Why Visceral Fat is Bad: Mechanisms of the Metabolic Syndrome

A consensus has emerged that fat stored in the central segment of the body is particularly damaging in that it portends greater risk for diabetes, cardiovascular disease, hypertension, and certain cancers (1–3). It is also accepted that insulin resistance is a related characteristic that may be an essential link between central fat and disease risk. Additionally, it is possible that the hyperinsulinemia that accompanies insulin resistance in non-diabetic but at-risk individuals may magnify, or even mediate, some of the detrimental effects of visceral adiposity (4–6). However, there is less information regarding the mechanisms that may link visceral fat with risk for disease. For example, there is controversy regarding the specific mechanisms by which fat in the visceral compartment confers greater risk than subcutaneous fat. Many investigators have suggested that one or more moieties secreted by the visceral adipocyte might mediate insulin resistance. Among the socalled “bad actors” are free fatty acids (FFAs) themselves (“portal theory”) (7–9) or the adipose tissue–released cytokines (adipokines) such as interleukin-1, interleukin-6, tumor necrosis factor, resistin, or a reduction in adiponectin, which has been repeatedly shown to be associated with reduced insulin resistance (10–13). Of course, insulin itself could be involved, as other adipose-secreted protein compounds not yet identified. But why visceral fat? Is it because of the unique anatomical position of the visceral fat depot, with effluent entering the liver, or is it because of molecular characteristics of visceral fat itself, which may favor release of damaging molecules into the systemic circulation? These questions remain unanswered. However, in our laboratory, we have developed the obese dog model, which has led to some understanding of the pathogenesis of the metabolic syndrome. The dog model has not been widely used for the study of the metabolic syndrome, but we have found it to have several important characteristics that we have been able to exploit: the ability to make longitudinal measurements and the ability to access the portal vein. In that sense the dog is a unique model, in that these latter measurements are daunting in rodents, and carrying out repetitive, invasive clinical measurements in non-human primates is challenging. Also, the dog with visceral obesity has turned out to be a reasonable model for a similar syndrome in humans (Figure 1). In fact, the dog is genetically more similar to humans than is the rodent. Here we summarize a significant amount of evidence in which we examined what we considered to be the simplest hypothesis composed of two postulates: 1) that FFAs per se are among the most important products of the visceral adipocyte to cause insulin resistance (and hence the metabolic syndrome) and 2) that the anatomical position of the visceral adipose depot (i.e., portal drainage into the liver) plays an important role in the pathogenesis of the metabolic syndrome. While we cannot say that these postulates are proven, there are data that support them, and Occam’s razor instructs us to accept them until proven untrue. Whether true or not, it appears that examining them has led us to a deeper understanding of the physiological basis for the metabolic syndrome itself. One similarity between dogs and humans is the wide variance in fat deposition in a “wild” or “natural” population. We measure distribution of fat about the truncal region using magnetic resonance imaging [Figure 2; 11 axial slices: 1-cm landmark slice at the umbilicus (left renal artery) 5 cm]. Similar to human subjects (14,15), there is surprising variability in distribution. Some animals are strikingly lean, with total fat varying over a factor of 5, from 10 to 50 cm/cm non-fat tissue. Interestingly, there is a tendency for visceral adiposity to increase rapidly as one examines animals with increasing body fat; the visceral fat depot tends to plateau, and subcutaneous fat increases more rapidly with overall obesity. This tendency for visceral fat to Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California. Address correspondence to Richard N. Bergman, Department of Physiology and Biophysics, MMR 630, 1333 San Pablo Street, Los Angeles CA 90033. E-mail: rbergman@usc.edu Copyright © 2006 NAASO