SLC6A14 deficiency is linked to obesity, fatty liver, and metabolic syndrome but only under conditions of a high-fat diet

SLC6A14 is a Na+/Cl−-coupled transporter for neutral/cationic amino acids, expressed in ileum and colon. A single-nucleotide polymorphism (SNP), rs2011162 (−22,510C > G), in SLC6A14 coding for the 3′-untranslated region (3′-UTR) is associated with obesity in humans. But the impact of this polymorphism on the transporter expression and its connection to obesity are not known. Our objective was to address these issues. The impact of rs2011162 (−22,510C > G) on SLC6A14 expression was monitored using a luciferase reporter. The link between Slc6a14 and obesity was investigated in wild type and Slc6a14−/− mice when fed a normal diet or a high-fat diet. The obesity-associated 3′-UTR polymorphism reduced SLC6A14 expression. With a high-fat diet, Slc6a14−/− mice gained more weight than wild type mice. With normal diet, there was no difference between the two genotypes. The gain in body weight with the high-fat diet in Slc6a14−/− mice was accompanied with metabolic syndrome. With the high-fat diet, Slc6a14−/− mice showed increased food intake, developed fatty liver, and altered plasma amino acid profile. The high-fat diet-associated hepatic steatosis in Slc6a14−/− mice showed male preponderance. We conclude that the 3′-UTR SNP in SLC6A14 associated with obesity decreases the expression of SLC6A14 and that the deficiency of SLC6A14 is linked to obesity. This is supported by the findings that Slc6a14−/− mice develop obesity, fatty liver, and metabolic syndrome. This connection is evident only with a high-fat diet. Therefore, dietary/pharmacologic interventions that induce SLC6A14 expression in the intestinal tract might have potential for obesity prevention.11Footnote added to the proof: The gene that encodes SLC6A14 is located on X chromosome in humans and mice. Accordingly, the correct genotype notation is Slc6a14y/- (instead of Slc6a14-/-) for Slc6a14-null males and Slc6a14-/- for Slc6a14-null females. •An obesity-associated SNP in 3′-UTR of SLC6A14 suppresses its expression.•Slc6a14−/− mice (males and females) are obese when fed high-fat diet.•Slc6a14−/− mice on high-fat diet develop metabolic syndrome and fatty liver.•Hepatic steatosis in Slc6a14−/− mice on high-fat diet has male preponderance.•Slc6a14−/− mice on high-fat diet show increased food intake but no change in RER.