulation, but under basal conditions in the absence of added catecholamines, the lipolytic rate of isolated HSL−/− adipocytes is at least as high as that of cells from normal controls. Cold tolerance during a 48‐hour period at 4 °C was similar in HSL−/− mice and controls. Overnight fasting was well‐tolerated clinically by HSL−/− mice, but after fasting, liver triglyceride content was significantly lower in HSL−/− mice compared with wild‐type controls. Conclusions: In isolated fat cells, the lipolytic rate after β‐adrenergic stimulation is mainly dependent on HSL. However, the observation of a normal rate of lipolysis in unstimulated HSL−/− adipocytes suggests that HSL‐independent lipolytic pathway(s) exist in fat. Physiologically, HSL deficiency in mice has a modest effect under normal fed conditions and is compatible with normal maintenance of core body temperature during cold stress. However, the lipolytic response to overnight fasting is subnormal.

A computational model of adipose tissue metabolism: Evidence for intracellular compartmentation and differential activation of lipases

“…The greater decrease of FA release by knocking down ATGL expression than that of HSL is consistent with experimental observations with transgenic mice, where ATGL-deficient mice have substantially lower levels of plasma FA (60% lower than the control) in association with massive accumulation of lipid (Haemmerle et al, 2006). In contrast, HSL-deficient mice have moderate reduction (10~20%) in the plasma FA levels without significant decrease in the basal lipolytic rate (Wang et al, 2001). As expected from the fact that DG can be hydrolyzed only by HSL, it was shown that DG accumulated in the adipose tissue of HSL-deficient mice (Haemmerle et al, 2002).…”

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].…”