Objective

Preference for dietary fat vs. carbohydrate varies markedly across free-living individuals. It is recognized that food choice is under genetic and physiological regulation, and that the central melanocortin system is involved. However, how genetic and dietary factors interact to regulate relative macronutrient intake is not well understood.

Methods

We investigated how the choice for food rich in carbohydrate vs. fat is influenced by dietary cholesterol availability and agouti-related protein (AGRP), the orexigenic component of the central melanocortin system. We assessed how macronutrient intake and different metabolic parameters correlate with plasma AGRP in a cohort of obese humans. We also examined how both dietary cholesterol levels and inhibiting de novo cholesterol synthesis affect carbohydrate and fat intake in mice, and how dietary cholesterol deficiency during the postnatal period impacts macronutrient intake patterns in adulthood.

Results

In obese human subjects, plasma levels of AGRP correlated inversely with consumption of carbohydrates over fats. Moreover, AgRP-deficient mice preferred to consume more calories from carbohydrates than fats, more so when each diet lacked cholesterol. Intriguingly, inhibiting cholesterol biosynthesis (simvastatin) promoted carbohydrate intake at the expense of fat without altering total caloric consumption, an effect that was remarkably absent in AgRP-deficient mice. Finally, feeding lactating C57BL/6 dams and pups a cholesterol-free diet prior to weaning led the offspring to prefer fats over carbohydrates as adults, indicating that altered cholesterol metabolism early in life programs adaptive changes to macronutrient intake.

Conclusions

Together, our study illustrates a specific gene-diet interaction in modulating food choice.