ESPE Abstracts (2018) 89 P-P1-106

Towards a Greater Understanding of the Pathophysiology of Obesity: Hypothalamic Obesity as a Model of Dysregulation of Appetite and Metabolic Homeostasis

Hoong-Wei Gana,b, Clare Leesonb, Helen Aitkenheadb, Sadaf Farooqic, Helen Spoudeasb & Mehul Dattania,b


aUniversity College London Great Ormond Street Institute of Child Health, London, UK; bGreat Ormond Street Hospital for Children NHS Foundation Trust, London, UK; cWellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK


Introduction: Hypothalamic obesity (HyOb) is a rare form of treatment-resistant morbid obesity associated with congenital or acquired hypothalamic damage. Its pathophysiology is incompletely understood, with weight gain being attributed to hyperphagia and hyperinsulinaemia. We sought to compare the physiology of various plasma appetite-regulating hormones in HyOb and ‘simple’ obesity (Ob) to improve our understanding of both forms of obesity and identify novel therapeutic targets.

Methods: Oral glucose-stimulated serum insulin and plasma oxytocin concentrations, and fasting concentrations of serum leptin, plasma α-MSH, BDNF, acylated ghrelin, AgRP and copeptin were measured by internally validated ELISA in obese (BMI≥+2 S.D.S.) and lean children with hypothalamic damage (HyOb and HyLean) and Ob and Lean controls. Hyperphagia was quantified using the Dykens’ Hyperphagia Questionnaire Score (DHQS).

Results: Participants (50 HyOb, 29 HyLean, 24 Ob, 19 Lean; 49.2% female) were of mean age 11.3±3.9 years at testing with a mean BMI SDS of 2.8±0.6 and 0.4±1.4 in the obese and lean groups respectively. DHQS did not significantly differ between HyOb and Ob participants (median DHQS 24 (17–34) vs. 24 (18–31), P=0.7), but both were significantly more hyperphagic compared to Lean controls (DHQS 17 (12–21), P=0.007 and 0.03 respectively). DHQS was positively correlated with fasting insulin (ρ=0.3, P=0.001), leptin (ρ=0.3, P=0.004) and BMI SDS (ρ=0.3, P<0.001) regardless of aetiology. Participants with a higher BMI SDS had higher insulin (R=0.4, P<0.001) and leptin (R=0.8, P<0.001) concentrations, but lower concentrations of acylated ghrelin (R=−0.3, P=0.045) and AgRP (R=−0.3, P=0.002). Lower fasting acylated ghrelin (β=−1.2 (95% CI −1.8 to −0.56), P=0.001) and αMSH (β=−0.2 (95% CI −0.4 to −0.02), P=0.04) concentrations were independently associated with more rapid BMI SDS changes at one year. Hormone concentrations did not significantly differ between HyOb and Ob subcohorts, but HyLean participants exhibited intermediate insulin, leptin and αMSH concentrations between HyOb and Lean controls despite normal BMIs, with 10/15 (66.7%) showing a BMI SDS increase over one year, and one patient developing impaired glucose tolerance.

Conclusion: There are no differences in appetite-regulating hormone concentrations or the degree of hyperphagia in HyOb and Ob, with peripheral anorexigens being compensatorily increased, and central and peripheral orexigens being suppressed. The association between lower central anorexigen concentrations (αMSH) and more rapid weight gain independent of baseline BMI requires further investigation. HyLean patients exhibit early hormone dysregulation and require careful follow-up as they remain at risk of HyOb.

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