The FTO A risk allele (rs9939609) attenuates Liraglutide effects on adipogenesis in an ex vivo, heterozygous hASC model

Abstract

The recently approved weight management drug Saxenda contains the GLP-1R agonist Liraglutide as the active ingredient. Because GLP-1R is expressed outside GI tract (1, 2), including adipose tissue, we sought to study the non-gastric functions of Liraglutide on adipose tissue in FTO wildtype and FTO mutant cells. In vitro, Liraglutide (100 nM) reduced adipogenesis in 3T3-L1 cell associated with downregulation of C/EBPα ((adjusted p-value < 0.0001), PPAR (adjusted p-value < 0.0001), and FABP4 (adjusted p-value < 0.0001). Results suggested Liraglutide regulates MCE possibly through regulating FTO function, expression, or both where Liraglutide had downregulated FTO expression during adipogenic induction (adjusted p-value < 0.0001 and adjusted p-value = 0.0002 at 24h and 48h post induction, respectively). The FTO A risk allele restored adipogenesis to back to the FTO WT vehicle levels that may explained by IRX3 and RPGRIP1L dependent mechanisms. In vivo, Liraglutide treated mice resisted DIO and weighed significantly less than vehicle treated mice, where lost weight was almost attributable to fat mass loss.