Deficient leptin signaling causes infertility via reduced activity of GnRH neurons causing a hypogonadal state in both rodents and humans. AGRP/NPY neurons within the hypothalamic arcuate nucleus are considered to be important intermediate neurons involved in leptin regulation of GnRH neurons. We previously reported that absence of AGRP and haploinsufficiency of MC4R in leptin receptor mutant (Lepr ^db/db) females restored fertility and lactation despite persistence of obesity and insulin resistance. The overarching hypothesis in the present study is that the absence or reduction of leptin's inhibition of AGRP/NPY neurons leads to suppression of GnRH release in cases of leptin signaling deficiency. Since TAC2 signaling plays a role in pubertal maturation and modulated by metabolic status, this study additionally hypothesized that TAC2 neurons may be regulated by melanocortinergic signals as part of leptin's action on female puberty and reproduction. Our data show that AGRP deficiency in Lepr ^db/db females restores normal timing of vaginal opening and estrous cycling although uterine weight gain and mammary gland development are morphologically delayed. Nonetheless, Agrp ^-/- Lepr ^db/db females are fertile and sustain adequate nutrition of pups with lactation to weaning age. AGRP deficiency results in advanced vaginal opening in wild-type female mice. Agrp ^-/- Lepr ^db/db rather Lepr ^db/db females presented the post-pubertal increase in hypothalamic Tac2 mRNA expression. Furthermore, MC4R activation with MTII induced FOS expression in TAC2 neurons. These studies suggest that AGRP imposes inhibitory effects on female puberty and reproduction, and that TAC2 neurons may transmit melanocortinergic inhibition of GnRH neurons.