A Lifetime on the Hips: Programming Lower-Body Fat to Protect Against Metabolic Disease

Abstract

In the 60 years since Vague (1) described that an “android” pattern of adipose tissue (AT) distribution was associated with diabetes, atherosclerosis, gout, and kidney stones, many of the physiological mechanisms underlying this relationship have been illuminated. To date, most of the effort has been directed at understanding how accumulation of intra-abdominal fat, also known as visceral AT (VAT), promotes insulin resistance (IR). IR is the common defect underlying glucose intolerance, central obesity, dyslipidemia, and hypertension. This phenotypic cluster, called the metabolic syndrome, is associated with a doubling of cardiovascular disease risk and a fivefold increased risk of type 2 diabetes (2). VAT is likely to promote IR in several ways. Enlarged adipocytes in VAT were originally thought to promote hepatic, and eventually systemic, IR via increased portal free fatty acid (FFA) flux (3). Other factors are likely to be involved, however, because although FFA flux from VAT does increase in obesity, it is not the major determinant of portal FFA concentrations (4). In obesity, VAT also may contribute to IR via alterations in its secreted products (adipokines), as well as proinflammatory molecules such as tumor necrosis factor-α, interleukin-6 (IL-6), C-reactive protein (CRP), and monocyte chemoattractant protein-1 (MCP-1) (5). Independently of VAT, parallel studies have established that a gynoid pattern of AT distribution, characterized by greater amounts of subcutaneous AT (SAT) in the lower body, is associated with improved glucose tolerance and lipid profile and that this fat pattern may protect against cardiovascular disease (6,7). These protective effects often vary with sex, but …