Obesity and Atherogenic Dyslipidemia

Obesity is associated with an increased risk of coronary heart disease, in part due to its strong association with atherogenic dyslipidemia, characterized by high triglycerides and low high-density lipoprotein (HDL) cholesterol. There has been substantial research effort focused on the mechanisms of the link between obesity and atherogenic dyslipidemia, both in the absence and presence of insulin resistance. After a brief overview of the epidemiology of atherogenic dyslipidemia, this article details the known molecular mechanisms of adipocyte function and its relationship to apoB-containing lipoprotein assembly and metabolism, both in the healthy as well as in the obese states. We also discuss the pathophysiology of low HDL cholesterol in obesity and the implications for cardiovascular disease risk. Obesity is associated with an increased risk of coronary heart disease, in part due to its strong association with atherogenic dyslipidemia, characterized by high triglycerides and low high-density lipoprotein (HDL) cholesterol. There has been substantial research effort focused on the mechanisms of the link between obesity and atherogenic dyslipidemia, both in the absence and presence of insulin resistance. After a brief overview of the epidemiology of atherogenic dyslipidemia, this article details the known molecular mechanisms of adipocyte function and its relationship to apoB-containing lipoprotein assembly and metabolism, both in the healthy as well as in the obese states. We also discuss the pathophysiology of low HDL cholesterol in obesity and the implications for cardiovascular disease risk. The dramatic increase in the prevalence of obesity has led to a marked increase in the metabolic syndrome, characterized by visceral adiposity, insulin resistance, elevated blood pressure, elevated triglycerides, and low levels of high-density lipoprotein cholesterol (HDL-C).1Ford E.S. Giles W.H. Dietz W.H. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey.JAMA. 2002; 287: 356-359Crossref PubMed Google Scholar, 2Grundy S.M. Cleeman J.I. Merz C.N. Brewer Jr, H.B. Clark L.T. Hunninghake D.B. Pasternak R.C. Smith Jr, S.C. Stone N.J. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.Circulation. 2004; 110: 227-239Crossref PubMed Scopus (4377) Google Scholar The diagnosis of the metabolic syndrome appears to confer substantial additional risk of coronary heart disease (CHD) above and beyond the individual risk factors.3McNeill A.M. Rosamond W.D. Girman C.J. Golden S.H. Schmidt M.I. East H.E. Ballantyne C.M. Heiss G. The metabolic syndrome and 11-year risk of incident cardiovascular disease in the atherosclerosis risk in communities study.Diabetes Care. 2005; 28: 385-390Crossref PubMed Scopus (671) Google Scholar, 4McNeill A.M. Katz R. Girman C.J. Rosamond W.D. Wagenknecht L.E. Barzilay J.I. Tracy R.P. Savage P.J. Jackson S.A. Metabolic syndrome and cardiovascular disease in older people: the cardiovascular health study.J Am Geriatr Soc. 2006; 54: 1317-1324Crossref PubMed Scopus (116) Google Scholar One of the strongest predictors of cardiovascular disease in metabolic syndrome is a low level of HDL-C.4McNeill A.M. Katz R. Girman C.J. Rosamond W.D. Wagenknecht L.E. Barzilay J.I. Tracy R.P. Savage P.J. Jackson S.A. Metabolic syndrome and cardiovascular disease in older people: the cardiovascular health study.J Am Geriatr Soc. 2006; 54: 1317-1324Crossref PubMed Scopus (116) Google Scholar Low HDL-C is one component of a constellation often referred to as “atherogenic dyslipidemia,” which also includes elevated triglycerides (TG), increased levels of remnant lipoproteins, and small, dense low-density lipoprotein (LDL) particles. The major focus of this article is to discuss the pathophysiological mechanisms underlying the strong and consistent association between obesity and atherogenic dyslipidemia.Epidemiology of Atherogenic Dyslipidemia and Relationship to CHDAtherogenic dyslipidemia, characterized primarily by elevated triglycerides and low HDL-C, is a phenotype associated with increased cardiovascular risk. Most evidence suggests that elevated fasting TG are, in fact, an independent risk factor for CHD.5Hokanson J.E. Austin M.A. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies.J Cardiovasc Risk. 1996; 3: 213-219Crossref PubMed Google Scholar, 6Austin M.A. Hokanson J.E. Edwards K.L. Hypertriglyceridemia as a cardiovascular risk factor.Am J Cardiol. 1998; : 7B-12BAbstract Full Text Full Text PDF PubMed Scopus (787) Google Scholar For example, fasting serum TG was independently associated with incidence of CHD in the Paris Prospective Study,7Cambien F. Jacqueson A. Richard J.L. Warnet J.M. Ducimetiere P. Claude J.R. Is the level of serum triglyceride a significant predictor of coronary death in “normocholesterolemic” subjects? The Paris Prospective Study.Am J Epidemiol. 1986; 124: 624-632Crossref PubMed Google Scholar the Prospective Cardiovascular Munster study,8Assmann G. Schulte H. Funke H. von Eckardstein A. The emergence of triglycerides as a significant independent risk factor in coronary artery disease.Eur Heart J. 1998; 19: M8-M14PubMed Google Scholar and the Copenhagen Male Study.9Jeppesen J. Hein H.O. Suadicani P. Gyntelberg F. Triglyceride concentration and ischemic heart disease: an eight-year follow-up in the Copenhagen Male Study.Circulation. 1998; 97 ([see comments] [published erratum appears in Circulation 1995;19:97] [see comments]): 1029-1036Crossref PubMed Google Scholar Multivariate analyses that adjust for HDL-C, obesity, diabetes, and other confounders demonstrate an attenuated relationship between elevated TG and CHD, but the relationship is usually statistically significant, especially in women. Decreased HDL-C is clearly an independent risk factor for CHD, as demonstrated in the Framingham Heart Study10Gordon T. Castelli W.P. Hjortland M.C. Kannel W.B. Dawber T.R. High density lipoprotein as a protective factor against coronary heart disease The Framingham Study.Am J Med. 1977; 62: 707-714Abstract Full Text PDF PubMed Scopus (3363) Google Scholar and confirmed in multiple other studies.11Gordon D.J. Rifkind B.M. High-density lipoproteins—the clinical implications of recent studies.N Engl J Med. 1989; 321: 1311-1316Crossref PubMed Google Scholar, 12Despres J.P. Lemieux I. Dagenais G.R. Cantin B. Lamarche B. HDL-cholesterol as a marker of coronary heart disease risk: the Quebec cardiovascular study.Atherosclerosis. 2000; 153: 263-272Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar, 13Goldbourt U. Yaari S. Medalie J.H. Isolated low HDL cholesterol as a risk factor for coronary heart disease mortality: A 21-year follow-up of 8000 men.Arterioscler Thromb Vasc Biol. 1997; 17: 107-113Crossref PubMed Google ScholarThe prevalence of atherogenic dyslipidemia, defined as abnormalities in the TG-HDL axis, is very high in patients with CHD. For example, in men with CHD screened for the Veterans Affairs High-Density Lipoprotein Intervention Trial, 33% had high TG levels (>200 mg/dL) and 64% had low HDL cholesterol levels (≤40 mg/dL).14Rubins H.B. Robins S.J. Collins D. Iranmanesh A. Wilt T.J. Mann D. Mayo-Smith M. Faas F.H. Elam M.B. Rutan G.H. et al.Department of Veterans Affairs HDL Intervention Trial Study GroupDistribution of lipids in 8,500 men with coronary artery disease.Am J Cardiol. 1995; 75: 1196-1201Abstract Full Text PDF PubMed Scopus (46) Google Scholar The prevalence of abnormalities in the TG-HDL axis in type 2 diabetic patients is also high.15Haffner S.M. Diabetes, hyperlipidemia, and coronary artery disease.Am J Cardiol. 1999; 83: 17F-21FAbstract Full Text Full Text PDF PubMed Google Scholar Even in unselected populations, atherogenic dyslipidemia is common. In the Third National Health and Nutrition Examination Survey,1Ford E.S. Giles W.H. Dietz W.H. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey.JAMA. 2002; 287: 356-359Crossref PubMed Google Scholar the prevalence of elevated TG (>150 mg/dL) was 30% and of low HDL-C levels (<40 mg/dL in men and <50 mg/dL in women) was 37%; in the same sample, the prevalence of obesity was 39%, and there was substantial overlap among these three phenotypes.Plasma lipid levels and cardiovascular risk are variable by race and ethnicity. For example, it is well established that African Americans have higher HDL-C and lower LDL-C and triglyceride levels than Americans of European descent,16Johnson J.L. Slentz C.A. Duscha B.D. Samsa G.P. McCartney J.S. Houmard J.A. Kraus W.E. Gender and racial differences in lipoprotein subclass distributions: the STRRIDE study.Atherosclerosis. 2004; 176: 371-377Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar in part due to differences in body fat distribution. Furthermore, there is a higher prevalence of atherogenic dyslipidemia in South Asians than in Caucasians,17Hoogeveen R.C. Gambhir J.K. Gambhir D.S. Kimball K.T. Ghazzaly K. Gaubatz J.W. Vaduganathan M. Rao R.S. Koschinsky M. Morrisett J.D. Evaluation of Lp[a] and other independent risk factors for CHD in Asian Indians and their USA counterparts.J Lipid Res. 2001; 42: 631-638PubMed Google Scholar thought to be in part due to a higher percentage of body fat mass.18Anand S.S. Yusuf S. Vuksan V. Devanesen S. Teo K.K. Montague P.A. Kelemen L. Yi C. Lonn E. Gerstein H. et al.Differences in risk factors, atherosclerosis, and cardiovascular disease between ethnic groups in Canada: the Study of Health Assessment and Risk in Ethnic groups (SHARE).The Lancet. 2000; 356: 279-284Abstract Full Text Full Text PDF PubMed Google Scholar, 19Dudeja V. Misra A. Pandey R.M. Devina G. Kumar G. Vikram N.K. BMI does not accurately predict overweight in Asian Indians in northern India.Br J Nutrition. 2001; 86: 105-112Crossref PubMed Google Scholar, 20Vikram N.K. Pandey R.M. Misra A. Sharma R. Rama Devi J. Khanna N. Non-obese (body mass index < 25 kg/m2) Asian Indians with normal waist circumference have high cardiovascular risk.Nutrition. 2003; 19: 503-509Abstract Full Text Full Text PDF PubMed Scopus (121) Google ScholarThus, atherogenic dyslipidemia is strongly associated with obesity, is common (∼60% of high-risk patients and ∼30% of unselected persons), and is an important risk factor for cardiovascular outcomes. Understanding the pathophysiological relationship between obesity and atherogenic dyslipidemia is of critical importance to reducing cardiovascular risk in obese persons.Physiology of Triglyceride-Rich Lipoprotein Metabolism and Interactions With Adipose TissueUptake of Lipoprotein-Derived Fatty Acids and Their Storage by Adipose TissueAdipose tissue is responsible for the coordinated uptake, storage, and release of energy in the form of triglycerides (storage) and fatty acids (uptake and release). Adipose acquires dietary fatty acids via the metabolism of triglyceride-rich lipoproteins (TRL), specifically chylomicrons. Lipids ingested via the diet are hydrolyzed within the intestinal lumen by lipases, and nonesterified fatty acids (NEFA) are transported into the enterocytes of the proximal small intestine (Figure 1). Fatty acids of >12 carbons in length are esterified by the enterocyte into triglycerides, which are packaged with apolipoprotein B-48 (apoB-48) and other lipids in a process requiring the microsomal triglyceride transfer protein (MTP) to form chylomicrons. Chylomicrons are initially secreted into the intestinal lymph and delivered via the thoracic duct directly to the systemic circulation, thus bypassing the hepatic first pass effect.21Goldberg I.J. Kako Y. Lutz E.P. Responses to eating: lipoproteins, lipolytic products and atherosclerosis.Curr Opin Lipidol. 2000; 11: 235-241Crossref PubMed Scopus (37) Google Scholar Skeletal and cardiac muscle have the ability to hydrolyze chylomicron TGs and extract fatty acids as necessary for their metabolic needs, but most of the energy in the form of chylomicron TGs is delivered to adipose tissue during the fed state for storage. In the capillaries of adipose tissue, chylomicrons encounter lipoprotein lipase (LPL), which is synthesized by the adipocytes but anchored to proteoglycans on the capillary endothelial surface (Figure 1). Chylomicrons contain apoC-II, which acts as a cofactor for LPL, triggering hydrolysis of triglycerides and release of NEFA, which are then largely taken up by adjacent adipocytes. Adipose-derived LPL expression and activity is increased in the fed state, whereas during fasting, the activity of LPL decreases in adipose tissue.22Goldberg I.J. Lipoprotein lipase and lipolysis: central roles in lipoprotein metabolism and atherogenesis.J Lipid Res. 1996; 37: 693-707Abstract Full Text PDF PubMed Google Scholar, 23Merkel M. Eckel R.H. Goldberg I.J. Lipoprotein lipase: genetics, lipid uptake, and regulation.J Lipid Res. 2002; 43: 1997-2006Crossref PubMed Scopus (343) Google Scholar Although there is uptake of circulating NEFAs by adipose, this is minor in comparison to uptake of chylomicron-TG–derived fatty acids.24Bickerton A.S.T. Roberts R. Fielding B.A. Hodson L. Blaak E.E. Wagenmakers A.J.M. Gilbert M. Karpe F. Frayn K.N. Preferential uptake of dietary fatty acids in adipose tissue and muscle in the postprandial period.Diabetes. 2007; 56: 168-176Crossref PubMed Scopus (123) Google Scholar Thus, fatty acid uptake by adipose is preferentially derived from hydrolysis of chylomicron-TG and not circulating NEFAs. In contrast to adipose, muscle-LPL is increased approximately twofold over adipose LPL in the fasting state, whereas it is decreased by about one-half in the fed state when compared to adipose LPL.25Ruge T. Svensson M. Eriksson J.W. Olivecrona G. Tissue-specific regulation of lipoprotein lipase in humans: effects of fasting.Eur J Clin Invest. 2005; 35: 194-200Crossref PubMed Scopus (28) Google Scholar Thus, LPL is up-regulated in adipose during the fed state directing dietary TRL-derived fatty acids preferentially to storage in adipose, whereas during fasting, it is down-regulated in adipose and up-regulated in muscle, directing TRL-derived fatty acids to muscle for energy utilization.Figure 1In the fed state, dietary lipids are hydrolyzed by lipases to produce NEFAs, which are re-esterified by the enterocyte into TG and packaged with apoB-48 by MTP into chylomicrons and secreted. Chylomicrons bind to endothelial LPL in adipose tissue, and apo C-II activates LPL resulting in hydrolysis of TG and generation of NEFAs. NEFAs are re-esterified by the adipocyte into TG and stored until lipolysis is activated. Resulting chylomicron remnants are targeted for hepatic catabolism.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Efficient trapping of TRL-derived NEFAs is critical for normal adipose function. This is accomplished in part through efficient facilitated transport of NEFAs across the endothelial barrier and the adipocyte plasma membrane26Large V. Peroni O. Letexier D. Ray H. Beylot M. Metabolism of lipids in human white adipocyte.Diabetes Metab. 2004; 30: 294-309Abstract Full Text PDF PubMed Google Scholar (Figure 1, Figure 2). Once FAs are taken up by the adipocyte, efficient acylation of the FAs is necessary to trap them within the adipocyte and prevent back-diffusion out of the cell (Figure 1, Figure 2). Ultimately, the final step in TG synthesis is catalyzed by the action of DGATs.27Buhman K.K. Smith S.J. Stone S.J. Repa J.J. Wong J.S. Knapp Jr, F.F. Burri B.J. Hamilton R.L. Abumrad N.A. Farese Jr, R.V. DGAT1 is not essential for intestinal triacylglycerol absorption or chylomicron synthesis.J Biol Chem. 2002; 277: 25474-25479Crossref PubMed Scopus (148) Google Scholar There are 2 known DGAT genes, DGAT1 and DGAT2, and both are expressed in adipose tissue. DGAT1-deficient mice are resistant to diet-induced obesity,28Smith S.J. Cases S. Jensen D.R. Chen H.C. Sande E. Tow B. Sanan D.A. Raber J. Eckel R.H. Farese Jr, R.V. Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat.Nat Genet. 2000; 25: 87-90Crossref PubMed Scopus (562) Google Scholar whereas adipose-specific DGAT1 over expressing mice are more obese but are not insulin resistant.29Chen H.C. Stone S.J. Zhou P. Buhman K.K. Farese Jr, R.V. Dissociation of obesity and impaired glucose disposal in mice overexpressing acyl coenzyme a: diacylglycerol acyltransferase 1 in white adipose tissue.Diabetes. 2002; 51: 3189-3195Crossref PubMed Google Scholar These studies support the concept that DGAT1 contributes to adipocyte TG synthesis and increased efficiency of FA trapping. DGAT2-deficient mice have reduced fat stores and die soon after birth, consistent with a role in DGAT2 in TG synthesis in adipose as well.30Stone S.J. Myers H.M. Watkins S.M. Brown B.E. Feingold K.R. Elias P.M. Farese Jr, R.V. Lipopenia and skin barrier abnormalities in DGAT2-deficient mice.J Biol Chem. 2004; 279: 11767-11776Crossref PubMed Scopus (311) Google Scholar Acylation-stimulating protein (ASP), generated by sequential cleavage of complement C3, has been suggested to play an important role in promoting FA acylation by adipocytes,31Maslowska M. Wang H.W. Cianflone K. Novel roles for acylation stimulating protein/C3adesArg: a review of recent in vitro and in vivo evidence.Vitam Horm. 2005; 70: 309-332Crossref PubMed Scopus (62) Google Scholar thus contributing to improved FA trapping. Its role in human physiology is still debated.Figure 2TRL TGs are hydrolyzed by LPL, and NEFAs are taken up by the adipocyte and stored as TG until there is a demand for FA release by peripheral tissues. Adipocyte TGs are hydrolyzed by HSL and ATGL. Stimulation of lipolysis occurs primarily via catecholamines such as adrenaline and noradrenaline and leads to activation of HSL. Insulin mediates antilipolytic action through the insulin receptor to promote storage of TAG within the adipocyte. Beta-hydroxybutyrate, via GPR109A, and alpha-adrenergic stimuli (not shown), are also inhibitors of lipolysis.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Lipolysis of Adipose TG and Release of NEFA by Adipose TissueDuring the fed state, energy is mobilized from adipose for use by other tissues, requiring lipolysis of stored TG (Figure 2). Adipocyte hydrolysis of TG is regulated by the enzyme hormone-sensitive lipase (HSL), an intracellular, neutral lipase that catalyzes hydrolysis of triacylglycerol (TAG) and diacylglycerol (DAG), as well as cholesteryl esters and retinyl esters.32Haemmerle G. Zimmermann R. Zechner R. Letting lipids go: hormone-sensitive lipase.Curr Opin Lipidol. 2003; 14: 289-297Crossref PubMed Scopus (40) Google Scholar HSL is predominantly expressed in white adipose tissue, but also in testes, adrenal gland, brown adipose tissue, muscle, and many other tissues. Induction of the lipolytic cascade starts with increased production of cyclic adenosine monophosphate (cyclic AMP) that activates the protein kinase A complex.33Arner P. Human fat cell lipolysis: biochemistry, regulation and clinical role.Best Pract Res Clin Endocrinol Metab. 2005; 19: 471-482Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar This allows the translocation of HSL from the cell cytosol to the surface of the lipid droplet; HSL is next phosphorylated and activated, leading to hydrolysis of TAG into diacylglycerol (DAG) and monoacylglycerol plus NEFAs.Insulin is a key negative regulator of HSL (Figure 2).33Arner P. Human fat cell lipolysis: biochemistry, regulation and clinical role.Best Pract Res Clin Endocrinol Metab. 2005; 19: 471-482Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar, 34Kraemer F.B. Shen W.-J. Hormone-sensitive lipase: control of intracellular tri-(di-)acylglycerol and cholesteryl ester hydrolysis.J. Lipid Res. 2002; 43: 1585-1594Crossref PubMed Scopus (251) Google Scholar During the fed state, insulin levels are high and HSL is inhibited, thus promoting TG storage. Conversely, during the fasted state, insulin levels are low, and HSL becomes activated, thus promoting TG hydrolysis. Positive regulation of HSL occurs via catecholamines (Figure 2). Specifically, beta-adrenergic receptor stimulation by catecholamines leads to increased cAMP and, ultimately, lipolysis via activation of HSL.35Langin D. Adipose tissue lipolysis as a metabolic pathway to define pharmacological strategies against obesity and the metabolic syndrome.Pharmacol Res. 2006; 53: 482-491Crossref PubMed Scopus (199) Google Scholar Interestingly, activation of alpha2-adrenoceptors exert antilipolytic effects on adipocytes via activation of an inhibitory G-protein.35Langin D. Adipose tissue lipolysis as a metabolic pathway to define pharmacological strategies against obesity and the metabolic syndrome.Pharmacol Res. 2006; 53: 482-491Crossref PubMed Scopus (199) Google Scholar The recently discovered nicotinic acid receptor GPR109A is another G protein-coupled receptor on adipocytes, activation of which inhibits adipocyte lipolytic activity.36Tunaru S. Kero J. Schaub A. Wufka C. Blaukat A. Pfeffer K. Offermanns S. PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect.Nat Med. 2003; 9: 352-355Crossref PubMed Scopus (476) Google Scholar, 37Offermanns S. The nicotinic acid receptor GPR109A (HM74A or PUMA-G) as a new therapeutic target.Trends Pharmacol Sci. 2006; 27: 384-390Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar This discovery has provided the molecular target for niacin action and helps to explain the ability of pharmacologic doses of niacin to suppress adipocyte release of NEFA. However, physiological concentrations of niacin are not adequate to activate GPR109A on adipocytes. An endogenous ligand of GPR109A was reported to be beta-hydroxybutyrate38Taggart A.K. Kero J. Gan X. Cai T.Q. Cheng K. Ippolito M. Ren N. Kaplan R. Wu K. Wu T.J. et al.(D)-beta-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G.J Biol Chem. 2005; 280: 26649-26652Crossref PubMed Scopus (214) Google Scholar (Figure 2). This suggests a physiology in which during ketosis, liver-derived beta-hydroxybutyrate feeds back on the adipocyte, activating GRP109A and suppresses adipocyte lipolysis and release of NEFA as a safeguard against life-threatening ketosis.Studies in HSL knockout mice have challenged the role of HSL as the sole enzyme responsible for lipolysis in adipocytes. Despite lack of rate-limiting lipolytic stimulation, these mice are not obese but have differences in adipose distribution, adipocyte size, and lipid composition within HSL-expressing tissues.32Haemmerle G. Zimmermann R. Zechner R. Letting lipids go: hormone-sensitive lipase.Curr Opin Lipidol. 2003; 14: 289-297Crossref PubMed Scopus (40) Google Scholar, 39Zimmermann R. Haemmerle G. Wagner E.M. Strauss J.G. Kratky D. Zechner R. Decreased fatty acid esterification compensates for the reduced lipolytic activity in hormone-sensitive lipase-deficient white adipose tissue.J Lipid Res. 2003; 44: 2089-2099Crossref PubMed Scopus (69) Google Scholar Also, accumulation of primarily DAG in adipocyte indicates that HSL may not be completely necessary for TAG breakdown and is likely the rate-limiting enzyme specifically for DAG breakdown.40Haemmerle G. Zimmermann R. Hayn M. Theussl C. Waeg G. Wagner E. Sattler W. Magin T.M. Wagner E.F. Zechner R. Hormone-sensitive lipase deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis.J Biol Chem. 2002; 277: 4806-4815Crossref PubMed Scopus (348) Google Scholar The presence of residual TG lipase activity in HSL-deficient adipose led to the discovery of a second hydrolytic lipase, termed adipose triglyceride lipase (ATGL),41Zimmermann R. Strauss J.G. Haemmerle G. Schoiswohl G. Birner-Gruenberger R. Riederer M. Lass A. Neuberger G. Eisenhaber F. Hermetter A. Zechner R. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase.Science. 2004; 306: 1383-1386Crossref PubMed Scopus (981) Google Scholar desnutrin,42Villena J.A. Roy S. Sarkadi-Nagy E. Kim K.H. Sul H.S. Desnutrin, an adipocyte gene encoding a novel patatin domain-containing protein, is induced by fasting and glucocorticoids: ectopic expression of desnutrin increases triglyceride hydrolysis.J Biol Chem. 2004; 279: 47066-47075Crossref PubMed Scopus (393) Google Scholar or iPLA2ζ.43Jenkins C.M. Mancuso D.J. Yan W. Sims H.F. Gibson B. Gross R.W. Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities.J Biol Chem. 2004; 279: 48968-48975Crossref PubMed Scopus (523) Google Scholar ATGL, expressed predominantly in white adipose tissue but also present in brown adipose tissue, is localized to the lipid droplet and initiates TG hydrolysis, generating DAG and NEFAs.41Zimmermann R. Strauss J.G. Haemmerle G. Schoiswohl G. Birner-Gruenberger R. Riederer M. Lass A. Neuberger G. Eisenhaber F. Hermetter A. Zechner R. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase.Science. 2004; 306: 1383-1386Crossref PubMed Scopus (981) Google Scholar In vitro, overexpression of ATGL produced enhanced lipolysis, whereas inhibition of ATGL using antisense methods reduced lipolysis.44Kershaw E.E. Hamm J.K. Verhagen L.A.W. Peroni O. Katic M. Flier J.S. Adipose triglyceride lipase: function, regulation by insulin, and comparison with adiponutrin.Diabetes. 2006; 55: 148-157Crossref PubMed Google Scholar In vivo, mouse studies have demonstrated that inhibition of ATGL led to decreased TG hydrolase activity.44Kershaw E.E. Hamm J.K. Verhagen L.A.W. Peroni O. Katic M. Flier J.S. Adipose triglyceride lipase: function, regulation by insulin, and comparison with adiponutrin.Diabetes. 2006; 55: 148-157Crossref PubMed Google Scholar Endogenous activators and inhibitors of ATGL have yet to be completely characterized.One question regarding adiposity, NEFA, and insulin resistance revolves around differential rates of lipolysis from various adipose stores, that is, visceral fat versus upper body fat, versus subcutaneous fat. This specific quantification of lipolysis is quite difficult. Studies have suggested that HSL-mediated lipolysis in gluteal fat is only one-eighth of abdominal fat and that upper body fat, including visceral fat, is strongly associated with insulin resistance and dyslipidemia. Jensen et al and Samra et al both demonstrated that NEFA concentrations in visceral fat and abdominal subcutaneous fat were similar.45Jensen M.D. Adipose tissue and fatty acid metabolism in humans.J R Soc Med. 2002; 95: 3-7Crossref PubMed Scopus (1) Google Scholar, 46Samra J.S. Sved P. Sullivan D. Hugh T.J. Smith R.C. Lipid metabolism in omental adipose tissue during operative surgery.J Surg Res. 2005; 124: 23-28Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Regardless of the origin of NEFAs, insulin regulation imposes rigid control over adipose lipolysis. In states of normal physiology, there is a large gradient between fasting and fed insulin levels, allowing greater lipolysis during the fasted state to supply NEFAs to tissues. However, in states of insulin excess, this gradient is reduced, which may help increase the threshold of lipolysis to prevent massive NEFA release into circulation.47Guo Z. Hensrud D.D. Johnson C.M. Jensen M.D. Regional postprandial fatty acid metabolism in different obesity phenotypes.Diabetes. 1999; 48: 1586-1592Crossref PubMed Scopus (140) Google Scholar, 48Karpe F. Tan G.D. Adipose tissue function in the insulin-resistance syndrome.Biochem Soc Trans. 2005; 33: 1045-1048Crossref PubMed Scopus (25) Google ScholarPathophysiology of Impaired Fatty Acid Trapping and Storage by Adipose TissueObesity and adipose insulin resistance are associated with impaired adipocyte trapping of fatty acids and excessive adipocyte lipolysis, both of which lead to increased circulating NEFAs relative to tissue requirements. As described in greater detail in the information to follow, this increased flux of NEFA from adipose tissue leads to increased uptake of NEFA by the liver, increased hepatic lipogenesis, increased hepatic very low density lipoprotein (VLDL) TG production, and atherogenic dyslipidemia (Figure 3). Obesity and insulin resistance are associated with dysregulation of LPL. Overall LPL activity is reduced in obese subjects. Although studies in obese subjects have suggested that adipose-specific LPL activity is elevated, skeletal-muscle–specific LPL activity is reduced.22Goldberg I.J. Lipoprotein lipase and lipolysis: central roles in lipoprotein metabolism and atherogenesis.J Lipid Res. 1996; 37: 693-707Abstract Full Text PDF PubMed Google Scholar, 49Yu Y.H. Ginsberg H.N. Adipocyte signaling and lipid homeostasis: sequelae of insulin-resistant adipose tissue.Circ Res. 2005; 96: 1042-1052Crossref PubMed Scopus (196) Google Scholar LPL activity increases in response to weight loss50Berman D.M. Nicklas B.J. Ryan A.S. Rogus E.M. Dennis K.E. Goldberg A.P. Regulation of lipolysis and lipoprotein lipase after weight loss in obese, postmenopausal women.Obesity Res. 2004; 12: 32-39Crossref PubMed Google Scholar and intensive insulin treatment of type 2 diabetes.51Miyashita Y. Ebisuno M. Ohhira