ChuanFeng Wang, M.D., Ph.D.
VA Medical Center, Minneapolis, MN
BDNF is a neurotrophin that plays important roles in differentiation, survival, and plasticity of the CNS. BDNF mRNA and protein are heavily distributed in the hypothalamus, limbic system and other areas. Its tyrosine kinase receptor, Trk B, is also widely spread throughout the CNS. Recent studies show that BDNF decreases feeding and body weight after injection into the ventricles. Systemic injection increases body temperature and oxygen consumption, and BDNF (+/-) heterozygous animals, which have low BDNF gene expression in specific hypothalamic sites, are obese.
Together these data suggest that BDNF may play an important role in energy balance. However, specific sites of BDNF action and short term BDNF effects have not yet been reported. A full understanding of CNS BDNF effects on energy balance is necessary. In our preliminary study targeting the paraventricular nucleus of hypothalamus (PVN), a single injection of BDNF significantly decreased feeding and body weight gain for up to 48 h, suggesting that BDNF may regulate energy balance in specific sites that are important to energy metabolism.
To test the hypothesis that BDNF in the CNS decreases energy intake and increases the capacity for thermogenesis, the proposed studies will determine:
specific brain sites of action for BDNF (via injecting BDNF with different doses into specific sites in food deprived rats and measuring food intake and body weight change);
non-aversive doses of BDNF that inhibit feeding (by measuring saccharin solution intake in a conditioned taste aversion paradigm);
influence of BDNF on capacity for thermogenesis (via measuring uncoupling protein gene expression in peripheral tissues) and other metabolic factors (via measuring leptin and free fatty acid levels); and
functional interactions between BDNF and other energy regulatory neuropeptide systems (via co-injecting BDNF and other neuropeptides and measuring food intake and body weight change, and via measuring neuropeptide mRNA and protein levels in specific brain sites after BDNF treatment).
The proposed studies will address the role of BDNF in energy balance regulation and will provide information important to the prevention and treatment of obesity.
Persons who are overweight or obese are at increased risk of developing diabetes. The numbers of overweight or obese persons have increased dramatically in recent decades, yet the extent to which these increases have resulted in more new cases of diabetes is unknown due to a scarcity of long-term data on a single geographically defined population. The opportunity to examine temporal trends in the association between body mass index (BMI) and diabetes is afforded with the longitudinal population-based resources of the Rochester Epidemiology Project (REP).
Previous REP studies revealed that the incidence of diabetes among Rochester residents has increased since the 1970's, that the rate of increase accelerated in recent years, and that the mean BMI among diabetic individuals at the time they first met criteria for diabetes has also increased over time. The extent to which temporal trends in BMI for persons with diabetes mirror those for persons without diabetes in this population is not known, however. The answer to this question is critical for determining from where, across the BMI spectrum, the largest increases in new cases of diabetes have come and thus where primary intervention efforts should be focused.
The need for such information is particularly timely in light of recent clinical trial results showing that interventions to reduce BMI can effectively reduce the risk of diabetes, and that the success of various interventions varies across the BMI spectrum. An appreciation for temporal trends in the relationship between diabetes and obesity is also important because both conditions are significant contributors to cardiovascular disease (CVD) morbidity, mortality, and health care costs.
In addition to addressing the specific aim proposed here, the resources and information obtained with this proposal will substantially enhance the value of existing REP resources for future investigations of the impact of increases in obesity and diabetes on other CVD risk factors, CVD incidence rates, and resource utilization.
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