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

Hongfei Ge; Jonitha Gardner; Xiaosu Wu; Ingrid Rulifson; Jinghong Wang; Yumei Xiong; Jingjing Ye; Edward Belouski; Ping Cao; Jie Tang; Ki Jeong Lee; Suzanne Coberly; Xinle Wu; Jamila Gupte; Lynn Miao; Li Yang; Natalie Nguyen; Bei Shan; Wen-Chen Yeh; Murielle M Véniant; Yang Li; Helene Baribault

doi:10.1371/journal.pone.0126924

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

PLoS One. 2015 Jun 17;10(6):e0126924. doi: 10.1371/journal.pone.0126924. eCollection 2015.

Authors

Hongfei Ge¹, Jonitha Gardner¹, Xiaosu Wu¹, Ingrid Rulifson¹, Jinghong Wang¹, Yumei Xiong¹, Jingjing Ye², Edward Belouski², Ping Cao², Jie Tang², Ki Jeong Lee³, Suzanne Coberly⁴, Xinle Wu¹, Jamila Gupte¹, Lynn Miao¹, Li Yang¹, Natalie Nguyen¹, Bei Shan¹, Wen-Chen Yeh¹, Murielle M Véniant⁵, Yang Li¹, Helene Baribault¹

Affiliations

¹ Amgen, Metabolic Disorders, South San Francisco, California, United States of America.
² Amgen, Protein Technologies, South San Francisco, California, United States of America.
³ Amgen, Lead Discovery, Thousand Oaks, California, United States of America.
⁴ Amgen, Pathology, South San Francisco, California, United States of America.
⁵ Amgen, Metabolic Disorders, Thousand Oaks, California, United States of America.

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.

MeSH terms

Animals
Blood Glucose / metabolism*
Cholesterol / blood
Dependovirus / genetics
Diet, High-Fat
Duodenum / metabolism
Duodenum / pathology
Eating / genetics*
Gene Expression
Gene Expression Regulation
Genetic Vectors / adverse effects*
Genetic Vectors / chemistry
Genetic Vectors / metabolism
Glucose Tolerance Test
Humans
Ileum / metabolism
Ileum / pathology
Insulin / blood
Jejunum / metabolism
Jejunum / pathology
Leptin / blood
Male
Metaplasia / etiology
Metaplasia / genetics*
Metaplasia / metabolism
Metaplasia / pathology
Mice
Mucins / administration & dosage
Mucins / genetics*
Mucins / metabolism
Obesity / etiology
Obesity / genetics*
Obesity / metabolism
Obesity / pathology
Recombinant Proteins / administration & dosage
Recombinant Proteins / genetics
Recombinant Proteins / metabolism
Signal Transduction
Trefoil Factor-2
Trefoil Factor-3
Triglycerides / blood

Substances

Blood Glucose
Insulin
Leptin
Mucins
Recombinant Proteins
TFF2 protein, human
Tff3 protein, mouse
Trefoil Factor-2
Trefoil Factor-3
Triglycerides
Cholesterol

Grants and funding

All authors were employees of Amgen Inc. at the time of their contribution to this manuscript. The authors received no specific funding for this work.