MON-685 - Disrupted FGFR1-KLB Signaling Impairs Adipocyte Browning and Insulin Signaling in Insulin-Mediated Pseudoacromegaly

Insulin-mediated pseudoacromegaly (IMPA) is a rare, severe insulin resistance syndrome characterized by tall stature, acanthosis nigricans, obesity, and acromegalic features despite normal growth hormone and IGF-1 levels, but with markedly elevated circulating insulin. We previously described an adolescent female with IMPA harboring digenic variants in FGFR1 and KLB, which encode the receptor complex for fibroblast growth factor 21 (FGF21), a hepatokine critical for adipose tissue insulin sensitivity and browning of white adipose tissue. We hypothesized that these variants impair adipocyte browning and insulin signaling.

A transgenic knock-in mouse model (IMPA mice) carrying patient-derived heterozygous variants in Fgfr1 and Klb was generated using CRISPR-Cas9 genome editing. Stromal vascular fractions isolated from white adipose tissue depots of wild-type and IMPA pups were differentiated into adipocytes in vitro. Cultures were treated with rosiglitazone (Rosi), a PPARγ agonist, or vehicle. Endpoints included lipid droplet morphology, expression of canonical beige adipocyte markers by qRT-PCR, and ERK phosphorylation following insulin stimulation.

Wild-type adipocytes exhibited a significant reduction in lipid droplet size and strong induction of the beige adipocyte markers Ucp1 and Cidea after Rosi treatment, reflecting effective PPARγ-mediated adipocyte browning. In contrast, IMPA adipocytes displayed larger lipid droplets at baseline and failed to undergo appropriate morphologic remodeling or transcriptional activation. In parallel, insulin stimulation resulted in robust ERK phosphorylation in wild-type adipocytes, whereas IMPA cells showed markedly diminished ERK activation, consistent with impaired insulin signal transduction. These defects were reproducible across independent differentiations and occurred despite preserved adipogenic differentiation.

These findings suggest that patient-derived FGFR1 and KLB variants impair PPARγ-mediated adipocyte browning and insulin signaling, providing a mechanistic link between disrupted FGF21 signaling in adipose tissue and severe insulin resistance in IMPA. Collectively, these data highlight adipose tissue FGF21 receptor signaling as a potential therapeutic target in severe insulin resistance syndromes. Ongoing studies aim to define downstream pathways and identify therapeutic strategies to restore adipose tissue insulin sensitivity.

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