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OBJECTIVELipotoxicity and ectopic fat deposition reduce insulin signaling. It is not clear whether excess fat deposition in nonadipose tissue arises from excessive fatty acid delivery from adipose tissue or from impaired adipose tissue storage of ingested fat.RESEARCH DESIGN AND METHODSTo investigate this we used a whole-body integrative physiological approach with multiple and simultaneous stable-isotope fatty acid tracers to assess delivery and transport of endogenous and exogenous fatty acid in adipose tissue over a diurnal cycle in lean (n = 9) and abdominally obese men (n = 10).RESULTSAbdominally obese men had substantially (2.5-fold) greater adipose tissue mass than lean control subjects, but the rates of delivery of nonesterified fatty acids (NEFA) were downregulated, resulting in normal systemic NEFA concentrations over a 24-h period. However, adipose tissue fat storage after meals was substantially depressed in the obese men. This was especially so for chylomicron-derived fatty acids, representing the direct storage pathway for dietary fat. Adipose tissue from the obese men showed a transcriptional signature consistent with this impaired fat storage function.CONCLUSIONSEnlargement of adipose tissue mass leads to an appropriate downregulation of systemic NEFA delivery with maintained plasma NEFA concentrations. However the implicit reduction in adipose tissue fatty acid uptake goes beyond this and shows a maladaptive response with a severely impaired pathway for direct dietary fat storage. This adipose tissue response to obesity may provide the pathophysiological basis for ectopic fat deposition and lipotoxicity.

Most tumors have an aberrantly activated lipid metabolism 1 , 2 , which enables them to synthesize, elongate and desaturate fatty acids to support proliferation. However, only particular subsets of cancer cells are sensitive toward approaches targeting fatty acid metabolism, and in particular fatty acid desaturation 3 . This suggests that many cancer cells harbor an unexplored plasticity in their fatty acid metabolism. Here, we discover that some cancer cells can exploit an alternative fatty acid desaturation pathway. We identify various cancer cell lines, murine hepatocellular carcinomas (HCC), and primary human liver and lung carcinomas that desaturate palmitate to the unusual fatty acid sapienate to support membrane biosynthesis during proliferation. Accordingly, we found that sapienate biosynthesis enables cancer cells to bypass the known stearoyl-CoA desaturase (SCD)-dependent fatty acid desaturation. Thus, only by targeting both desaturation pathways the in vitro and in vivo proliferation of sapienate synthesizing cancer cells is impaired. Our discovery explains metabolic plasticity in fatty acid desaturation and constitutes an unexplored metabolic rewiring in cancers.

OBJECTIVE Nonalcoholic fatty liver disease (i.e., increased intrahepatic triglyceride [IHTG] content), predisposes to type 2 diabetes and cardiovascular disease. Adipose tissue lipolysis and hepatic de novo lipogenesis (DNL) are the main pathways contributing to IHTG. We hypothesized that dietary macronutrient composition influences the pathways, mediators, and magnitude of weight gain-induced changes in IHTG. RESEARCH DESIGN AND METHODS We overfed 38 overweight subjects (age 48 ± 2 years, BMI 31 ± 1 kg/m2, liver fat 4.7 ± 0.9%) 1,000 extra kcal/day of saturated (SAT) or unsaturated (UNSAT) fat or simple sugars (CARB) for 3 weeks. We measured IHTG (1H-MRS), pathways contributing to IHTG (lipolysis ([2H5]glycerol) and DNL (2H2O) basally and during euglycemic hyperinsulinemia), insulin resistance, endotoxemia, plasma ceramides, and adipose tissue gene expression at 0 and 3 weeks. RESULTS Overfeeding SAT increased IHTG more (+55%) than UNSAT (+15%, P < 0.05). CARB increased IHTG (+33%) by stimulating DNL (+98%). SAT significantly increased while UNSAT decreased lipolysis. SAT induced insulin resistance and endotoxemia and significantly increased multiple plasma ceramides. The diets had distinct effects on adipose tissue gene expression. CONCLUSIONS Macronutrient composition of excess energy influences pathways of IHTG: CARB increases DNL, while SAT increases and UNSAT decreases lipolysis. SAT induced the greatest increase in IHTG, insulin resistance, and harmful ceramides. Decreased intakes of SAT could be beneficial in reducing IHTG and the associated risk of diabetes.

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on behalf of the WELCOME Study InvestigatorsThere is no licensed treatment for nonalcoholic fatty liver disease (NAFLD), a condition that increases risk of chronic liver disease, type 2 diabetes, and cardiovascular disease. We tested whether 15-18 months of treatment with docosahexaenoic acid (DHA) plus eicosapentaenoic acid (EPA; Omacor/Lovaza, 4 g/day) decreased liver fat and improved two histologically validated liver fibrosis biomarker scores (primary outcomes). Patients with NAFLD were randomized in a double-blind, placebo-controlled trial (DHA1EPA, n 5 51; placebo, n 5 52). We quantified liver fat percentage by magnetic resonance spectroscopy in three liver zones. We measured liver fibrosis using two validated scores. We tested adherence to the intervention (Omacor group) and contamination (with DHA and EPA; placebo group) by measuring erythrocyte percentage DHA and EPA enrichment (gas chromatography). We undertook multivariable linear regression to test effects of (1) DHA1EPA treatment (intention-to-treat analyses) and (2) erythrocyte DHA and EPA enrichment (secondary analysis). Median (interquartile range) baseline and end-of-study liver fat percentage were 21.7 (19.3) and 19.7 (18.0) (placebo) and 23.0 (36.2) and 16.3 (22.0) (DHA1EPA). In the fully adjusted regression model, there was a trend toward improvement in liver fat percentage with DHA1EPA treatment (b 5 23.64; 95% confidence interval [CI]: 28.0, 0.8; P 5 0.1), but there was evidence of contamination in the placebo group and variable adherence to the intervention in the Omacor group. Further regression analysis showed that DHA enrichment was independently associated with a decrease in liver fat percentage (for each 1% enrichment: b 5 21.70; 95% CI: 22.9, 20.5; P 5 0.007). No improvement in fibrosis scores occurred. Conclusion: Erythrocyte DHA enrichment with DHA1EPA treatment is linearly associated with decreased liver fat percentage. Substantial decreases in liver fat percentage can be achieved with high-percentage erythrocyte DHA enrichment in NAFLD. (HEPATOLOGY 2014;60:1211-1221

Aims/hypothesis Previous studies have shown relationships between fatty acid ratios in adipose tissue triacylglycerol (TG), adipocyte size and measures of insulin sensitivity. We hypothesised that variations in adipose tissue de novo lipogenesis (DNL) in relation to adiposity might explain some of these observations. Methods In a cross-sectional study, subcutaneous abdominal adipose tissue biopsies from 59 people were examined in relation to fasting and post-glucose insulin sensitivity. Adipocyte size, TG fatty acid composition and mRNA expression of lipogenic genes were determined. Results We found strong positive relationships between adipose tissue TG content of the fatty acids myristic acid (14:0) and stearic acid (18:0) with insulin sensitivity (HOMA model) (p<0.01 for each), and inverse relationships with adipocyte size (p<0.01, p<0.05, respectively).

Parallel activation of DNL and SCD was found after a short period of HC feeding.