The transcripts forBdnf(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 ofBdnfpromoters I and II but not IV and VI in mice (Bdnf-e1−/−,Bdnf-e2−/−) results in obesity. WhereasBdnf-e1−/−exhibited impaired thermogenesis,Bdnf-e2−/−showed hyperphagia and reduced satiety before the onset of obesity. TheBdnf-e2transcripts were primarily expressed in ventromedial hypothalamus (VMH), a nucleus known to regulate satiety. Re-expressingBdnf-e2transcript in VMH or chemogenetic activation of VMH neurons rescued the hyperphagia and obesity ofBdnf-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 ofBdnf-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.