Abdominal Obesity: Role in the Pathophysiology of Metabolic Disease and Cardiovascular Risk Richard N. Bergman, PhD, Stella P. Kim, BS, Isabel R. Hsu, MS, Karyn J. Catalano, MS, Jenny D. Chiu, BS, Morvarid Kabir, PhD, Joyce M. Richey, PhD, and Marilyn Ader, PhD Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA ABSTRACT Visceral adiposity has been identified as an independent risk factor for cardiovascular disease and the so-called metabolic syndrome. The canine obesity model closely recapitulates the correlation between human visceral adiposity and insulin resistance. A recent canine study indicates that insulin expands the volume of distribution associated with skeletal muscle, and that its ability to enhance macromolecular distribution within this space is blunted in the fat-fed obese canine model. Our canine study supports the portal theory of insulin resistance, in which free fatty acids (FFAs) from visceral fat directly enter the liver and have a detrimental effect on insulin action. The role of adipokines in this condition remains less clear. Sympathetic nervous system hyperactivity in obesity may also contribute to excessive FFA release, hypertension, and insulin resistance. Pathologies interrelated with insulin resistance include -cell hyper- secretion, reduced insulin clearance, and resultant hyperinsulinemia. An observed nocturnal increase in plasma FFA levels may account for both insulin resistance and compensatory hyperinsulinemia and warrants further investigation. The elucidation of these interrelated pathologies may help reveal points where medical intervention can reduce metabolic disease. © 2007 Elsevier Inc. All rights reserved. KEYWORDS: Free fatty acids; Insulin resistance; Metabolic syndrome; Obesity Accumulating evidence supports an association among obe- sity, insulin resistance, and risk factors for chronic diseases. 1,2 The latter category includes impaired glucose tolerance and diabetes mellitus; cardiovascular disease (CVD) and hyperten- sion; and certain cancers, including breast, prostate, and colon cancers. 3,4 These associations have been given several names, including the metabolic syndrome, 5 syndrome X, 6 the plu- rimetabolic syndrome, 7 and the cardiometabolic syndrome. 8 The latter 2 designations have been useful for clinical pur- poses, because they have allowed physicians to identify a cluster of risk factors in their patients and to encourage lifestyle modifications to reduce risk. However, there has been recent criticism of the concept of a metabolic syndrome, with sug- gestions instead that there is no single etiology for these several chronic diseases and that they cluster with no special causali- ty. 9 It is possible that the idea was too all-encompassing, and that only some of the chronic diseases that comprise the met- abolic syndrome should be considered. Nevertheless, the con- cept is useful for understanding the pathophysiology of disease (Figure 1). PATHOGENESIS OF THE METABOLIC SYNDROME: THE ROLE OF VISCERAL FAT The pathogenesis of the metabolic syndrome remains unclear (Figure 1). It is likely that fat storage in the visceral depot is particularly offensive, 10,11 although the particular relevance of fat in the omental and mesenteric depots remains controver- sial. 12 However, it is clear that visceral fat is more closely correlated with insulin resistance than with overall obesity, suggesting its particular role in the syndrome. Visceral fat, quantified as waist size, has been identified as an independent risk factor for insulin resistance, CVD, hypertension, and stroke, 13-15 but the mechanisms that account for the particu- larly deleterious effects of visceral fat remain controversial. The Canine Obesity Model of Visceral Adiposity. The use of animal models is 1 approach to examining the patho- physiologic mechanisms accounting for danger of visceral fat. Although rodent models have been particularly useful owing to our ability to manipulate rodent genetics, they have some Requests for reprints should be addressed to Richard N. Bergman, PhD, Department of Physiology/Biophysics, MMR 630, Keck School of Medi- cine, University of Southern California, 1333 San Pablo Street, Los An- geles, California 90033. E-mail address: rbergman@usc.edu. 0002-9343/$ -see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2006.11.012 The American Journal of Medicine (2007) Vol 120 (2A), S3–S8