Tff3 Deficiency Protects against Hepatic Fat Accumulation after Prolonged High-Fat Diet

Abstract

Trefoil factor 3 (Tff3) protein is a small secretory protein expressed on various mucosal surfaces and is involved in proper mucosal function and recovery via various mechanisms, including immune response. However, Tff3 is also found in the bloodstream and in various other tissues, including the liver. Its complete attenuation was observed as the most prominent event in the early phase of diabetes in the polygenic Tally Ho mouse model of diabesity. Since then, its role in metabolic processes has emerged. To elucidate the complex role of Tff3, we used a new Tff3-deficient mouse model without additional metabolically relevant mutations (Tff3-/-/C57BL/6NCrl) and exposed it to a high-fat diet (HFD) for a prolonged period (8 months). The effect was observed in male and female mice compared to wild-type (WT) counter groups (n = 10 animals per group). We monitored the animals’ general metabolic parameters, liver morphology, ultrastructure and molecular genes in relevant lipid and inflammatory pathways. Tff3-deficient male mice had reduced body weight and better glucose utilization after 17 weeks of HFD, but longer HFD exposure (32 weeks) resulted in no such change. We found a strong reduction in lipid accumulation in male Tff3-/-/C57BL/6NCrl mice and a less prominent reduction in female mice. This was associated with downregulated peroxisome proliferator-activated receptor gamma (Pparγ) and upregulated interleukin-6 (Il-6) gene expression, although protein level difference did not reach statistical significance due to higher individual variations. Tff3-/-/C57Bl6N mice of both sex had reduced liver steatosis, without major fatty acid content perturbations. Our research shows that Tff3 protein is clearly involved in complex metabolic pathways. Tff3 deficiency in C57Bl6N genetic background caused reduced lipid accumulation in the liver; further research is needed to elucidate its precise role in metabolism-related events.

Tff3−/− Knock-Out Mice with Altered Lipid Metabolism Exhibit a Lower Level of Inflammation following the Dietary Intake of Sodium Chloride for One Week

“…When looking further into these differences and changes following the HS diet, there seems to be a genetically determined predisposition regarding pro-inflammatory IL-6, as it was higher when lacking Tff3 . The same effect was observed following a high-fat diet in knock-out mice, where IL-6 upregulation was associated with a sort of a protective role in the absence of Tff3 when it came to metabolic disorders [ 39 , 40 , 41 ]. It was also found that (3) CD25 expressing T cell rates (MLN) were significantly higher in TFF3ko mice compared with the baseline rates in WT mice.…”

Tff3 Deficiency Differentially Affects the Morphology of Male and Female Intestines in a Long-Term High-Fat-Diet-Fed Mouse Model

“…We found that Tff3-deficient males (21 weeks old) had significantly reduced body weight, which could not be noticed at later stages (age 36 weeks and 40 weeks) of HFD feeding [46]. Tff3-deficient females exhibited no such body weight time line variation, but at the end point (40 weeks), they had significantly lower blood glucose levels (Figure 1) [46].…”

“…The novel congenic mouse Tff3-/-/C57BL/6NCrl, without additional mutations present in the C57Bl/6J strain and without the impact of unintentional genetic variants due to a mixed genetic background, was fed a HFD to determine the impact of Tff3 deficiency and Tff3 protein function in this disease-related model that appears to include some adaptation mechanisms [45]. We found that Tff3-deficient males (21 weeks old) had significantly reduced body weight, which could not be noticed at later stages (age 36 weeks and 40 weeks) of HFD feeding [46]. Tff3-deficient females exhibited no such body weight time line variation, but at the end point (40 weeks), they had significantly lower blood glucose levels (Figure 1) [46].…”

“…This was not observed in Tff3-deficient female mice fed a standard diet for the same duration. During the monitored period from 4 to 40 weeks of age, we performed functional metabolic tests of glucose and insulin tolerance, as presented elsewhere [46]. We observed different time-related changes but no major difference in body weight due to Tff3 deficiency.…”

“…A group of animals consisting of 10 male WT, 10 male Tff3-/-, 10 female WT, and 10 female Tff3-/mice was fed a high-fat diet (HFD) from weaning at 4 weeks of age until sacrifice 36 weeks later (at 40 weeks of age). During that time, mice were monitored by functional metabolic tests of glucose tolerance (21 and 36 weeks old) and insulin tolerance (23 and 38 weeks old) as described in a previously published manuscript [46]. Weight and blood glucose levels at 40 weeks of age were determined.…”