Hepatic De Novo Lipogenesis in Obese Youth Is Modulated by a Common Variant in the GCKR Gene

Abstract

Objective: This study's aim was to evaluate whether the GCKR rs1260326 variant increases hepatic de novo lipogenesis (DNL).

Setting and design: To test this hypothesis, 14 adolescents, seven homozygous for the common allele (CC) and seven homozygous for the risk allele (TT), underwent measurement of hepatic DNL during the fasting state and after consumption of a carbohydrate (CHO) drink (75 g glucose and 25 g fructose). DNL was assessed through incorporation of deuterium in the palmitate contained in the very low-density lipoprotein.

Results: Subjects with TT demonstrated higher fasting fractional DNL (P = .036) and a lower increase in fractional DNL after the CHO challenge (P = .016). With regard to absolute lipogenesis, TT subjects had both higher fasting rates (P = .015) and 44% greater area under the curve of absolute lipogenesis during the study (P = .016), compared to CC subjects. Furthermore, subjects carrying the TT genotype showed higher basal rates of glucose oxidation (P = .0028) and a lower ability than CC subjects to increase the rates of glucose oxidation after the CHO load (P = .054).

Conclusions: This study reports for the first time rates of DNL in obese adolescents and suggests that the GCKR rs1260326 gene variant, which is associated with greater glycolysis, increases hepatic DNL. These data highlight the role of glycolytic carbon flux in liver lipid synthesis and hypertriglyceridemia in these youngsters.

Figures

Figure 1.

The design of the study to assess DNL.

Figure 2.

Changes in concentrations of plasma metabolites. Values represent mean ± SEM, showing changes in glucose (A), insulin (B), glycerol (C), free fatty acids (D), lactate (E), and delta lactate (F) associated with the CHO challenge (75 g glucose + 75 g fructose). The dashed lines represent the TT subjects, and each data point is shown as a closed square; the continuous lines represent the CC, and each data point is represented by an open circle. F, White bar represents the CC, and black bar represents the TT. The groups were compared by a paired t test. P values are given only for statistically significant comparisons.

Figure 3.

Changes in VLDL-TG concentration and fractional and absolute DNL. Values are mean ± SEM data for the plasma concentration of VLDL-TG (A), area under the curve (AUC) of VLDL-TG (B), fractional DNL (C), delta increase DNL (D), rates of absolute lipogenesis (E), and AUC of the rates of absolute lipogenesis (F) according to the GCKR rs1260326 genotypes. The dashed lines represent the TT, and each time point is shown as a closed square; the continuous lines represent the CC, and each time point is represented by an open circle. White bars represent the CC, and black bars represent the TT. The groups were compared by a paired t test. P values are given only for statistically significant comparisons.

Figure 4.

Changes in RQ and REE during the study. In the upper panels are described the basal RQ (A), the RQ after the glucose/fructose load (B), and the delta RQ (C). In the lower panels are shown the basal REE (D), the REE after the glucose/fructose load (E), and the delta REE (F). Values are expressed as mean ± SEM. The groups were compared by a paired t test. P values are given only for statistically significant comparisons.

Figure 5.

Rates of glucose and lipid oxidation during the study. Values are expressed as mean ± SEM. Upper panels describe the rates of glucose oxidation during the fasting state (A) and after the glucose/fructose load (B), as well as the absolute changes in the rates of glucose oxidation (C). In the lower panels are shown the fasting rates of lipid oxidation (D), the rates of lipid oxidation after the glucose/fructose load (E), and the change in rates of lipid oxidation (F). The groups were compared by a paired t test. P values are given only for statistically significant comparisons.