LAUSR

The transcripts for Bdnf (brain-derived neurotrophic factor), driven by different promoters, are expressed in different brain regions to control different body functions. Specific promoter(s) that regulates energy balance remain unclear. We show that disruption of Bdnf promoters I and II but not IV and VI in mice (Bdnf-e1−/−, Bdnf-e2−/−) results in obesity. Whereas Bdnf-e1−/− exhibited impaired thermogenesis, Bdnf-e2−/− showed hyperphagia and reduced satiety before the onset of obesity. The Bdnf-e2 transcripts were primarily expressed in ventromedial hypothalamus (VMH), a nucleus known to regulate satiety. Re-expressing Bdnf-e2 transcript in VMH or chemogenetic activation of VMH neurons rescued the hyperphagia and obesity of Bdnf-e2−/− mice. Deletion of BDNF receptor TrkB in VMH neurons in wildtype mice resulted in hyperphagia and obesity, and infusion of TrkB agonistic antibody into VMH of Bdnf-e2−/− mice alleviated these phenotypes. Thus, Bdnf-e2-transcripts in VMH neurons play a key role in regulating energy intake and satiety through TrkB pathway.