Table 2. Potential mechanisms causing hyperphagia in Prader-Willi syndrome (PWS)

Factor	Type of abnormality	Function	Reference
Thyroid hormone	Decreased	Regulates whole-body metabolism. In PWS: Altering metabolic rate and energy consumption as a consequence.	[57]
Ghrelin	Elevated	Temporally regulates food intake, heightens appetite, and lessens appetite after eating. In PWS: prolonged elevation of ghrelin levels, even after meals, leads to weight gain.	[58]
Leptin	Elevated	Helps regulate the body's long-term food intake and use.	[59]
Brain-derived neurotrophic factor (BDNF) and leptin	BDNF: decreased Leptin: elevated	Serves as an indicator of fullness. In PWS: local BDNF levels decrease as a result of a disruption in BDNF signaling, which boosts leptin levels and leads to leptin resistance, ultimately resulting in obesity and hyperphagia.	[60]
Insulin	Decreased	Activates melanocortin-4 receptor (MC4R) and cause satiety, stimulates Pro-opiomelanocortin (POMC) and inhibits Neuropeptide Y (NPY) neurons. In PWS: decreased insulin causes MC4R not to be stimulated.	[61]
Peptide YY	Decreased	Induces satiety by decreasing stomach emptying and activating α and β- Melanocyte-stimulating hormone(MSH) through the inhibition of NPY and stimulation of POMC. In PWS: reduced PYY stops stimulating α- and β-MSH and results in a decrease of stimulating signals to POMC.	[62]
Altered brain structure	Cortical volume: decreased White matter integrity: reduced fractional anisotropy Gray matter volume: decreased	Reduced cortical volume in the bilateral frontal, medial prefrontal cortex, and anterior cingulate causes imbalances in cognitive and emotional processing, which in turn causes appetite management dysfunctions, elevated self-reported hunger, and an increased risk of overeating. White matter function decreases in proportion to the fractional anisotropy decrease. The PWS brain areas linked to food consumption showed abnormalities in both the white and gray matter.	[63]
Orexin A	Elevated	Boosts food consumption and stimulates appetite. In PWS: the hypothalamus overstimulates orexin signaling, which exacerbates food addiction and leads to hyperphagia.	[64]