Trefoil Factor 3 (TFF3) Is Regulated by Food Intake, Improves Glucose Tolerance and Induces Mucinous Metaplasia

Abstract

Trefoil factor 3 (TFF3), also called intestinal trefoil factor or Itf, is a 59 amino acid peptide found as a homodimer predominantly along the gastrointestinal tract and in serum. TFF3 expression is elevated during gastrointestinal adenoma progression and has been shown to promote mucosal wound healing. Here we show that in contrast to other trefoil factor family members, TFF1 and TFF2, TFF3 is highly expressed in mouse duodenum, jejunum and ileum and that its expression is regulated by food intake. Overexpression of TFF3 using a recombinant adeno-associated virus (AAV) vector, or daily administration of recombinant TFF3 protein in vivo improved glucose tolerance in a diet-induced obesity mouse model. Body weight, fasting insulin, triglyceride, cholesterol and leptin levels were not affected by TFF3 treatment. Induction of mucinous metaplasia was observed in mice with AAV-mediated TFF3 overexpression, however, no such adverse histological effect was seen after the administration of recombinant TFF3 protein. Altogether these results suggest that the therapeutic potential of targeting TFF3 to treat T2D may be limited.

Trefoil Factor 3 Deficiency Affects Liver Lipid Metabolism

“…This is in line with our observation of miRNA species being used to identify glycolysis/gluoconeogenesis pathways as a possible target of Tff3 action [34]. Another study by Ge at al., also in the dietinduced obesity mouse model, showed that overexpression of Tff3 in vivo improved glucose tolerance without affecting body weight, fasting insulin, triglyceride, cholesterol and leptin levels [10]. The fact that our Tff3 -/-mice exhibit improved glucose tolerance as well as Tff3 protein overexpressing obese mice models [9] is contradictory at the first moment.…”

“…All of the above contributes to the complexity of this issue and additionally underlines the complexity of metabolic regulation. Nevertheless, reduced expression of liver Tff3 was noticed in different obese mice models of various genetic background (High fat induced obesity, Lepr db /Lepr db and Lepr ob /Lepr ob ) [10], early diabetic mice [8] and steatotic liver [12], connecting Tff3 deficiency with conditions caused by specific diseases. Additionally, liver Tff3 expression was most dramatic (reduction by 600x) in the early diabetes phase of multigene diabesity model called Tally Ho mice [8].…”

“…In another study, serum level of Tff3 was increased by insulin, glucose and food intake in T1D patients as well as in healthy subjects [9]. In addition, Tff3 overexpression in vivo improved glucose tolerance in a dietary induced obesity mouse model without affecting the body weight, fasting insulin, triglyceride, cholesterol and leptin levels [10].…”

Nuclear Factor Erythroid 2-Related Factor 2 Deficiency Results in Amplification of the Liver Fat-Lowering Effect of Estrogen

“…This peptide is induced in biliary duct epithelial cells in biliary diseases (Srivatsa et al, 2002;Nozaki et al, 2004;Sasaki et al, 2007;Jiang et al, 2010). The TFF3 gene maps to the Obq4 obesity quantitative trait locus, which is highly associated with total calorie intake; indeed, the expression of Obq4 in the intestine is regulated by food intake (Kumar and Smith Richards, 2008;Ge et al, 2015). Hepatic TFF3 expression is increased in hepatic steatosis and decreased in db/ db mice and mice with diet-induced obesity (DIO), suggesting its involvement in lipid metabolism (Guillén et al, 2009;Xue et al, 2013).…”

“…Adenovirus-mediated 5.5-fold overexpression of mouse TFF3 in the liver reduces blood glucose and improves glucose tolerance in db/db mice and ameliorates insulin resistance in DIO mice (Xue et al, 2013). Adeno-associated virusmediated overexpression of human TFF3, reaching 900 ng/ml in 2 weeks after virus infection, improves glucose tolerance in DIO mice without affecting body weight, fasting insulin, and levels of triglycerides, cholesterol, and leptin in the blood (Ge et al, 2015). These two studies highlighted the critical role of TFF3 in maintaining glucose homeostasis.…”