Research Project
7977411
DESCRIPTION (provided by applicant): Exposure to low protein diets (LPD) during gestation and lactation (perinatal) imprints alterations in lipid homeostasis. Our laboratory and other investigators have shown that perinatal LPD decreases plasma triglyceride levels, fat pad weights, total body lipid content and produces reliable and robust decreases in liver triglyceride content in the adult offspring. Remarkably, such an imprinted lipid profile is associated with decreased susceptibility to fatty liver and obesity. These findings support clinical data demonstrating that the early life nutritional milieu alters susceptibility to obesity during adulthood. Despite the clinically relevant implications of the model, the mechanisms underlying perinatal LPD mediated alterations in lipid metabolism are not well understood. Elucidating these mechanisms could identify biochemical pathways that decrease susceptibility to fatty liver and obesity and could help design therapeutic strategies to alleviate these conditions. The overall objective of our research is to determine the mechanisms underlying the perinatal LPD mediated decrease in liver triglyceride content. We hypothesize that perinatal LPD decreases liver triglyceride content by decreasing hepatic lipid synthesis and increasing hepatic lipid utilization. Lipid synthesis can be decreased by: 1. decrease in the synthesis of fatty acids, the precursors of triglyceride 2. decrease in the subsequent synthesis of triglyceride from fatty acids. Lipid utilization can be increased by: 1. increase in fatty acid oxidation 2. increase in secretion of triglyceride rich very low density lipoprotein particles out of the liver. Our first specific aim will evaluate each of these four mechanisms in adult LPD offspring in the basal fed state. Clinical and animal studies reveal that basal fed state lipid metabolism can be normal despite underlying biochemical alterations in lipid metabolism. Fasting decreases lipid synthesis and dramatically increases lipid utilization. The magnitude of these responses to the metabolic stress of a fast can unmask and reveal underlying alterations in lipid metabolism. Using a 24 hour fast as a diagnostic tool and the four step strategy outlined earlier, our final studies will determine if perinatal exposure to LPD affects the magnitude of fasting induced alterations in hepatic lipid synthesis and lipid utilization. PUBLIC HEALTH RELEVANCE: Maternal low protein diets during pregnancy and lactation produce long term reduction in the body weight of the offspring. Our recent results demonstrate that the reduction in body weight is accompanied by consistent and robust decreases in the liver lipid content of the male offspring. The proposal will determine the mechanisms by which the early life nutritional milieu imprints long term alterations in liver lipid metabolism. Understanding these mechanisms may help develop new therapeutic strategies for the treatment of fatty liver and obesity.
