The adipose tissue phenotype of hormone-sensitive lipase deficiency in mice

Objective: To directly ascertain the physiological roles in adipocytes of h ormone-sensitive lipase (HSL; E.C. 3.1.13), a multifunctional hydrolase tha t can mediate triacylglycerol cleavage in adipocytes. Research Methods and Procedures: We performed constitutive gene targeting o f the mouse HSL gene (Lipe), subsequently studied the adipose tissue phenot ype clinically and histologically, and measured lipolysis in isolated adipo cytes. Results: Homozygous HSL-/- mice have no detectable HSL peptide or cholester yl esterase activity in adipose tissue, and heterozygous mice have intermed iate levels with respect to wild-type and deficient littermates. HSL-defici ent mice have normal body weight but reduced abdominal fat mass compared wi th normal littermates. Histologically, both white and brown adipose tissues in HSL-/- mice show marked heterogeneity in cell size, with markedly enlar ged adipocytes juxtaposed to cells of normal morphology. In isolated HSL-/- adipocytes, lipolysis is not significantly increased by beta (3)-adrenergi c stimulation, but under basal conditions in the absence of added catechola mines, 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 per iod at 4 degreesC was similar in HSL-/- mice and controls, Overnight fastin g was well-tolerated clinically by HSL-/- mice, but after fasting, liver tr iglyceride content was significantly lower in HSL-/- mice compared with wil d-type controls. Conclusions: In isolated fat cells, the lipolytic rate after beta -adrenerg ic stimulation is mainly dependent on HSL. However, the observation of a no rmal rate of lipolysis in unstimulated HSL-/- adipocytes suggests that HSL- independent lipolytic pathway(s) exist in fat. Physiologically, HSL deficie ncy in mice has a modest effect under normal fed conditions and is compatib le with normal maintenance of core body temperature during cold stress. How ever, the lipolytic response to overnight fasting is subnormal.