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Abstract
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder strongly associated with hepatic glucose intolerance and insulin resistance. The trefoil peptides are a family of small regulatory proteins and Tff3 is widely expressed in multiple tissues including liver. But the roles of Tff3 in regulation of glucose metabolism and insulin sensitivity in liver remain unclear. Here we show that the hepatic Tff3 expression levels were decreased in ob/ob and high-fat diet-induced obese mice. Overexpression of Tff3 in primary mouse hepatocytes inhibited the expression of gluconeogenic genes, including G6pc, PEPCK and PGC-1α, subsequently decreasing cellular glucose output. GTT and ITT experiments revealed that adenovirus-mediated overexpression of Tff3 in diabetic or obese mice improved glucose tolerance and insulin sensitivity. Collectively, our results indicated that Tff3 peptides are involved in glucose homeostasis and insulin sensitivity, providing a promising peptide on new therapies against the metabolic disorders associated with T2DM.
Highlights
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder strongly associated with hepatic glucose intolerance and insulin resistance
To eliminate concerns related to potential impact of leptin signaling deficiency in db/db or ob/ob mice, we examined the effects of Tff3 activation on glucose intolerance and insulin resistance in diet-induced obese (DIO) mice
We found that the protein levels of PGC-1α were decreased in livers of adenovirus expressing c-Myc-tagged Tff3 (Ad-Tff3)-infected mice compared to adenoviruscontaining green fluorescent protein (Ad-GFP)-infected mice (Figure 5C)
Summary
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder strongly associated with hepatic glucose intolerance and insulin resistance. In mammals the trefoil factor (TFF) family comprises 3 members: Tff (originally termed pS2), Tff ( called hSP) and Tff (formerly called ITF) [10] These proteins are small and compact peptides containing one or two trefoil domains. Our microarray analysis of gene expression in the livers of obese mice identified that Tff expression levels were decreased. We hypothesized that decreased Tff expression in livers is associated with abnormal glucose metabolism in these obese mice. We found that adenovirus-mediated overexpression of Tff in the livers of diabetic or obese mice inhibited the expression of gluconeogenic genes, thereby decreasing blood glucose levels and improving glucose tolerance. Our results indicate that secreted peptide Tff is involved in hepatic glucose homeostasis, providing a promising new lead for developing therapies against the metabolic disorders associated with T2DM
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