LAUSR

Objective: Adipose tissue dysfunction may be a pathophysiological factor promoting cardiovascular disease due to altered lipid metabolism in fat cells. We previously showed that impaired ability to mobilize lipids from adipocytes following catecholamine stimulation links adipose tissue to cardio-metabolic disease (J Clin Invest, 1995 and Nature, 2011). If such defects also involve effects of the major anabolic hormone insulin is unknown and was presently examined. Design and method: Abdominal subcutaneous adipose tissue was obtained from 555 women and 167 men who were scored for cardiovascular risk factors according to ATP III criteria. Insulin-stimulated lipogenesis (lipid synthesis from glucose) and insulin-inhibited lipolysis (hydrolysis of neutral lipids) were determined in vitro in isolated fat cells. Half maximum effects (sensitivity) and maximum effects (responsiveness) for insulin were determined and related to ATPIII risk score in multivariate analysis adjusting for age, gender and either body mass index (BMI) or fat cell size. Results: Independently of age, sex and BMI, ATPIII score was negatively correlated with sensitivity as well as responsiveness (&bgr;-values 0.13–0.30) of insulin inhibition of lipolysis and stimulation of lipogenesis. Similar results were obtained if associations were corrected for fat cell size instead of BMI. Together variations in the sensitivity and responsiveness of insulin action on fat cell lipid metabolism explained as much as 25% of the variation in ATPIII scores (adjusted r2). Variation in insulin sensitivity reflects changes in initial insulin signal events (receptor number, affinity and coupling) whereas changes in insulin responsiveness reflect distal events in hormone signaling that are beyond the receptor. Because insulin signaling to lipolysis and lipogenesis diverge after phosphoinositide 3-kinase, the results suggest that the negative association between ATPIII and insulin action is attributed to multiple changes in hormone signaling, possibly involving its receptor and/or the insulin receptor substrate proteins in addition to phosphoinositide 3-kinase. Conclusions: Increased cardiovascular risk is strongly linked to resistance of the major metabolic actions of insulin in subcutaneous human fat cells. This is independent of age, sex, BMI and fat cell size. The mechanisms behind the resistance are currently studied and preliminary data will be reported.