2. Academic Validation
  3. TNFSF14-Derived Molecules as a Novel Treatment for Obesity and Type 2 Diabetes

TNFSF14-Derived Molecules as a Novel Treatment for Obesity and Type 2 Diabetes

  • Int J Mol Sci. 2021 Sep 30;22(19):10647. doi: 10.3390/ijms221910647.
Mark Agostino 1 2 3,  Jennifer Rooney 4,  Lakshini Herat 4,  Jennifer Matthews 4,  Allyson Simonds 1,  Susan E Northfield 5,  Denham Hopper 5 6,  Markus P Schlaich 7 8 9,  Vance B Matthews 4
Affiliations

Affiliations

  • 1 Curtin Medical School, Curtin University, Bentley, WA 6102, Australia.
  • 2 Curtin Health and Innovation Research Institute, Curtin University, Perth, WA 6845, Australia.
  • 3 Curtin Institute for Computation, Curtin University, Perth, WA 6845, Australia.
  • 4 Dobney Hypertension Centre, School of Biomedical Sciences-Royal Perth Hospital Unit, University of Western Australia, Perth, WA 6009, Australia.
  • 5 Department of Biochemistry and Pharmacology, School of Biomedical Sciences, The University of Melbourne, Parkville, VIC 3010, Australia.
  • 6 School of Chemistry, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC 3010, Australia.
  • 7 Department of Cardiology, Royal Perth Hospital, Perth, WA 6000, Australia.
  • 8 Department of Nephrology, Royal Perth Hospital, Perth, WA 6000, Australia.
  • 9 Department of Medicine, Royal Perth Hospital, Perth, WA 6000, Australia.
PMID: 34638990 DOI: 10.3390/ijms221910647
Abstract

Obesity is one of the most prevalent metabolic diseases in the Western world and correlates 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 protein, 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 optimised 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.

Keywords

LIGHT; TNFSF14; Type 2 Diabetes; metabolic syndrome; obesity; therapy.

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