The role of enterocyte fatty acid-binding proteins in the intestine and whole-body energy homeostasis

The fatty acid binding protein (FABP) family consists of 14‐15 kDa cytoplasmic proteins which are abundantly expressed in various mammalian tissues. In the proximal small intestinal enterocyte, at least three FABPs are highly expressed: liver FABP (LFABP; FABP1), which is also expressed in the liver, intestinal FABP (IFABP; FABP2), which is only expressed in the small intestine, and cellular retinoid binding protein 2 (CRBP2), which is also only expressed in the small intestine. Previous studies in high fat (HF) fed mice null for either LFABP or IFABP revealed a divergent phenotype, with LFABP-/- mice displaying a metabolically healthy obese (MHO) phenotype, while IFABP-/- mice remained lean. Conditional knock out LFABP mice (LFABP-cKO) were generated to assess what role intestinal-LFABP may have in the MHO phenotype. Like HF fed whole-body LFABP-/- mice, intestine-specific LFABP-/- (LFABPint-/-) were found to have better capacity for endurance exercise when compared to their wild-type (WT) “floxed” controls (LFABPfl/fl). Additionally, female LFABPint-/- were found to be more obese after the HF feeding challenge, having greater BW gain and increased fat mass. Thus, the ablation of intestine-specific ablation of LFABP is enough to induce the MHO phenotype in female mice, and improved exercise capacity in male and female mice. To assess the intestinal phenotypic changes that might explain their lean phenotype, HF feeding studies were performed in IFABP-/- mice. Additionally, as it was observed that HF fed IFABP-/- mice had a more fragile small intestine, we hypothesized that the ablation of IFABP may result in alterations in intestinal morphology and structure. IFABP-/- mice were found to have reduced energy absorption, taking in fewer calories while excreting the same amount of calories as their WT counterparts. Additionally, IFABP-/- mice had more rapid intestinal transit, partly explaining the reduction in energy absorption. IFABP-/- mice were observed to have a shortened average villus length, a thinner muscularis layer, reduced goblet cell density, and reduced Paneth cell abundance. The ablation of IFABP also resulted in alterations in tissue retinoid levels, and mucosal vitamin A-related gene expression. Although IFABP-/- mice were found to have a drastic reduction in mucosal CRBP2 gene expression, no changes were observed in CRBP2 protein abundance. Taken together, this work has demonstrated a role for enterocyte lipid binding proteins in efficient uptake and trafficking of not only dietary lipid, but nutrients in general. These studies have also revealed a role for the enterocyte FABPs in modulating intestinal physiology, intestinal morphology, and the whole-body ramifications of such alterations.Ph.D.Includes bibliographical reference