L-Lysine is one of the essential amino acids, thereby being absolutely necessary for growth, reproduction, and survival. Because of its intrinsic bitter taste, normal animals show low preferences for lysine solutions. However, following exposure to a lysine-deficient diet, animals will display robust preferences for lysine solutions in such a way that lysine intake becomes sufficient to result in repletion. Lysine deficiency does not alter the responses of primary taste nerves (chorda tympani and glossopharyngeal nerves) to lysine solutions, while the sensitivity of hepatic vagal afferents to intraportal administration of lysine increases up to 100-fold within just 4 days. Concentrations of inhibin, a blood-borne growth factor, also increase under these conditions. In addition, some neurons in the lateral hypothalamic area (LHA) respond specifically to lysine during ingestion. Microinjection of lysine solutions or inhibitors of activin A (inhibin, follistatin, or activin antiserum) in the LHA reduces bar-pressing behavior to obtain lysine-containing diets. Furthermore, during lysine deficiency, norepinephrine release in the ventromedial hypothalamus, but not in the lateral hypothalamus, is reduced. Lesions of dopaminergic neurons in the ventral tegmental area, a reward area, do not affect lysine preference during lysine deficiency. These results suggest that signals via vagal hepatic afferents play an important role in detecting states of systemic lysine deficiency. On the other hand, taste information is important for the expression of taste-guided behaviors during the develo pment of lysine preferences. Brain circuits including the lateral and medial hypothalamus integrate neural and humoral inputs to regulate taste preferences under states of essential nutrient deficiency