Complex interactions between periphery and the brain regulate food intake in mammals. Cannabinoid type-1 (CB₁) receptor antagonists are potent hypophagic agents, but the sites where this acute action is exerted and the underlying mechanisms are not fully elucidated. To dissect the mechanisms underlying the hypophagic effect of CB₁ receptor blockade, we combined the acute injection of the CB₁ receptor antagonist rimonabant with the use of conditional CB₁-knockout mice, as well as with pharmacological modulation of different central and peripheral circuits. Fasting/refeeding experiments revealed that CB₁ receptor signaling in many specific brain neurons is dispensable for the acute hypophagic effects of rimonabant. CB₁ receptor antagonist-induced hypophagia was fully abolished by peripheral blockade of β-adrenergic transmission, suggesting that this effect is mediated by increased activity of the sympathetic nervous system. Consistently, we found that rimonabant increases gastrointestinal metabolism via increased peripheral β-adrenergic receptor signaling in peripheral organs, including the gastrointestinal tract. Blockade of both visceral afferents and glutamatergic transmission in the nucleus tractus solitarii abolished rimonabant-induced hypophagia. Importantly, these mechanisms were specifically triggered by lipid-deprivation, revealing a nutrient-specific component acutely regulated by CB₁ receptor blockade. Finally, peripheral blockade of sympathetic neurotransmission also blunted central effects of CB₁ receptor blockade, such as fear responses and anxiety-like behaviors. These data demonstrate that, independently of their site of origin, important effects of CB₁ receptor blockade are expressed via activation of peripheral sympathetic activity. Thus, CB₁ receptors modulate bidirectional circuits between the periphery and the brain to regulate feeding and other behaviors.