Abstract
BackgroundHormone-sensitive lipase (HSL) is expressed predominantly in adipose tissue, where it plays an important role in catecholamine-stimulated hydrolysis of stored tri- and diglycerides, thus mobilizing fatty acids. HSL exhibits broad substrate specificity and besides acylglycerides it hydrolyzes cholesteryl esters, retinyl esters and lipoidal esters. Despite its role in fatty acid mobilization, HSL null mice have been shown to be resistant to diet-induced obesity.Methodology/Principal FindingsFollowing a high-fat diet (HFD) regimen, energy expenditure, measured using indirect calorimetry, was increased in HSL null mice. White adipose tissue of HSL null mice was characterized by reduced mass and reduced protein expression of PPARγ, a key transcription factor in adipogenesis, and stearoyl-CoA desaturase 1, the expression of which is known to be positively correlated to the differentiation state of the adipocyte. The protein expression of uncoupling protein-1 (UCP-1), the highly specific marker of brown adipocytes, was increased 7-fold in white adipose tissue of HSL null mice compared to wildtype littermates. Transmission electron microscopy revealed an increase in the size of mitochondria of white adipocytes of HSL null mice. The mRNA expression of pRb and RIP140 was decreased in isolated white adipocytes, while the expression of UCP-1 and CPT1 was increased in HSL null mice compared to wildtype littermates. Basal oxygen consumption was increased almost 3-fold in white adipose tissue of HSL null mice and was accompanied by increased uncoupling activity.ConclusionsThese data suggest that HSL is involved in the determination of white versus brown adipocytes during adipocyte differentiation The exact mechanism(s) underlying this novel role of HSL remains to be elucidated, but it seems clear that HSL is required to sustain normal expression levels of pRb and RIP140, which both promote differentiation into the white, rather than the brown, adipocyte lineage.
Highlights
Obesity is a growing health problem globally, predisposing individuals to disorders such as type 2 diabetes, cardiovascular disease and certain cancers
These data suggest that Hormone-sensitive lipase (HSL) is involved in the determination of white versus brown adipocytes during adipocyte differentiation The exact mechanism(s) underlying this novel role of HSL remains to be elucidated, but it seems clear that HSL is required to sustain normal expression levels of pRb and Receptor interacting protein 140 (RIP140), which both promote differentiation into the white, rather than the brown, adipocyte lineage
HSL null mice are resistant to diet-induced obesity As already reported in an independently generated strain of HSL null mice [18], our strain of HSL null mice displayed a significant reduction in both body weight (Figure 1A) and white adipose tissue (WAT) mass (Figure 1B,C) compared to wildtype mice following a 6month high-fat diet (HFD) regimen
Summary
Obesity is a growing health problem globally, predisposing individuals to disorders such as type 2 diabetes, cardiovascular disease and certain cancers. Understanding the molecular events underlying adipogenesis and determination of the differentiation of white versus brown adipocytes is of both basic and clinical importance. Brown adipocytes are characterized by expression of UCP1 and high energy expenditure potential. Attainment of brown adipocyte features in white adipocytes has evolved as a legitimate strategy to combat obesity. Considerable efforts over the last decades have led to the identification of a large plethora of transcription factors involved in differentiation and determination of adipocytes. Hormone-sensitive lipase (HSL) is expressed predominantly in adipose tissue, where it plays an important role in catecholamine-stimulated hydrolysis of stored tri- and diglycerides, mobilizing fatty acids. Despite its role in fatty acid mobilization, HSL null mice have been shown to be resistant to diet-induced obesity
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