Disruption of hypothalamic leptin signaling in mice leads to early-onset obesity, but physiological adaptations in mature animals stabilize adiposity levels

Distinct 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 foxed leptin receptor allele (Lepr(f1)) to mice transgenic for Nkx2.1-Cre, which drives Cre expression in the hypothalamus and not in more caudal brain regions, generating Lepr(Nkx2.1)KO mice. From weaning, Lepr(Nkx2.1)KO 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(Nkx2.1)KO 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(Nkx2.1)KO mice with age was concomitant with increased rates of linear growth and energy expenditure in Lepr(Nkx2.1)KO mice. These data suggest that remaining leptin signals in Lepr(Nkx2.1)KO mice mediate physiological adaptations that prevent the escalation of the adiposity phenotype in adult mice. The persistence of severe adiposity in Lepr(Nkx2.1)KO mice, however, suggests that compensatory actions of circuits regulating growth and energy expenditure are not sufficient to reverse obesity established at an early age.