Dietary Macronutrient Regulation of Acyl and Desacyl Ghrelin Concentrations in Children With Prader-willi Syndrome (PWS)

Maha Alsaif; Mohammadreza Pakseresht; Michelle L. Mackenzie; Bruce Gaylinn; Michael O. Thorner; Michael Freemark; Catherine J. Field; Carla M. Prado; Andrea M. Haqq


Clin Endocrinol. 2020;93(5):579-589. 

In This Article

Abstract and Introduction


Background: The effects of dietary macronutrients on orexigenic and anorexigenic hormones in children are poorly understood.

Objective: To explore effects of varying dietary macronutrients on appetite-regulating hormones [acyl ghrelin (AG) and desacyl ghrelin (DAG), glucagon-like peptide 1 (GLP-1), peptide tyrosine tyrosine (PYY) and insulin] in children with PWS and healthy children (HC).

Design: Randomized, cross-over experiments compared two test diets [high protein-low carbohydrate (HP-LC) and high protein-low fat (HP-LF)] to a STANDARD meal (55% carbohydrate, 30% fat, 15% protein). Experiment 1 included ten children with PWS (median age 6.63 years; BMI z 1.05); experiment 2 had seven HC (median age 12.54 years; BMI z 0.95). Blood samples were collected at baseline and at 60-minute intervals for 4 hours. Independent linear mixed models were adjusted for age, sex and BMI z-score.

Results: Fasting and post-prandial AG and DAG concentrations are elevated in PWS children; the ratio of AG/DAG is normal. Food consumption reduced AG and DAG concentrations in both PWS and HC. GLP-1 levels were higher in PWS after the HP-LC and HP-LF meals than the STANDARD meal (P = .02–0.04). The fasting proinsulin to insulin ratio (0.08 vs 0.05) was higher in children with PWS (P = .05) than in HC. Average appetite scores in HC declined after all three meals (P = .02) but were lower after the HP-LC and HP-LF meals than the STANDARD meal.

Conclusion: Altered processing of proinsulin and increased GLP-1 secretion in children with PWS after a high protein meal intake might enhance satiety and reduce energy intake.


Prader-Willi syndrome (PWS) is a syndromic obesity disorder with a prevalence approximating 1 in 10 000/15 000 live births.[1] Infants with PWS present with hypotonia and failure to thrive, and tube feeding is often required. This is followed by hyperphagia and progressive weight gain in childhood. Relative to children with nonsyndromic obesity, children with PWS have elevated fasting and post-prandial concentrations of ghrelin.[2] The high circulating concentrations of ghrelin may play a role in the pathogenesis of obesity in PWS because ghrelin stimulates food intake and weight gain.[3] Thus, studies of the regulation of ghrelin secretion may provide important insights into the control of appetite and weight gain in children with PWS.

Food intake is controlled by pre- and post-prandial physiological responses regulated by orexigenic (ghrelin) and anorexigenic (leptin, insulin, GLP-1 and peptide tyrosine tyrosine (PYY)) hormones.[4] Ghrelin circulates as acylated (AG) and desacyl (DAG) forms.[5,6] Acylated ghrelin stimulates appetite and induces a positive energy balance.[7] Desacyl ghrelin can improve glycaemic control.[8] The ratio of AG and DAG concentrations (AG:DAG) plays an important role in maintaining energy balance and metabolic control.[9,10]

Acylated ghrelin and DAG are suppressed by food intake; the rate and magnitude of post-prandial suppression depend on the macronutrient (fat, carbohydrates, protein) composition and distribution of the particular meal ingested. Meals high in carbohydrates (≥65% of total energy intake) are generally more potent than meals high in fat in suppressing ghrelin concentrations.[1,11] In a recent study,[15] we compared the effects of low-fat, high-carbohydrate (LF-HC) and low carbohydrate, high-fat (LC-HF) intake in children with PWS, and we found that the LC-HF diet lowered post-prandial insulin concentration, increased fasting and post-prandial glucagon-like peptide 1 (GLP-1) concentrations and increased fatty acid oxidation relative to the LF-HC diet. However, the effect of dietary protein on AG and DAG has not yet been examined.

The goal of this study was to explore the effects of varying dietary macronutrient composition on appetite-regulating hormones in children with PWS (experiment 1) and healthy children (HC) without the syndrome (Experiment 2). We hypothesized that 1. the fasting and post-prandial levels and ratio of AG and DAG in children with PWS differ from those of healthy children without obesity; 2. a higher protein, lower carbohydrate meal or higher protein, lower fat meal suppresses the level of AG to a greater extent and for greater duration than a meal containing standard amounts of protein; 3. higher protein meals increase post-prandial levels of PYY and GLP-1 and reduce post-prandial insulin levels to a greater extent and for greater duration than a meal containing standard amounts of protein and fat.

To test these hypotheses, we used a randomized cross-over design. Two test diets were compared to a STANDARD meal containing 55% carbohydrate, 30% fat and 15% animal protein. The first test meal (HP-LC) contained higher concentrations of animal protein (30%), lower concentrations of carbohydrate (40%) and equivalent concentration of fat (30%) (Table 1, Figure 1); this allowed us to test the effect of substituting protein for carbohydrate in a calorie- and fat-balanced meal. The second (HP-LF) contained higher concentrations of animal protein (30%), lower concentrations of fat (15%) and equivalent concentrations of carbohydrate (55%) (Table 1, Figure 1); this allowed us to test the effect of substituting protein for fat in a calorie- and carbohydrate-balanced meal.

Figure 1.

Macronutrient distribution of the STANDARD, HP-LC and HP-LF meals. Abbreviations: HP-LC, High protein-low carbohydrate; HP-LF, High protein-low fat