Catecholamine-induced lipolysis in adipose tissue and skeletal muscle in obesity
Introduction
Obesity is one of the major public health problems reaching epidemic proportions in several countries. Today, more then 1.1 billion adults worldwide are overweight, and 312 million of them are obese [1]. The obese state is characterized by increased fat storage in the form of triacylglycerol (TAG), mainly in adipose tissue. Impairments in catecholamine-induced lipolysis have been hypothesized to contribute to the development or maintenance of increased adipose tissue stores and obesity. The increased adipose tissue mass and a reduced insulin-mediated suppression of lipolysis may lead to lipid overflow in the circulation. Lipid overflow may lead to increased storage of fat in non-adipose tissues like muscle, liver and pancreas, also known as ectopic fat deposition. Increased storage of lipids (TAG) and in particular lipid intermediates (e.g. fatty acyl CoA, ceramides, diacylglycerol (DAG)) in skeletal muscle may inhibit insulin signal transduction, leading to insulin resistance [2]. Beside an increased lipid overflow also intrinsic disturbances in skeletal muscle fatty acid (FA) handling and lipolysis may contribute to this. So far, little information is available on the regulation of muscle lipolysis and to what extent disturbances in this regulation may contribute to the accumulation of TAG and lipid metabolites in muscle. This review focuses on the regulation of intracellular adipose tissue and skeletal muscle lipolysis in obese subjects. At first, the regulation of intracellular lipolysis by hormones, lipases and proteins that associate with the lipid droplet is discussed (Section 2). Secondly, disturbances in catecholamine-induced lipolysis in adipose tissue (Section 3) and skeletal muscle (Section 4) under obese insulin resistant conditions will be highlighted. Thirdly, it is questioned whether a blunted lipolysis is a cause or rather a consequence of the obese insulin resistant state (Section 5).
Section snippets
The lipolytic pathway
Almost 95% of the body's fat is found in adipose tissue. Beside adipose tissue a small amount of fat is stored in muscle, liver and pancreas (i.e. ectopic fat deposition). The process of lipolysis may occur extracellularly, mediated by lipoprotein lipase (LPL), and may occur intracellularly. In this section a brief overview of the intracellular catecholamine-mediated lipolytic pathway in adipose tissue and skeletal muscle will be given under normal physiological circumstances.
Catecholamine-induced lipolysis
In vivo a blunted whole-body catecholamine-induced lipolysis has been shown in obese subjects [78], [79], [80], [81], [82], [83]. In vitro studies suggest that the site of this catecholamine resistance is abdominal subcutaneous adipose tissue [84]. Some [83] but not all [85], [86] in situ microdialysis studies support this. Recently, we showed a blunted in vivo glycerol release from abdominal subcutaneous adipose tissue during intravenous infusion of the non-selective beta-agonist isoprenaline
Skeletal muscle lipolysis in obesity
The obese state is characterized by increased intramuscular TAG (IMTAG) storage [110]. A strong link between increased IMTAG stores and skeletal muscle insulin resistance has been shown in lean [111] and obese subjects [112]. On the other hand, IMTAG content has been found to be increased in endurance trained subjects, who, on the contrary, have high insulin sensitivity. This initial apparent paradox showed that although quantitative measures of IMTAG are often indicative of insulin
The case for prosecution: a blunted catecholamine-induced lipolysis as primary defect in obesity
It has been shown that an impaired catecholamine-induced lipolysis in adipose tissue does not improve after weight reduction [79], is a feature of childhood onset obesity [117], [118] and is already present in adipocytes from first-degree relatives of obese subjects [119]. These data indicate that catecholamine resistance of lipolysis may be an important early, even primary, factor for the development of increased fat stores in obesity. More evidence that a blunted lipolysis may be an early
Closing remarks and perspectives
Catecholamine resistance of lipolysis commonly reported in obese and insulin resistant subjects may involve defects at different steps of the lipolytic pathway. To date, the best characterized defect is a decreased expression of HSL in adipocytes of obese subjects. The characterization of ATGL as ‘a new player on the team’ has revised the classic lipolytic picture. There is an urgent need to reevaluate the role of the various lipases in adipose tissue and skeletal muscle lipolysis, and obesity.
References (159)
- et al.
Etiology of insulin resistance
Am J Med
(2006) - et al.
Identification of novel phosphorylation sites in hormone-sensitive lipase that are phosphorylated in response to isoproterenol and govern activation properties in vitro
J Biol Chem
(1998) - et al.
Perilipins, ADRP, and other proteins that associate with intracellular neutral lipid droplets in animal cells
Semin Cell Dev Biol
(1999) - et al.
Translocation of hormone-sensitive lipase and perilipin upon lipolytic stimulation during the lactation cycle of the rat
Metabolism
(2001) - et al.
Translocation of hormone-sensitive lipase and perilipin upon lipolytic stimulation of rat adipocytes
J Biol Chem
(2000) - et al.
Perilipin targets a novel pool of lipid droplets for lipolytic attack by hormone-sensitive lipase
J Biol Chem
(2005) - et al.
Analysis of lipolytic protein trafficking and interactions in adipocytes
J Biol Chem
(2007) - et al.
The phosphorylation of serine 492 of perilipin a directs lipid droplet fragmentation and dispersion
J Biol Chem
(2006) - et al.
Fatty acid-binding protein-hormone-sensitive lipase interaction. Fatty acid dependence on binding
J Biol Chem
(2003) - et al.
Interaction of the adipocyte fatty acid binding protein with the hormone sensitive lipase: regulation by fatty acids and phosphorylation
J Biol Chem
(2007)