Relatively low endogenous fatty acid mobilization and uptake helps preserve insulin sensitivity in obese women

BACKGROUND: Although obesity is commonly linked with metabolic disease risk, some obese adults do not develop metabolic abnormalities, such as insulin resistance. OBJECTIVES: The primary aim of this study was to determine whether alterations in fatty acid mobilization and uptake underlie differences in insulin sensitivity (S-i) among a seemingly homogeneous cohort of obese women. METHODS: Insulin sensitivity (frequently sampled intravenous glucose tolerance test), basal fatty acid rate of disappearance from plasma (Rd), resting whole-body fat oxidation, intramyocellular triacylglycerol (IMTG) concentration and markers of skeletal muscle inflammation were measured in 21 obese women. Participants were divided into tertiles based on their S-i. The subset of participants with the lowest S-i (LOW-S-i; S-i <= 2.1 (mU/l)(-1) min(-1); n = 7) was compared with the subset of participants with the highest S-i, who exhibited relatively normal insulin sensitivity (NORM-S-i; S-i <= 3.4 (mU/l)(-1) min(-1); n = 8). RESULTS: Despite nearly identical physical characteristics in LOW-S-i vs NORM-S-i (body mass index: 34 +/- 2 vs 34 +/- 1 kg m(-2); % body fat: 48 +/- 1 vs 47 +/- 1%; waist circumference: 104 +/- 2 vs 104 +/- 2 cm; VO2 max: 2.2 +/- 0.2 vs 2.3 +/- 0.1 l min(-1)), fatty acid Rd was nearly 30% lower in NORM (P = 0.02). Importantly, the greater rate of fatty acid uptake in LOW-S-i vs NORM-S-i did not translate to higher rate of fat oxidation (3.5 +/- 0.2 vs 3.7 +/- 0.2 mu mol kg(-1) min(-1)) or to a measureable difference in IMTG content (68.3 +/- 12.7 vs 63.7 +/- 6.7 mu mol g(-1) dry weight). In conjunction with the lower fatty acid Rd in NORM-S-i vs LOW-S-i, activation of inflammatory pathways known to impair insulin action in skeletal muscle was also lower (lower phosphorylated c-jun N-terminal kinase (JNK) and higher inhibitor of kappa B (I kappa B-alpha) abundance). In contrast, LOW-S-i and NORM-S-i exhibited no differences in plasma markers of inflammation (TNF alpha, IL-6 (interleukin-6), MCP-1). CONCLUSION: These findings suggest that obese women who maintain a relatively low rate of endogenous fatty acid uptake may be somewhat 'protected' against the development of insulin resistance potentially by less activation of inflammatory pathways within skeletal muscle.