Tissue-Specific Ablation of Liver Fatty Acid-Binding Protein Induces a Metabolically Healthy Obese Phenotype in Female Mice

Tawfeeq, H. R.; Lackey, A. I.; Zhou, Y.; Diolintzi, A.; Zacharisen, S.; Lau, Y. H.; Quadro, L.; Storch, J.

doi:10.1101/2025.01.02.631082

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bioRxiv · 10.1101/2025.01.02.631082

Tissue-Specific Ablation of Liver Fatty Acid-Binding Protein Induces a Metabolically Healthy Obese Phenotype in Female Mice

Tawfeeq, H. R.·Lackey, A. I.·Zhou, Y.·Diolintzi, A.·Zacharisen, S.·Lau, Y. H.·Quadro, L.·Storch, J.

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Abstract

Background/ObjectivesObesity is associated with numerous metabolic complications including insulin resistance, dyslipidemia, and a reduced capacity for physical activity. Whole-body ablation of liver fatty acid-binding protein (LFABP) in mice was shown to alleviate several of these metabolic complications; high fat (HF) fed LFABP knockout (LFABP-/-) mice developed higher fat mass than their wild-type (WT) counterparts but displayed a metabolically healthy obese (MHO) phenotype with normoglycemia, normoinsulinemia, and reduced hepatic steatosis compared with WT. LFABP is expressed in both liver and intestine, thus in the present study, LFABP conditional knockout (cKO) mice were generated to determine the contributions of LFABP specifically within the liver or the intestine to the whole body phenotype of the global knockout. MethodsFemale liver-specific LFABP knockout (LFABPliv-/-), intestine-specific LFABP knockout (LFABPint-/-), and floxed LFABP (LFABPfl/fl) control mice were fed a 45% Kcal fat semipurified HF diet for 12 weeks. ResultsWhile not as dramatic as found for whole-body LFABP-/- mice, both LFABPliv-/- and LFABPint-/- mice had significantly higher body weights and fat mass compared with LFABPfl/fl control mice. As with the global LFABP nulls, both LFABPliv-/- and LFABPint-/- mice remained normoglycemic and normoinsulinemic. Despite their greater fat mass, the LFABPliv-/- mice did not develop hepatic steatosis. Additionally, LFABPliv-/- and LFABPint-/- mice had higher endurance exercise capacity when compared with LFABPfl/fl control mice. ConclusionsThe results suggest, therefore, that either liver-specific or intestine-specific ablation of LFABP in female mice is sufficient to induce, at least in part, the MHO phenotype observed following whole-body ablation of LFABP.

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Tawfeeq, H. R., Lackey, A. I., Zhou, Y., Diolintzi, A., Zacharisen, S., Lau, Y. H., Quadro, L., Storch, J.. 2025-01-02. Tissue-Specific Ablation of Liver Fatty Acid-Binding Protein Induces a Metabolically Healthy Obese Phenotype in Female Mice. https://doi.org/10.1101/2025.01.02.631082

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