Tnfsf14-derived molecules as a novel treatment for obesity and type 2 diabetes

Mark Agostino, Jennifer Rooney, Lakshini Herat, Jennifer Matthews, Allyson Simonds, Susan E. Northfield, Denham Hopper, Markus P. Schlaich, Vance B. Matthews

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Obesity is one of the most prevalent metabolic diseases in the Western world and corre-lates directly with glucose intolerance and insulin resistance, often culminating in Type 2 diabetes (T2D). Importantly, our team has recently shown that the TNF superfamily (TNFSF) member pro-tein, TNFSF14, has been reported to protect against high fat diet induced obesity and pre-diabetes. We hypothesized that mimics of TNFSF14 may therefore be valuable as anti-diabetic agents. In this study, we use in silico approaches to identify key regions of TNFSF14 responsible for binding to the Herpes virus entry mediator and Lymphotoxin β receptor. In vitro evaluation of a selection of opti-mised peptides identified six potentially therapeutic TNFSF14 peptides. We report that these peptides increased insulin and fatty acid oxidation signalling in skeletal muscle cells. We then selected one of these promising peptides to determine the efficacy to promote metabolic benefits in vivo. Importantly, the TNFSF14 peptide 7 reduced high fat diet-induced glucose intolerance, insulin resistance and hyperinsulinemia in a mouse model of obesity. In addition, we highlight that the TNFSF14 peptide 7 resulted in a marked reduction in liver steatosis and a concomitant increase in phospho-AMPK signalling. We conclude that TNFSF14-derived molecules positively regulate glucose homeostasis and lipid metabolism and may therefore open a completely novel therapeutic pathway for treating obesity and T2D.

Original languageEnglish
Article number10647
JournalInternational Journal of Molecular Sciences
Volume22
Issue number19
DOIs
Publication statusPublished - 1 Oct 2021

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