Recent studies indicate that excessive fat intake by pregnant dams can lead to offspring that exhibit hyperlipidemia, increased food intake, preference for fat, and higher body weight. These long-term physiological and behavioral changes are driven, in part, by increased postnatal neurogenesis of galanin- expressing cells and expression of peptides that stimulate the intake of fat. These same peptides have been linked to increased alcohol intake. It follows, therefore, that these hypothalamic changes in the offspring of fat- consuming dams might create an avidity for alcohol. Here, we propose to study the effects on prenatal exposure to high-fat diet on alcohol consumption in the offspring. This will be done by (Exp.1) replicating preliminary results indicating that adolescent females, with prenatal exposure to a high-fat diet, consume significantly more alcohol than controls. This finding will be extended to males and adult offspring. Profiling age and sex specific trends in alcohol intake among animals born to fat-consuming mothers will allow us to characterize a new animal model of alcohol preferring rat. Once we have characterized this behavioral model, we will (Exp. 2) explore aberrations in peptides and sex hormones that might be driving the phenomena. We know of a neural circuit that evolved with the capability to augment fat intake;moreover, it can be co-opted by alcohol. It is also clear that drinking ethanol can increase expression of the peptides in this circuit. Therefore the new question is whether pups born to fat-consuming dams, and therefore growing up with additional hypothalamic cells producing elevated levels of orexigenic peptides, will stimulate expression of these peptides even further by drinking ethanol. This could create a triple threat for alcohol abuse: triple in the sense that the rats have, more galanin cells due to in utero programming, more galanin expression due to hormones at puberty and more galanin expression when they start drinking. Exp. 2 will address the roles of peptides and hormones underlying the behaviors seen in Exp. 1. Lastly, studies indicate that elevated triglycerides (TG) during gestation might be responsible for the behavior seen in Exp. 1 and the physiological changes seen in Exp. 2. Consumption of a high-fat diet raises TG in pregnant dams, which leads to elevated TG in the pups. This elevation of TG increases expression of fat-stimulating peptides that drive excessive intake of alcohol. Our laboratory finds that animals maintained on a diet with free access to high-fructose corn syrup show significantly elevated TG levels, as compared to controls. Therefore (Exp. 3), high dietary fructose might lead to elevated intake of alcohol in the offspring. The translational implications of prenatal dietary intake on alcohol consumption are vast. In the current "fast food" culture, mothers might be programming their offspring with a propensity for alcohol abuse. Through understanding the causation, as well as the mechanism of alcohol prone behavior, we will be better able to advise in optimal prenatal care, as well as prevention and treatment for alcohol-prone individuals.
In a new discovery, we find that a high-fat diet during pregnancy can program the female offspring to consume excessive amounts of alcohol during adolescence. In this proposal, the applicant plans to elucidate the mechanism of this fetal programming and its expression as a function of sex hormones, peptides and age, as well as comparing both females and males. Further, these findings will be applied to prenatal exposure of other common macronutrients, such as those found in high-fructose corn syrup. Understanding the cause and mechanism of gestational diet-induced, alcohol preference will improve prenatal care with the aim of preventing destructive, alcohol prone behavior in the next generation.
|Avena, Nicole M; Bocarsly, Miriam E; Hoebel, Bartley G (2012) Animal models of sugar and fat bingeing: relationship to food addiction and increased body weight. Methods Mol Biol 829:351-65|