No abstract

To determine whether increased lipogenesis contributes to human obesity, we measured (postabsorptive state), in lean and obese subjects, lipid synthesis (deuterated water method) and the mRNA concentration (RT-competitive PCR) in subcutaneous adipose tissue of fatty acid synthase (FAS) and sterol regulatory element-binding protein (SREBP)-1c. Before energy restriction, obese subjects had an increased contribution of hepatic lipogenesis to the circulating triglyceride pool (14.5 +/- 1.3 vs. 7.5 +/- 1.9%, P < 0.01) without enhancement of cholesterol synthesis. This increased hepatic lipogenesis represented an excess of 2-5 g/day of triglycerides, which would represent 0.7-1.8 kg on a yearly basis. The lipogenic capacity of adipose tissue appeared, on the contrary, decreased with lower FAS mRNA levels (P < 0.01) and a trend for decreased SREBP-1c mRNA (P = 0.06). Energy restriction in obese patients decreased plasma insulin (P < 0.05) and leptin (P < 0.05) and normalized hepatic lipogenesis. FAS mRNA levels were unchanged, whereas SREBP-1c increased. In conclusion, subjects with established obesity have an increased hepatic lipogenesis that could contribute to their excessive fat mass but no evidence for an increased lipogenic capacity of adipose tissue.

The addition of high-performance inulin to a moderately high-carbohydrate, low-fat diet has a beneficial effect on plasma lipids by decreasing hepatic lipogenesis and plasma triacylglycerol concentrations. These results support the use of nondigestible carbohydrate for reducing risk factors for atherosclerosis.

No abstract

No abstract

We assessed the contributions of human liver and adipose tissue de novo lipogenesis (DNL) to triacylglycerol (TAG) synthesis. Volunteers were fed a high-energy, highcarbohydrate diet (HC, n ‫؍‬ 5) or a normocaloric diet (NC, n ‫؍‬ 10). NC subjects remained in the fasting state (Study 1, n ‫؍‬ 5) or received oral glucose (Study 2, n ‫؍‬ 5) throughout the test (12 h). HC subjects remained in the fasting state

Pancreatic b-cell dysfunction is central to the pathogenesis of type 2 diabetes and may involve secretory failure through glucolipotoxity. The relative importance of the transcription factors carbohydrate-responsive element binding protein (ChREBP), sterol-responsive element binding protein-1c (SREBP-1c), and upstream stimulatory factor (USF) in the induction of lipogenic genes by glucose remains unclear. By confocal imaging, we show that ChREBP translocates to the nucleus in MIN6 b cells in response to glucose. Both ChREBP and SREBP-1c were required for the induction of the fatty acid synthase (FAS) promoter by glucose, and chromatin immunoprecipitation (ChIP) assay revealed that glucose induced the binding of both ChREBP and SREBP-1c to the FAS promoter without affecting USF2 binding. By contrast, ChIP assay revealed that high glucose prompted direct binding of ChREBP, but not SREBP-1c or USF2, to the liver-type pyruvate kinase (L-PK) promoter. This event was indispensable for the induction of the L-PK gene by glucose, as demonstrated by RNA silencing, single-cell promoter analysis, and quantitative real-

To measure 1) the contribution of hepatic de novo lipogenesis (DNL) and plasma free fatty acid (FFA) reesterification to plasma triglyceride (TG) secretion, and 2) the role of oxidation and hepatic and extrahepatic reesterification in FFA utilization, five normal subjects drank deuterated water and were infused (postabsorptive state) with [1-13C]palmitate and [1,2,3-2H5]glycerol. Total lipid oxidation (Lox) was measured by indirect calorimetry. FFA oxidation (2.76 ± 0.65 μmol ⋅ kg−1 ⋅ min−1) accounted for 45% of FFA turnover rate (Rt) (1.04 μmol ⋅ kg−1 ⋅ min−1) and 91% of Lox; FFA reesterification was 3.27 ± 0.54 μmol ⋅ kg−1 ⋅ min−1. Fractional and absolute TG Rt were 0.21 ± 0.02 h−1 and 0.11 ± 0.05 μmol ⋅ kg−1 ⋅ min−1. DNL accounted for 3.9 ± 0.9% of TG secretion, and hepatic FFA reesterification accounted for 49.4 ± 5.7%; this last process represented a utilization of FFA of 0.16 ± 0.02 μmol ⋅ kg−1 ⋅ min−1. We conclude that, in the postabsorptive state, 1) DNL and FFA reesterification account for only 50–55% of TG secretion, the remaining presumably being provided by stored lipids or lipoproteins taken up by liver, 2) most reesterification occurs in extrahepatic tissues, and 3) oxidation and reesterification each contribute about one-half to FFA utilization; FFA oxidation accounts for almost all Lox.