PPARalpha L162V underlies variation in serum triglycerides and subcutaneous fat volume in young males

Abstract

Background: Of the five sub-phenotypes defining metabolic syndrome, all are known to have strong genetic components (typically 50-80% of population variation). Studies defining genetic predispositions have typically focused on older populations with metabolic syndrome and/or type 2 diabetes. We hypothesized that the study of younger populations would mitigate many confounding variables, and allow us to better define genetic predisposition loci for metabolic syndrome.

Methods: We studied 610 young adult volunteers (average age 24 yrs) for metabolic syndrome markers, and volumetric MRI of upper arm muscle, bone, and fat pre- and post-unilateral resistance training.

Results: We found the PPARalpha L162V polymorphism to be a strong determinant of serum triglyceride levels in young White males, where carriers of the V allele showed 78% increase in triglycerides relative to L homozygotes (LL = 116 +/- 11 mg/dL, LV = 208 +/- 30 mg/dL; p = 0.004). Men with the V allele showed lower HDL (LL = 42 +/- 1 mg/dL, LV = 34 +/- 2 mg/dL; p = 0.001), but women did not. Subcutaneous fat volume was higher in males carrying the V allele, however, exercise training increased fat volume of the untrained arm in V carriers, while LL genotypes significantly decreased in fat volume (LL = -1,707 +/- 21 mm3, LV = 17,617 +/- 58 mm3 ; p = 0.002), indicating a systemic effect of the V allele on adiposity after unilateral training. Our study suggests that the primary effect of PPARalpha L162V is on serum triglycerides, with downstream effects on adiposity and response to training.

Conclusion: Our results on association of PPARalpha and triglycerides in males showed a much larger effect of the V allele than previously reported in older and less healthy populations. Specifically, we showed the V allele to increase triglycerides by 78% (p = 0.004), and this single polymorphism accounted for 3.8% of all variation in serum triglycerides in males (p = 0.0037).

Figure 1

3D determination of fat volume. Rapidia determination of subcutaneous fat volume. Panel A: the pink selected area shows the subcutaneous fat of one of the six slices measured in the right arm. The red arrow shows the epypheseal flare (anatomical landmark used as the starting point of fat determination). Panel B: Left arm, the pink area shows the subcutaneous fat volume for other subject. Panel C and D represent the 3D image of panel A and B.

Figure 2

Pearson correlation between baseline and post-training subcutaneous fat in the untrained arm of the entire cohort. The correlation coefficient between baseline and post exercise subcutaneous fat volume in the untrained-arm was R² = 0.943 (P = 0.001).

Figure 3

PPARα L162V is associated with changes in subcutaneous fat volume in response to exercise in men. In men heterozygote for the V162 exercise training increased fat volume of the untrained arm. LL genotypes significantly decreased in fat volume. No significant differences were seen for women. Aged adjusted model.