title: Stage-specific inhibition of TrkB activity leads to long-lasting and sexually dimorphic effects on body weight and hypothalamic gene expression.
abstract: During development, prenatal and postnatal factors program homeostatic set points to regulate food intake and body weight in the adult. Combinations of genetic and environmental factors contribute to the development of neural circuitry that regulates whole-body energy homeostasis. Brain-derived neurotrophic factor (Bdnf) and its receptor, Tyrosine kinase receptor B (TrkB), are strong candidates for mediating the reshaping of hypothalamic neural circuitry, given their well-characterized role in the central regulation of feeding and body weight. Here, we employ a chemical-genetic approach using the TrkB(F616A/F616A) knock-in mouse model to define the critical developmental period in which TrkB inhibition contributes to increased adult fat mass. Surprisingly, transient TrkB inhibition in embryos, preweaning pups, and adults all resulted in long-lasting increases in body weight and fat content. Moreover, sex-specific differences in the effects of TrkB inhibition on both body weight and hypothalamic gene expression were observed at multiple developmental stages. Our results highlight both the importance of the Bdnf/TrkB pathway in maintaining normal body weight throughout life and the role of sex-specific differences in the organization of hypothalamic neural circuitry that regulates body weight.
authors: Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America ; Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America ; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors: Mardi S
authors: MS
authors: Byerly
authors: Roy D
authors: RD
authors: Swanson
authors: G William
authors: GW
authors: Wong
authors: Seth
authors: S
authors: Blackshaw
mesh_terms: D000818:Animals; D001823:Body Composition / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects* / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D020813:Receptor, trkB / Q000037:antagonists & inhibitors* / Q000235:genetics; D012727:Sex Characteristics
chemical_list: D047428:Protein Kinase Inhibitors; D020813:Receptor, trkB