Abstract
Background Android fat distribution (abdominal obesity) is associated with insulin resistance, hepatic steatosis and greater secretion of large very low density lipoprotein (VLDL) particles in men. Since abdominal obesity is becoming increasingly prevalent in women we aimed to investigate the relationship between android fat and hepatic lipid metabolism in pre- and post-menopausal women. Methods and Results We used a combination of stable isotope tracer techniques to investigate intrahepatic fatty acid synthesis and partitioning in 29 lean and 29 abdominally obese women (android fat/total fat 0.065 (0.02-0.08) and 0.095 (0.08-0.11) respectively). Thirty women were pre-menopausal aged 35-45 and they were matched for abdominal obesity with 28 post-menopausal women aged 55-65. As anticipated, abdominal obese women were more insulin resistant with enhanced hepatic secretion of large (404±30 v 268±26 mg/kg lean mass, P<0.001) but not small VLDL (160±11 v 142±13). However, post-menopausal status had a pronounced effect on the characteristics of small VLDL particles which were considerably triglyceride (TG)-enriched (production ratio of VLDL2-TG:apolipoprotein B 30±5.3 v 19±1.6, P<0.05). In contrast to post-menopausal women, there was a tight control of hepatic fatty acid metabolism and TG production in pre-menopausal women, whereby oxidation (rs=-0.49, P=0.006), de novo lipogenesis (rs=0.55, P=0.003) and desaturation (rs=0.48, P=0.012) were closely correlated with abdominal obesity-driven large VLDL-TG secretion rate. Conclusions In women, abdominal obesity is a major driver of hepatic large VLDL particle secretion whereas post-menopausal status was characterised by increased small VLDL particle size. These data provide a mechanistic basis for the hyperlipidemia observed in post-menopausal obesity.