Role of Liver Fatty Acid-Binding Protein (LFABP) in Adipose Tissue Metabolism

Obesity and adipose tissues quality are important risk factors for the development of type 2 diabetes and metabolic syndrome; this risk is related to intrinsic differences in the behavior of adipocytes in different fat depots. We have shown that the liver fatty acid-binding protein null (LFABP-/-) mouse is a model of the 'metabolically healthy obese' (MHO) state. Here, we demonstrate that the LFABP-/- mouse is a novel model of hyperplastic subcutaneous adipose tissue (SAT). LFABP-/-mice fed a high-fat diet (HFD) for 12 weeks gained 27% more weight (BW, g: 43.6 LFABP-/- vs 34.4 WT, P<0.001, n=10) and their fat mass was almost double (Fat, g: 15.4 LFABP-/-vs8.3 WT, P<0.001, n=10) that of WT. Intriguingly, despite the substantial increase in mass, inguinal white adipose tissue (iWAT) adipocyte size was >4-fold smaller (46pL LFABP-/-vs222pL WT per cell, P<0.001, n=5) and adipocyte number was 5-fold higher (23.6 LFABP-/-vs4.7 WT x 106, P=0.001, n=5) in the iWAT of LFABP-/-compared to WT mice. Upon obesity development, Lfabp deletion results in transcriptomic differences that include large effects on cholesterol biosynthesis and extracellular matrix (ECM) remodeling, likely leading to tissue growth and a state of 'adaptive fibrosis' and 'homeostatic adipogenesis' for safe excess energy storage. Since LFABP is not expressed in adipose tissues, these results suggest that its ablation promotes interorgan signaling that may limit hypertrophy and drive hyperplasia in expansion of potentially metabolically beneficial SAT, contributing to the MHO phenotype of the LFABP-/-mouse. Overall design: Male mice on a C57Bl/6J background were used for this study separated in two groups: (a) LFABP-/- males (n=5), and (b) (WT) males (n=5). The WT mice served as controls. Mice were maintained on a 12-h light/dark cycle and had unrestricted access to standard rodent chow. At 2 months of age, male LFABP-/-, and WT mice were housed 2-3 per cage and fed a 45 kcal % fat diet high in saturated fat (D10080402, Research Diets, Inc., New Brunswick, NJ) for 12 weeks. At the end of the HF feeding, mice were food deprived for 4 hours and anesthetized with ketamine/xylazine/acepromazine (80:100:150 mg/kg, intraperitoneally, respectively), prior to collection of blood and tissues. Adipose tissue depots (iWAT and iBAT) and the liver were dissected rapidly, snap-frozen in liquid nitrogen and then stored at -80oC for future analysis. Total RNA was extracted from the iWAT, iBAT, and the liver of HF-fed LFABP-/- (n=5) and WT (n=5) males, and 15uL of RNA extract were submitted for bulk RNA-seq analysis to the Molecular and Genomics Informatics Core Facility of Rutgers University.