Background

Understanding pathophysiology of human obesity is limited by heterogeneity among patients’ phenotype. Recently, we classified obesity based on phenotypes: satiation (14%), satiety (16%), hedonic (13%), slow metabolism (11%), mixed (34%) and other (14%).The abnormal-satiety phenotype (ASP) is characterized by decreased sensation of fullness. The mechanisms associated with ASP remain unknown.

Methods

We performed a case-control GWAS (Infinium Omni2.5) on subjects with obesity in a discovery cohort (n=167, age 36(28-46)y, BMI 35(32-38)kg/m2, 75% females), and an independent validation cohort (n=93, age 34(28-43)y, BMI 36(32-41)kg/m2, 82% females). Phenotyping included body composition, resting energy expenditure, gastric emptying, ad libitum buffet meal, VAS-appetite, GI peptides fasting and postprandial and behavioral surveys. RTqPCR gene expression studies were conducted on colonic biopsies (collected by sigmoidoscopy) from 10 patients with obesity (age 38±4, 50% female) and 8 healthy weight controls (age 33±4, 62% female).

Results

Patients with ASP had lower fullness scores over 120min (p=0.04) and higher hunger scores over 120min (p=0.008). Additionally, ASP had rapid gastric emptying and decreased postprandial PYY and GLP-1.GWAS analysis identified a novel SNP, rs17108978, within the 3’UTR of human free fatty acid receptor-4, FFAR4, (GPR120) in association with ASP in the discovery cohort (OR=11, P<10-5), confirmed in the validation cohort (OR=4.2, P<10-5). In colonic tissue, the mRNA expression of GPR120, GLP-1 (GCG) and PYY in sigmoid mucosal biopsies was lower in ASP compared to other obesity phenotypes and healthy weight controls (p<0.05). rs17108978 A allele in GPR120 was associated with higher postprandial GLP1 (p=0.01) and PYY (p=0.06).

Conclusions

The ASP is associated with a genetic variant in GPR120 (rs17108978) and decreased colonic mucosal expression of GPR120, GLP-1 and PYY. These data suggest suboptimal enteroendocrine cell function may be a component of the ASP in obesity.