Insulin-mediated pseudoacromegaly (IMPA) is a rare, severe insulin resistance syndrome characterized by tall stature, acanthosis nigricans, obesity, and acromegalic features. Patients with IMPA have normal growth hormone and IGF-1. However, they have markedly increased insulin levels. Our group previously described a patient with IMPA who carries digenic mutations in fibroblast growth factor receptor 1 (FGFR1) and beta-klotho (KLB) , which form the receptor complex for FGF21. FGF21 is a hepatokine that plays a critical role in adipose insulin sensitivity. To assess the pathogenicity of these mutations, we isolated iPSC from the proband with IMPA. We used CRISPR gene editing to correct the FGFR1 and KLB mutations and differentiated the iPSC lines into adipocytes. Both the uncorrected (mutant) and corrected (wild-type) lines were able to undergo successful differentiation to adipocytes. Western immunoblotting demonstrated that the uncorrected cells demonstrated decreased levels of FGFR1, pERK1/2, and p38-MAPK in response to insulin and/or FGF21. Additionally, the mutant adipocytes demonstrated significantly larger lipid droplets when stained with BODIPY (mean droplet size 62.6 μm2 uncorrected; 40.8 μm2 corrected; p= 0.00016) . To complement the iPSC work, a transgenic knock-in mouse line was created using CRISPR gene editing. Explants of gonadal white adipose tissue isolated from these mice demonstrated significantly decreased lipolysis (Max NEFA in mutant 0.mEq/L; wild-type 0.13 mEq/L; p=0.003) . Additionally, qRT PCR was performed in brown adipose tissue demonstrating decreased Ucp1 expression (mutant mice 37.2% of WT; p=4.0x10-5) . These results suggest that the FGFR1 and KLB mutations lead to decreased FGF21 signaling. Mutant adipose tissues are dysfunctional with impaired lipolysis and Ucp1 expression. Therefore these models are useful for determining the role of the FGF21 signaling in human insulin resistance syndromes.


N.Phan: None. D.M.Ornitz: None. S.I.Stone: Speaker's Bureau; Rhythm Pharmaceuticals, Inc.


NICHD (R21 HD098872) , NIDDK (KDK124574) , NCATS (UL1TR000448) , NIDDK (P30 DK020579) , NIDDK (P30 DK056341) , Burroughs Wellcome Fund Physician-Scientist Institutional Award, and Centene Precision Medicine Initiative

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