Obesity is a risk factor for the development of type 2 diabetes, cardiovascular disease and other afflictions. This is troubling as close to 30% of the population in the United States is obese and 64% is overweight. The study of brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, provides a new and promising avenue in obesity research. They mediate neuronal survival, differentiation, function and plasticity in the developing and mature brain. The relevance of this signaling pathway in the etiology of energy balance disorders is highlighted by the dramatic obesity exhibited by mice with brain-specific targeting of the Bdnf gene. Mutants display hyperphagic behavior and become hyperleptinemic, hyperinsulinemic and hyperglycemic, indicating that this neurotrophin is an essential regulator of food intake acting through as yet unknown mediators in the central nervous system. Human studies also show links between genetic alterations in the TrkB gene and hyperphagic behavior and obesity. This proposal outlines studies designed to ascertain the molecular and cellular mechanisms facilitating the satiety effects of the BDNF/TrkB signaling pathway in the adult animal. For this, the effects of energy signals on the expression and activity of BDNF and TrkB in distinct appetite-modulating regions of the brain will be evaluated. Moreover, the Bdnf gene will be targeted in adult animals in a site-specific manner in hypothalamic and caudal hindbrain nuclei associated with these processes. The impact of these manipulations on energy intake and expenditure will be evaluated. Finally, as BDNF has emerged as a prominent facilitator of synaptic plasticity, we will investigate whether it is required for synaptic plasticity- related processes in the hypothalamus thought to influence energy homeostasis. Together, these studies will distinguish developmental roles of BDNF from ones in the mature brain that influence body weight. This analysis will help clarify disease mechanisms and critical periods of intervention for obesity disorders. Moreover, they will bring us closer to novel strategies for the treatment of obesity and its associated syndromes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK073311-04
Application #
7864331
Study Section
Special Emphasis Panel (ZRG1-MDCN-K (90))
Program Officer
Hyde, James F
Project Start
2007-09-01
Project End
2011-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
4
Fiscal Year
2010
Total Cost
$325,187
Indirect Cost
Name
Tufts University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
Felsted, Jennifer A; Chien, Cheng-Hao; Wang, Dongqing et al. (2017) Alpha2delta-1 in SF1+ Neurons of the Ventromedial Hypothalamus Is an Essential Regulator of Glucose and Lipid Homeostasis. Cell Rep 21:2737-2747
Cordeira, Joshua W; Felsted, Jennifer A; Teillon, Sarah et al. (2014) Hypothalamic dysfunction of the thrombospondin receptor ?2?-1 underlies the overeating and obesity triggered by brain-derived neurotrophic factor deficiency. J Neurosci 34:554-65
Vithlani, Mansi; Hines, Rochelle M; Zhong, Ping et al. (2013) The ability of BDNF to modify neurogenesis and depressive-like behaviors is dependent upon phosphorylation of tyrosine residues 365/367 in the GABA(A)-receptor ?2 subunit. J Neurosci 33:15567-77
Rios, Maribel (2013) BDNF and the central control of feeding: accidental bystander or essential player? Trends Neurosci 36:83-90
Camerino, C; Zayzafoon, M; Rymaszewski, M et al. (2012) Central depletion of brain-derived neurotrophic factor in mice results in high bone mass and metabolic phenotype. Endocrinology 153:5394-405
Daftary, S S; Calderon, G; Rios, M (2012) Essential role of brain-derived neurotrophic factor in the regulation of serotonin transmission in the basolateral amygdala. Neuroscience 224:125-34
Rios, Maribel (2011) New insights into the mechanisms underlying the effects of BDNF on eating behavior. Neuropsychopharmacology 36:368-9
Klein, Anders B; Williamson, Rebecca; Santini, Martin A et al. (2011) Blood BDNF concentrations reflect brain-tissue BDNF levels across species. Int J Neuropsychopharmacol 14:347-53
Cordeira, Joshua; Rios, Maribel (2011) Weighing in the role of BDNF in the central control of eating behavior. Mol Neurobiol 44:441-8
Klein, A B; Santini, M A; Aznar, S et al. (2010) Changes in 5-HT2A-mediated behavior and 5-HT2A- and 5-HT1A receptor binding and expression in conditional brain-derived neurotrophic factor knock-out mice. Neuroscience 169:1007-16

Showing the most recent 10 out of 13 publications