Hormone Sensitive Lipase (HSL) is a key enzyme in the regulation of lipid, the largest energy reserve in the body. Recently, there has been a renewed interest in HSL as an attractive therapeutic candidate for obesity because of its crucial role in lipolysis. The lipolytic pathway has been described for quite some time; however, the regulation of this pathway is not as well defined. In this study, we examine regulation of lipolysis and specifically HSL modulation by reactive oxygen species (ROS), which are increased in obesity.
Reduced activity of HSL improves metabolic homeostasis. Mice that lack a functional copy of the gene encoding HSL are resistant to both genetic and diet-induced obesity 
. Additionally, human studies have revealed that carrying an allele associated with decreased HSL hydrolytic activity is associated with an improved metabolic phenotype. Specifically, women carrying this allele have lower basal and stimulated insulin secretion, and men with this allele have lower circulating non-esterified fatty acids (NEFAs) 
As the name suggests, HSL hydrolyzes esters of neutral lipids, principally diacylglyceride (DG), in a manner activated by a variety of hormones that increase cAMP, including catecholamines, adrenocorticotropic hormone (ACTH) and glucagon 
. Protein Kinase A (PKA), activated via an increase in cAMP, phosphorylates rat HSL on three serine residues, Ser563, Ser659 and Ser660 
. These three sites are conserved in human HSL, as Ser552, Ser649 and Ser650, respectively 
. In vitro
, phosphorylation of human HSL Ser649 and Ser650 are the major determinants of its hydrolytic activity 
Upon phosphorylation, HSL translocates to the lipid droplet to participate in lipolysis. PKA phosphorylation induces a conformational change to expose hydrophobic groups on HSL, which facilitates HSL binding to its substrate, lipid 
. However, it is unknown which of these three PKA-mediated serine residues is the major determinant of translocation of HSL from the cytosol to the lipid droplet upon lipolytic stimulation. This important layer of regulation also regulates other lipid handling enzymes, including Lipin 1 and ACSL 
ROS is a candidate for the regulation of lipolysis, because there is a positive correlation between both ROS and lipolysis with obesity 
. In obesity, inflammation and overnutrition converge on an increase in ROS. Recently, there has been a paradigm shift that ROS, previously described as a trigger of programmed cell death and a useless by-product of cellular respiration, is also a signaling molecule and can be helpful rather than exclusively harmful 
. In fact, ROS has been shown to be a metabolic signal for glucose-stimulated insulin secretion 
. Given the increase of ROS in obesity and its role as a metabolic signal, we hypothesize that ROS is a modulator of adipocyte lipolysis.