Obesity is approaching epidemic proportions in the United States with an estimated 30 percent of the adult population classified as clinically overweight with a body mass index (BMI) of above 25. Whether the overweight threshold is defined by BMI, bioimpedance, or anthromorphic measures of waist circumference, waist-hip ratio or skinfold thickness, it is clear that obesity is linked with diabetes mellitus, cardiovascular disease, hyperlipidemia, and impaired glucose tolerance. These are major concerns for an aging population, but even more alarming is the recent upswing in childhood obesity, as the correlation with obesity in adulthood is compelling. Multiple factors bias an individual towards heaviness with increased energy intake, low physical activity and genetic factors all major contributors. With the advances in the Human Genome Project, major strides have been taken in identifying candidate """"""""obesity"""""""" genes. In combination with pharmacological tools, the serotonin system of transporters and the 14 serotonin receptors have received much scrutiny. The serotonin 2C receptor knockout mouse (5-HT2cR KO) appears indistinguishable from its wild type sibling for 10-12 weeks followed by a late-onset hyperphagic phenotype. Subsequently, the KO mouse develops hyperinsulinemia and mid-life obesity. We have surprising pilot data that the 5-HT2cR KO mouse is hyperphagic at 10 days of age and is heavier at weaning (21 days). If the 21-day old 5-HT2cR KO is obese at weaning, this mouse line may serve as a model of childhood obesity that presages adult obesity. This KO mouse might provide techniques to identify children at-risk and lead to clinical interventions in the progression of this disease. We propose to use neuroanatomical, endocrine, behavioral and physiological measures to determine: 1. If the weanling 5-HT2cR KO mouse is obese, 2. If the preweanling 5-HT2cR KO 10 day old pup is behaviorally hyperphagic, and 3. whether the 5-HT2cR KO mouse has a lower metabolic rate.
| Akana, Susan F (2008) Feeding and stress interact through the serotonin 2C receptor in developing mice. Physiol Behav 94:569-79 |
