Hypophagia induced by 3,4-dihydroxybutanoic acid (2-deoxytetronic acid, 2-DTA), an endogenous short-chain polyhydroxymonocarboxylic acid, was investigated in rats. Intraperitoneal injection of 2500 mumol 2-DTA did not suppress feeding, but 2.5 mumol 2-DTA injected into the third cerebroventricle did. To efficiently transport exogenous 2-DTA into the brain, its encapsulation and delivery in specially made sulfatide liposomes was attempted. Feeding was suppressed dose-dependently by intraperitoneally injected 2-DTA in liposomes. Injection of 2500 mumol 2-DTA into the common carotid artery also suppressed feeding. Administration by either route prolonged postprandial intermeal interval with no change in meal size, as was observed after central administration of 2-DTA. Injection of 2.5 mumol 2-DTA into the third cerebroventricle elevated plasma glucose level, leaving insulin and free fatty acids unaffected. These findings, together with previous results, indicate that at least one site for the physiological action of 2-DTA is in the hypothalamic centers for food intake.