A lifetime on the hips: programming lower-body fat to protect against metabolic disease.

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-a, 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 they are well supported by populationbased studies using simple anthropometry (8). Taken together, a large body of research shows that VAT and lower-body SAT exert opposing influences on the risk of metabolic disease in humans. How does lower-body SAT protect against metabolic disease? In women with lower-body obesity, gluteal SAT (GSAT) takes up more meal-related fatty acids than in either upper-body obese women or men (9). GSAT is thought to function as a “metabolic sink,” protecting nonadipose tissues from excessive FFA exposure and development of IR (10). Once sequestered in GSAT, these lipids are relatively more resistant to mobilization than when they are stored in other depots (11). Compared with VAT and abdominal SAT (ASAT), GSAT also produces greater amounts of palmitoleate, a lipid-signaling molecule that improves insulin action in liver and skeletal muscle (12). Many key studies on GSAT have been performed by Fredrik Karpe, Keith Frayn, and colleagues at the University of Oxford (reviewed in 13). In this issue of Diabetes, these investigators extend their previous work by studying relationships between regional adiposity (measured by DEXA), IR (by HOMA-IR), and fasting plasma concentrations of insulin, triglycerides, HDL cholesterol, and CRP. Notably, the new study was conducted in a sample of 3,399 healthy adults (14). When overall adiposity was accounted for, the amount of GSAT in both males and females was negatively associated with fasting insulin, IR, and dyslipidemia. In males, GSAT was negatively associated with CRP concentrations. As in other studies (15), ASAT mass was positively correlated with both IR and dyslipidemia. To further investigate the protective effects of GSAT, transcriptomic analysis was performed in paired samples of GSAT and ASAT, an approach that revealed marked