D istinct populations of leptin-sensing neurons in the hypothalamus, midbrain, and brainstem contribute to the regulation of energy homeostasis. To assess the requirement for leptin signaling in the hypothalamus, we crossed mice with a floxed leptin receptor allele (Lepr^fl) to mice transgenic for Nkx2.1-Cre, which drives Cre expression in the hypothalamus and not in more caudal brain regions, generating Lepr^Nkx2.1KO mice. From weaning, Lepr^Nkx2.1KO mice exhibited phenotypes similar to those observed in mice with global loss of leptin signaling (Lepr^db/db mice), including increased weight gain and adiposity, hyperphagia, cold intolerance, and insulin resistance. However, after 8 weeks of age, Lepr^Nkx2.1KO mice maintained stable adiposity levels, whereas the body fat percentage of Lepr^db/db animals continued to escalate. The divergence in the adiposity phenotypes of Lepr^db/db and Lepr^Nkx2.1KO mice with age was concomitant with increased rates of linear growth and energy expenditure in Lepr^Nkx2.1KO mice. These data suggest that remaining leptin signals in Lepr^Nkx2.1KO mice mediate physiological adaptations that prevent the escalation of the adiposity phenotype in adult mice. The persistence of severe adiposity in Lepr^Nkx2.1KO mice, however, suggests that compensatory actions of circuits regulating growth and energy expenditure are not sufficient to reverse obesity established at an early age.