Observations from MC4R deficient patients suggest that rapid pubertal growth due to MC4R dysfunction may occur as a consequence of pubertal growth hormone (GH) excess. This contradicts the anabolic actions of GH relative to insulin in sustaining endogenous fatty acid and glucose homeostasis during periods of excess energy intake. We anticipate that rapid pubertal growth in hyperphagic MC4R deficient patients occur secondary to metabolic alterations that sustain fatty acid and glucose balance in response to hyperphagia. To address this, we assessed the relationship between pulsatile GH secretion and linear growth throughout hyperphagia induced weight gain in the MC4R knockout (MC4RKO) mouse model, and demonstrate the inverse relationship between GH and insulin in modulating adiposity, and fatty acid and glucose homeostasis.

Our observations confirmed that hyperphagic MC4RKO mice developed profound GH deficiency, despite sustained rapid pubertal growth. Moreover, rapid linear growth did not coincide with circulating elevated insulin-like growth factor 1 (IGF-1) levels. Thus, rapid linear growth in MC4RKO mice does not occur as a consequence of increased GH/IGF-1 actions. The early suppression of GH release occurred alongside hyperphagia-associated hyperinsulinemia. Prevention of hyperphagia in MC4R KO mice by pair feeding attenuated hyperinsulinemia, normalized rate of linear growth, and restored pulsatile GH release. Circulating nonesterified free fatty acids (NEFA) and glucose were maintained, regardless of weight gain and increased adiposity. Thus, we proposed that altered GH/insulin balance in hyperphagic MC4RKO mice reflect metabolic adaptations that sustain NEFAs/glucose homeostasis in response to excess energy consumption. Consequently, we anticipate that hyperphagia-associated hyperinsulinemia contribute to the suppression of GH relative to increased adiposity. Second to this, hyperphagia-associated hyperinsulinemia mimic the growth-promoting actions of GH in driving linear growth in MC4RKO mice. Findings provide valuable insights underlying altered somatic growth during pubertal hyperphagia, and address misconceptions of GH dependent growth in obese-hyperinsulinemic adolescence.