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

Abstract

Aims/hypothesis: The recent identification of murine adipose triglyceride lipase (ATGL, now known as patatin-like phospholipase domain containing 2 [PNPLA2]), gene product of Pnpla2, has questioned the unique role of hormone sensitive lipase (HSL, now known as LIPE), gene product of Lipe, in fat cell lipolysis. Here, we investigated human ATGL and HSL adipose tissue gene expression and in vitro lipase activity. Subjects, materials and methods: Levels of mRNA in adipose tissue from healthy obese and non-obese subjects were measured and lipase activity and adipocyte lipolytic capacity determined. HSL and ATGL cDNAs were transfected into Cos-7 cells and the relative tri-and diglyceride hydrolase activities were measured. Results: Obesity was associated with a decreased subcutaneous and increased omental adipose tissue level of HSL mRNA. Subcutaneous HSL mRNA content was normalised upon weight reduction. In contrast, ATGL mRNA levels were unaffected by obesity and weight reduction. A high adipose tissue lipase activity was associated with increased maximal lipolysis and increased HSL, but not with ATGL mRNA levels. The in vitro triglyceride hydrolase activity of HSL was markedly higher than that of ATGL and contrary to HSL, ATGL was devoid of diglyceride hydrolase activity. The use of a selective HSL-inhibitor resulted in complete inhibition of HSL-mediated tri-and diglyceride hydrolase activity. The pH profile of human white adipose tissue triolein hydrolase activity was identical to that of HSL but differed from the ATGL profile. Conclusions/interpretation: HSL, but not ATGL gene expression shows a regulation according to obesity status and is associated with increased adipose tissue lipase activity. Moreover, HSL has a higher capacity than ATGL to hydrolyse triglycerides in vitro.

Obesity and polymorphisms in genes regulating human adipose tissue

“…[90][91][92] The in vivo importance of ATGL in fat tissue is uncertain. 93 ATGL mRNA levels are unaffected by obesity and adipose tissue lipase activity. 93 Recently, several ATGL SNPs have been associated with the risk of T2DM and the levels of circulating lipids, but not with obesity.…”

“…93 ATGL mRNA levels are unaffected by obesity and adipose tissue lipase activity. 93 Recently, several ATGL SNPs have been associated with the risk of T2DM and the levels of circulating lipids, but not with obesity. 94 Adiponutrin (ADPN) is a protein expressed at high levels in human adipose tissue and displaying triacylglycerol lipase activity.…”

Adipose tissue distribution and risk of metabolic disease: does thiazolidinedione-induced adipose tissue redistribution provide a clue to the answer?

“…In contrast, as an antagonist of the lipolytic effect of catecholamines, insulin activates phosphodiesterase-3B, which reduces intracellular cAMP levels, leading to reduced PKA and HSL activation. Unlike HSL, ATGL is not regulated by PKA and is mainly involved in basal triacylglycerol hydrolysis [14]. Adipocytes from the visceral adipose depot have a low basal, but a high catecholamine-stimulated, rate of lipolysis compared with cells from abdominal, gluteal, and femoral subcutaneous fat depots.…”

Endothelin-1 stimulates human adipocyte lipolysis through the ETA receptor

“…The freshly isolated adipocytes were washed several times and used immediately for lipolysis experiments. 15 The stroma vascular cells were washed and plated out at a density of 30 000 cells per cm 2 for the differentiation process. Cells were differentiated in a serumfree adipogenic culture medium described earlier supplemented with 10 mmol l À1 rosiglitazone for 6 days and maintained in the same adipogenic medium but without rosiglitazone until the cells had differentiated fully into adipocytes, which was approximately 12 days after the initiation of the differentiation process.…”