Samantha Hocking, Dorit Samocha-Bonet, Kerry-Lee Milner, Jerry R. Greenfield, and Donald J. Chisholm
Garvan Institute of Medical Research (S.H., D.S.-B., K.-L.M., J.R.G., D.J.C.), Darlinghurst, New South Wales 2010, Sydney, Australia; Department of Endocrinology (S.H.), Royal North Shore Hospital, Sydney, New South Wales 2065, Australia; Department of Medicine (D.S.-B., K.-L.M., J.R.G., D.J.C.), University of New South Wales, Sydney, New South Wales 2052, Australia; Department of Endocrinology (K.-L.M.), Prince of Wales Hospital, Sydney, New South Wales 2031, Australia; and Department of Endocrinology (J.R.G., D.J.C.), St Vincent’s Hospital, Sydney, New South Wales 2010, Australia.
Human adiposity has long been associated with insulin resistance and increased cardiovascular risk, and abdominal adiposity is considered particularly adverse. Intra-abdominal fat is associated with insulin resistance, possibly mediated by greater lipolytic activity, lower adiponectin levels, resistance to leptin, and increased inflammatory cytokines, although the latter contribution is less clear. Liver lipid is also closely associated with, and likely to be an important contributor to, insulin resistance, but it may also be in part the consequence of the lipogenic pathway of insulin action being up-regulated by hyperinsulinemia and unimpaired signaling. Again, intramyocellular triglyceride is associated with muscle insulin resistance, but anomalies include higher intramyocellular triglyceride in insulin-sensitive athletes and women (vs men). Such issues could be explained if the “culprits” were active lipid moieties such as diacylglycerol and ceramide species, dependent more on lipid metabolism and partitioning than triglyceride amount. Subcutaneous fat, especially gluteofemoral, appears metabolically protective, illustrated by insulin resistance and dyslipidemia in patients with lipodystrophy. However, some studies suggest that deep sc abdominal fat may have adverse properties. Pericardial and perivascular fat relate to atheromatous disease, but not clearly to insulin resistance. There has been recent interest in recognizable brown adipose tissue in adult humans and its possible augmentation by a hormone, iris in, from exercising muscle. Brown adipose tissue is metabolically active, oxidizes fatty acids, and generates heat but, because of its small and variable quantities, its metabolic importance in humans under usual living conditions is still unclear.
In the general population, a powerful correlation between insulin resistance and adiposity has been long recognized; this relationship applies, at least in univariate analysis, to all lipid depots with, not surprisingly, strong correlations between the various lipid depots themselves. Therefore, these data alone are relatively unhelpful in determining insulin resistance causation. For a long time, there has been great interest in the question of whether body fat distribution was an important determinant of metabolic characteristics, including insulin resistance, and consequential deleterious health outcomes including diabetes and cardiovascular disease; this relationship of insulin resistance, abdominal obesity, dysglycemia, dyslipidemia, and hypertension has been referred to as the “insulin resistance syndrome” or, more recently, the metabolic syndrome; it has additional associations, including nonalcoholic fatty liver disease. Early work of Vague and others suggested an adverse effect of upper body, or “android,” compared with lower body, or “gynoid,” adiposity on components of the metabolic syndrome. Progressing our understanding of this issue and dissecting potentially causative relationships is dependent on careful analyses of human studies of the general population, assessment of unusual human disorders, and extrapolation from relevant animal studies.