The role of liver fatty acid-binding protein (LFABP; FABP1) in adipose tissues cellularity and function: implications of interorgan signaling
Creators: name: Diolintzi, Anastasia
Publisher: name: No Publisher Supplied
Year: 2023

description: Liver fatty acid-binding protein (LFABP) is involved in intracellular lipid traffickingin the liver and the proximal small intestine. In addition to binding long chain fatty acids (LCFAs), LFABP also binds bile acids (BAs), endocannabinoids (eCBs), and other lipidbased molecules. We have previously shown that the LFABP null (LFABP-/-) mouse is a model of the ‘metabolically healthy obese’ (MHO) state. When challenged with a highfat diet (HFD), LFABP-/- male mice become significantly more obese, however, they display a MHO phenotype, characterized by normal plasma glucose and insulin levels, decreased hepatic steatosis, as well as increased spontaneous activity and resistance to obesity-induced decline in exercise capacity. The HF-fed LFABP-/- have markedly increased subcutaneous and visceral adipose tissue depots; however, nothing is known regarding adipose tissue cellularity, which may differentially affect obesity-associated metabolic decline.In the present study, we demonstrate that the male LFABP-/- mouse is a novel model of hyperplastic subcutaneous adipose tissue expansion, where the development of a bigger subcutaneous fat depot is due to a high number of smaller adipocytes; these are thought to be healthier than larger adipocytes, possibly contributing to the MHO phenotype of the LFABP-/- mouse. In female mice, by contrast, the marked adipose tissue growth relative to WT is also observed, but appears to be due to hypertrophic expansion. To gain insight into changes in adipose tissue growth upon Lfabp deletion and diet-induced obesity (DIO) in males, we performed RNA sequencing of adipose tissue. Changes at the transcript and pathway levels are suggestive of enhanced adipocyte differentiation in the subcutaneous fat depot of the null mice, upregulation of cholesterol biosynthesis and non-canonical NF-κB signaling, as well as downregulation of extracellular matrix (ECM) remodeling. Collectively, transcriptomic findings and immunohistochemical analyses for inflammation and fibrosis suggest healthy adipose tissue growth and, possibly, a state of ‘adaptive fibrosis’ and ‘homeostatic adipogenesis’ for safe excess energy storage through hyperplastic adipose tissue expansion, which is associated with a MHO state.LFABP is expressed in the liver and proximal small intestine but not in adipose tissues; therefore, the distinct adipocyte phenotype of HF-fed LFABP-/- mice may be due to interorgan signaling. We focused on bile acid (BA) and endocannabinoid (eCB) levels and metabolism, as LFABP is an intracellular binding protein for both. The results show marked decreases in plasma BAs and increased levels of plasma eCB, particularly oleoylethanolamide. Based on these changes as well as transcriptomic analysis we propose that the adipocyte phenotype in the MHO male LFABP-/- mice may be mediated by BA and ECS -related changes, possibly secondary to changes in gut microbiota composition.Overall, we show that the adipose tissue of the LFABP null mouse expands via hyperplasia and shows decreased inflammation, enhanced immune tolerance, and ECM remodeling that may support healthy adipose tissue expansion and protect against metabolic dysfunction in a sex-dependent fashion. Changes related to BAs and the ECS, in concert with gut microbiota alterations may be of regulatory importance, impacting adipose tissue quality in the MHO LFABP null mouse model.