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

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.

Impact of Lipids on Insulin Resistance: Insights from Human and Animal Studies

“…Peptide 7, derived from TNFSF14, reduced this problem in mice. [ 37 ] N/A N/A Male C57BL/6 mice, 5 weeks old; NGBR fl/fl mice; NGBR hepKO mice; db/db mice (B6.BKS(D)-Lepr db/J ) (n = 27) HFD for 4 weeks and STZ 50 mg/kg BW for 7 days NC (citrate buffer + fed normal chow, n = 5); T2D (HFD diet + AAV9-GFP, n = 7); and T2D+NGBR (HFD diet + AAV9-NGBR, n = 7) HFD and STZ induction in mice increased lipid accumulation, NEFA and TG, and influenced IR, while NGBR regulates lipid metabolism and insulin sensitivity. [ 38 ] N/A N/A Male Wistar rats, weight 170–200 g (n = 24) HFD for 12 weeks CTL (diet and distilled water); MLT (melatonin 4 mg/kg BW); OBS (HFD 40%); and OBS+MLT (HFD and melatonin combination) (n = 6/group) HFD feeding leads to weight gain, hyperinsulinemia, oxidative stress, and inflammation in adipose tissue, triggering IR and T2DM risk.…”

“…Various studies show that mice treated with an HFD experience increased glucose intolerance and IR, 37 characterized by increased fasting blood glucose (FBG), insulin, 51 total cholesterol, TG, 68 and FFA levels, as well as decreased adiponectin levels. 53 The underlying mechanisms involve complex biological pathways.…”

“…TNFSF14, specifically Peptide 7, increases insulin signaling and fatty acid oxidation in skeletal muscle cells, improving glucose management and IR in mice fed with HFD. 37 Overexpression of NGBR suggests that this protein functions in the improvement of insulin sensitivity and the reduction of endoplasmic reticulum stress in the liver and skeletal muscle. 38 …”