Immunomodulatory effects of distinct bioactive lipid groups on T lymphocytes within the obesity-induced inflammatory microenvironment

Kucuk, Salih ORCID: 0000-0002-0939-8508 (2024). Immunomodulatory effects of distinct bioactive lipid groups on T lymphocytes within the obesity-induced inflammatory microenvironment. University of Birmingham. Ph.D.

Preview

Kucuk2024PhD.pdf
Text
Available under License All rights reserved.
Download (24MB) | Preview

Abstract

Diet-induced obesity (DIO) is a global pandemic with an increasing trend in all age groups around the world. Overconsumption of energy dense obesogenic diets, with a high fat content, induce and escalate obesity-linked low grade chronic inflammatory microenvironment (OIIM). The OIIM is one of the main immune dysfunctions which induces and contributes to many obesity-associated diseases such as cardiovascular diseases, type-II diabetes and autoimmune diseases. Distinct bioactive fatty acids (FAs): palmitate and stearic acid, found within the high fat diet, augment the OIIM via their pro-inflammatory immunomodulatory effects. This pro-inflammatory biasing immunomodulation by bioactive FAs can lead to functional, epigenetic, developmental and migratory cellular modulations. Considering the critical contributions of T cells to OIIM, we have investigated the OIIM at two different stages by using early-DIO (3-weeks) and fully established-DIO (14-weeks) models. The aim of this thesis was to investigate the critical immunomodulatory potential of bioactive lipid groups that could potentially both alleviate or aggravate the OIIM.
WD-feeding in early-DIO model illustrated a profound bias towards pro-inflammatory Th17 phenotype with a codominant reduction of anti-inflammatory regulatory T cells which are key modulators of OIIM. Importantly, omega-3 supplementation into obesogenic WD significantly reverted the obesity-induced distortion in Th17/Treg balance and alleviated the OIIM.

Furthermore, consistent with the background literature, 14-week HFD-feeding in an fully-established DIO model was shown to induce a profound elevation towards pro- inflammatory CXCR3+ and LFA-1+ CD44+ EM CD4+ T populations compared to CD control. Interestingly, introduction of dieting and weight loss (WGWL model), illustrated the same exacerbated potential for the expansion of pro-inflammatory EM populations even after the weight loss. This preserved HFD-driven priming phenotype was further associated with epigenetic alterations driven by bioactive saturated-FAs. Importantly, utilisation of in vitro experiments further identified the potential functional alterations including autophagy and senescence which are associated with the epigenetically modified genes STK26 and CDKN1C. Altogether this work identified various obesogenic diet-derived bioactive lipid inducing DIO- linked alterations on distinct T cell populations that prone a persistent pro-inflammatory phenotype inducing the OIIM pathophysiology.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):

Supervisor(s)	Email	ORCID
Mauro, Claudio	UNSPECIFIED	orcid.org/0000-0002-3736-0099
Jones, Simon Wyn	UNSPECIFIED	orcid.org/0000-0001-6785-2310
Caamaňo, Jorge	UNSPECIFIED	orcid.org/0000-0003-3530-7056