UC San Diego

The dramatic rise in obesity rates in the United States over the last 30 years is likely a result of a combination of genetic and environmental factors. Genetic background can predispose an individual to obesity, while an environment rich in energy dense foods can promote overconsumption. Working in conjunction, genes and environment alter the regulatory systems responsible for maintaining energy balance. It has become increasingly clear that environmental factors can affect energy homeostasis beginning in utero. Exposure to a high-fat, high-carbohydrate diet in the perinatal period increases obesity risk. Maternal overnutrition and obesity or associated complications putatively mediate the obesogenic effects of perinatal energy-dense diet on developing offspring. It remains unclear whether energy-dense diets promote offspring obesity even if the mother remains slim and does not overeat. The work described in this dissertation uses an animal model of genetic obesity risk and resistance to determine the relative contributions of genes and environment and the importance of maternal diet per se in obesity susceptibility, to identify novel hypothalamic genes overexpressed in association with increased genetic or environmental obesity risk, and to determine the functional significance of those genes. Results showed that a high-fat, high-carbohydrate "Western" diet developmental environment promotes obesity not only in offspring from obesity-prone (DIO) mothers, but also in those from obesity-resistant (DR) dams, implicating a deleterious role for Western diet in and of itself. DR dams did not overeat or become obese while eating a Western diet during pregnancy and lactation, yet their offspring had increased body weight and adiposity as early as one day after birth, and decreased energy expenditure and increased fat gain in response to high-fat diet in adulthood. Microarray analysis of gene expression in the lateral hypothalamus identified TRHDE, which codes for thyrotropin-releasing hormone degrading enzyme (TRH- DE), as being overexpressed in both DIO and DR-Western offspring, indicating it may play a role in increased obesity susceptibility. In vivo behavioral studies showed that the thyrotropin-releasing hormone (TRH) system may be dysfunctional in DR-Western offspring, and normal TRH function is restored with administration of a TRH-DE inhibitor. This indicates that the overexpression of TRHDE in DR-Western offspring may be functionally related to increased obesity risk, providing a novel target for obesity treatment research