ApoB-lipoproteins and dysfunctional white adipose tissue: Relation to risk factors for type 2 diabetes in humans

Abstract

Elevated plasma apoB is an independent predictor of T2D; however, underlying mechanisms remain unclear. Chronic reduction in white adipose tissue (WAT) function promotes T2D. We reported that differentiation of preadipocytes and acute incubation of human WAT with LDL induce their dysfunction (decreased hydrolysis and storage of triglyceride-rich lipoproteins [TRL]). To examine the hypothesis that the association of plasma apoB with T2D risk factors, hypertriglyceridemia (hyperTG), insulin resistance (IR), and hyperinsulinemia, was dependent on WAT dysfunction. Thirty normoglycemic subjects were enrolled (≥27kg/m2, 45-74years). Fasting gynoid WAT biopsy was obtained followed by the ingestion of a 13C-triolein-labeled-high-fat meal. WAT function was measured exvivo as the hydrolysis and storage of 3H-triolein-labeled-TRL as 3H-lipids over 4 hours. Insulin sensitivity and secretion were measured by Botnia clamps. WAT function correlated with higher insulin sensitivity (M/Iclamp r=0.60) and faster plasma clearance of chylomicrons in women (iAUC6hrs apoB48, r=-0.60). Plasma apoB correlated with WAT dysfunction (r=-0.52), postprandial hyperTG (iAUC6hrs-TG, r=0.51, 13C-TG, r=0.48), IR (M/Iclamp r=-0.38) and hyperinsulinemia (second phase-glucose-induced-insulin-secretion, r=0.41). Co-incubation of subjects' WAT with their LDL increased medium accumulation of 3H-TRL and 3H-NEFA with no sex differences. Adjusting for WAT function eliminated the association of plasma apoB with IR independent of sex and body fat or adipocyte diameter. Its association with other risk factors was unaffected. Association of plasma apoB with IR in obese subjects is dependent on gynoid WAT dysfunction. We propose that targeting hyperapoB, without increasing their uptake into nonhepatic peripheral tissues, ameliorates WAT function and risk for T2D.