AGRP and Morbid Obesity

The current evidence evaluating the role of AGRP (HGNC:330) in morbid obesity (MONDO_0005139) is mixed, with clinical genetic studies failing to support a robust association. In a comprehensive mutational analysis of melanocortin pathway genes in severely obese children, AGRP screening revealed two polymorphisms – including the missense variant c.199G>A (p.Ala67Thr) – that were observed at similar frequencies in both patient and control cohorts (PMID:11487744). No segregation of these variants with the obesity phenotype was reported, thereby weakening the genetic evidence for a causative role of AGRP in morbid obesity.

In contrast, experimental studies have consistently demonstrated that AGRP acts as a natural antagonist of melanocortin receptors, reinforcing its biological role in the regulation of appetite and feeding behavior (PMID:9892020). While additional genetic data from an obesity disorder study identified rare variants in AGRP, including c.199G>A (p.Ala67Thr), these findings did not translate into a clear pathogenic link with morbid obesity (PMID:19602223). Overall, despite supportive functional evidence, the current genetic evidence remains disputed, implying that further studies are required to determine the clinical utility of AGRP screening in morbid obesity.

References

• The Journal of pediatrics • 2001 • Mutational analysis of melanocortin-4 receptor, agouti-related protein, and alpha-melanocyte-stimulating hormone genes in severely obese children PMID:11487744
• BMC medical genetics • 2009 • Association between a rare SNP in the second intron of human Agouti related protein gene and increased BMI PMID:19602223
• Molecular endocrinology (Baltimore, Md.) • 1999 • Characterization of Agouti-related protein binding to melanocortin receptors PMID:9892020

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