Physiological and anatomical circuitry between Agouti-related protein and leptin signaling

Agouti-related protein (AGRP) is an orexigenic neuropeptide that acts via c entral melanocortin receptors, and whose messenger RNA (mRNA) levels are el evated in leptin-deficient mice. Fasting associated with a decline in circu lating leptin normally causes a 15-fold elevation of hypothalamic Agrp mRNA levels but has no effect in leptin-deficient mice. Chronic hyperleptinemia associated with the tubby and Cpe(fat) mutations has no effect on Agrp mRN A levels, but short term leptin administration causes a 17% reduction of Ag rp mRNA levels in nonmutant mice and a 700% reduction in leptin-deficient m ice. In young nonobese animals, melanocortin receptor blockade associated w ith the AY mutation causes complete resistance to leptin-induced weight los s. Dual in situ hybridization reveals that Agrp-expressing neurons in the m edial portion of the arcuate nucleus constitute a subpopulation different f rom Pome-expressing neurons, and that a significant proportion of Agrp-expr essing neurons (10-25%) coexpresses the leptin receptor, Lepr-b. Immunocyto chemistry confirms distinct locations of AGRP- and POMC-expressing cell bod ies, but reveals an overlapping distribution of their terminal fields in th e arcuate nucleus, the paraventricular hypothalamus, and the dorsomedial hy pothalamus. These results suggest that in the fed state, AGRP is normally s uppressed by leptin, and that release of this suppression during fasting le ads to increased ingestive behavior.