Rapid Linear Growth in Hyperphagic MC4R KO mice is a Lateral Consequence of Physiological Adaptations that Sustain NEFA and Glucose Balance

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 649-659-Basic Mechanisms of Obesity
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-658
Hwee Yim Tan*1, Frederik Jacobus Steyn2, Lili Huang1, Johannes D Veldhuis3 and Chen Chen2
1The University of Queensland, Brisbane, Australia, 2The University of Queensland, Australia, 3Mayo Clinic & Grad Sch of Med, Rochester, MN
Melanocortin 4 receptor (MC4R) deficiency is the most commonly known monogenic cause of human obesity. Disruption of this receptor results in an obese phenotype, characterized by hyperphagia and accelerated linear growth. Clinical observations demonstrate a partially recovered GH pulsatility in MC4R deficient patients relative to obese individuals of a similar body mass index (BMI). While this suggests that MC4R deficiency may contribute to an increased GH secretion in obesity, it remains unclear whether defects in MC4R signaling directly contribute to rapid linear growth and increased final height often observed in this population.

Using the MC4R knockout (MC4R KO) mouse model, we further assessed the relationship between pulsatile GH secretion and linear growth throughout hyperphagia induced weight gain. Moreover, we extended observations to assess the role of GH and insulin in modulating adiposity, and fatty acid/glucose balance. Measures were collected from MC4R KO and age-matched littermates from 4 to 20 weeks of age.

Observations demonstrate the early suppression of pulsatile GH secretion relative to weight gain and increased adiposity in MC4R KO mice. Impairments in pulsatile GH secretion occurred alongside rapid linear growth, suggesting that GH may not drive linear growth in MC4R KO mice. Circulating measures of nonesterified free fatty acids (NEFA) and glucose were maintained regardless of rapid weight gain and increased adiposity. These changes occurred together with a striking increase in circulating measures of insulin. The increase in insulin occurred prior to GH reduction. Insulin resistance did not develop until after the slowing in linear growth. We propose that the suppression of GH secretion relative to an elevation in circulating levels of insulin in MC4R KO mice is an essential physiological adaptation to sustain NEFA and glucose balance. Moreover, we anticipate that the consequential elevation in circulating levels of insulin promotes rapid linear growth.

Data provide valuable insights underlying altered somatic growth in mouse models of abnormal melanocortin signalling. Our observations contribute to the current understanding of mechanisms that sustain NEFA and glucose balance following hyperphagia induced weight gain, and clarifies the dichotomy of enhanced pubertal growth despite obesity associated GH deficiency.

Nothing to Disclose: HYT, FJS, LH, JDV, CC

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This work has been funded by NHMRC, University of Queensland. Hwee Yim Tan is a PhD candidate funded by Australian International Postgraduate Research Scholarship (IPRS) and Australian Postgraduate Scholarship (APS) at The University of Queensland.