Adipocyte Lipases and Defect of Lipolysis in Human Obesity

Abstract

The mobilization of fat stored in adipose tissue is mediated by hormone-sensitive lipase (HSL) and the recently characterized adipose triglyceride lipase (ATGL), yet their relative importance in lipolysis is unknown. We show that a novel potent inhibitor of HSL does not inhibit other lipases. The compound counteracted catecholamine-stimulated lipolysis in mouse adipocytes and had no effect on residual triglyceride hydrolysis and lipolysis in HSL-null mice. In human adipocytes, catecholamine-and natriuretic peptide-induced lipolysis were completely blunted by the HSL inhibitor. When fat cells were not stimulated, glycerol but not fatty acid release was inhibited. HSL and ATGL mRNA levels increased concomitantly during adipocyte differentiation. Abundance of the two transcripts in human adipose tissue was highly correlated in habitual dietary conditions and during a hypocaloric diet, suggesting common regulatory mechanisms for the two genes. Comparison of obese and nonobese subjects showed that obesity was associated with a decrease in catecholamine-induced lipolysis and HSL expression in mature fat cells and in differentiated preadipocytes. In conclusion, HSL is the major lipase for catecholamine-and natriuretic peptide-stimulated lipolysis, whereas ATGL mediates the hydrolysis of triglycerides during basal lipolysis. Decreased catecholamine-induced lipolysis and low HSL expression constitute a possibly primary defect in obesity. Diabetes 54:3190 -3197, 2005 O besity, which is characterized by an excess of fat stores, is the most important risk factor for type 2 diabetes. Adipose tissue lipolysis leads to the hydrolysis of triglycerides and release of free fatty acids (FFAs). Because of the link between elevated circulating FFA levels and the development of insulin resistance and the metabolic syndrome (1,2), adipose tissue lipolysis constitutes a target for the drug industry. Nicotinic acid, which acts by inhibiting adipose tissue lipolysis, was the first extensively used lipid-lowering agent (3). Catecholamines and natriuretic peptides are the major hormones stimulating this catabolic pathway in humans (4). Resistance to catecholamine-induced lipolysis in subcutaneous adipose tissue has been demonstrated in obese adults and children (5,6) and is attributed to decreased expression of lipolytic ␤ 2 -adrenoceptors (7), increased antilipolytic properties of ␣ 2 -adrenoceptors (8), and decreased expression of hormone-sensitive lipase (HSL) (9). It is possible that the HSL defect is the most important factor because it is also observed in nonobese first-degree relatives to obese subjects (10) and because there is a positive relationship between lipolytic capacity and HSL expression in human subcutaneous fat cells (11).The rate-limiting role of HSL in adipose tissue lipolysis has been challenged by the data from HSL knockout mice (12-15). Catecholamine-induced lipolysis is abrogated, but residual basal lipolysis is observed in adipocytes from HSL-null mice. These data suggest the existence of non-HSL lipases in adipos...

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

“…We have recently demonstrated that subcutaneous adipose tissue ATGL expression levels are strongly correlated to the levels of HSL [11]. Here, we confirm this finding by showing a high level of correlation between ATGL and HSL expression in omental adipose tissue as well, suggesting that the expression of the two lipases may be tightly co-regulated in humans.…”

“…These data further support our hypothesis on the respective role of HSL and ATGL in human adipose tissue lipolysis [11]. Stimulation of the catecholamine and natriuretic peptide pathways leads to the protein kinase-A (PKA)-and cGMP-dependent kinase (PKG)-dependent phosphorylation of HSL and hydrolysis of triglycerides by the enzyme.…”

“…Hence, there is no evidence in vitro of a synergistic effect of the two enzymes on hydrolysis of triglycerides. As previously shown [11], BAY completely inhibits HSL-mediated triglyceride hydrolase activity, but it had no effect on ATGL (Fig. 4a).…”

“…No triolein hydrolase activity activity was detected in Cos cells transfected with an empty vector (data not shown). To determine HSL-independent triglyceride lipase activity, we used the selective HSL inhibitor 4-isopropyl-3-methyl-2- [11,15]. CAT activity was determined on cellular extracts collected in lipase homogenisation buffer [16].…”

“…Using a selective inhibitor of HSL, we recently showed that in mouse and human adipocytes, catecholamineinduced lipolysis is mediated by HSL, whereas a non-HSL lipase contributes to basal lipolysis [11]. To gain further insight into the relative roles of ATGL and HSL in humans, we investigated their adipose tissue gene expression patterns in relation to obesity and lipolytic capacity.…”