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The transcripts for <i>Bdnf</i> (<i>brain-derived neurotrophic factor</i>), 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 <i>Bdnf</i> promoters I and II but not IV and VI in mice (<i>Bdnf-e1^−/−</i>, <i>Bdnf-e2^−/−</i>) results in obesity. Whereas <i>Bdnf-e1^−/−</i> exhibited impaired thermogenesis, <i>Bdnf-e2^−/−</i> showed hyperphagia and reduced satiety before the onset of obesity. The <i>Bdnf-e2</i> transcripts were primarily expressed in ventromedial hypothalamus (VMH), a nucleus known to regulate satiety. Re-expressing <i>Bdnf-e2</i> transcript in VMH or chemogenetic activation of VMH neurons rescued the hyperphagia and obesity of <i>Bdnf-e2^−/−</i> 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 <i>Bdnf-e2^−/−</i> mice alleviated these phenotypes. Thus, <i>Bdnf</i>-<i>e2-</i>transcripts in VMH neurons play a key role in regulating energy intake and satiety through TrkB pathway.