An investigation into physiological, dietary and therapeutic factors that influence inflammation and adipose tissue characteristics in humans

: (Alternative Format Thesis)

Abstract

The immune system plays an important role in protecting our body against external pathogens and in responding to changes or dysfunction in internal organs. Inflammation is a fundamental component of this process, which inflammatory cytokine concentrations reflecting both acute and chronic immune activity and varying according to health status and across the lifespan. It is now well established that adipose tissue is a metabolically active organ with important endocrine and immunological functions, acting as a reservoir for immune cells and a key regulator of inflammatory responses. Alterations in adipose tissue composition and function, associated with obesity, are key drivers of inflammation, characterised by increased immune cell infiltration, impaired adipocyte function, and a shift towards a pro-inflammatory cytokine profile. However, it has not been fully investigated whether known variation in adipose tissue characteristics with biological sex influences systemic and local inflammatory processes leading to sex-specific risk for disease. In addition, an important gap is the unexplored area of research into how lifestyle, dietary, or therapeutic interventions affect inflammatory responses at systemic and, specifically, adipose tissue levels across diverse populations by health status and age. Therefore, the overall aim of this thesis is to investigate links between inflammation, adipose tissue, and metabolic health, exploring differences across diverse populations and examining changes with lifestyle, dietary or pharmacological interventions.

Chapter 2 provides a comprehensive analysis of systemic and adipose tissue-specific inflammatory and metabolic outcomes in a cross-sectional study in healthy adults (age 30 ±11 years, BMI 24.1 ± 2.6 kg/m2). Plasma leptin and resist in concentrations were significantly higher in women than in men. Additional analyses showed that the relationships between body composition and inflammatory markers exhibited statistically significant interaction effects with sex. In men, greater adiposity was positively correlated with adipocyte-secreted adhesion molecules (ICAM-1, VCAM-1 and adiponectin). In contrast, in women, adiposity was positively correlated with plasma MCP-1 and plasma leptin. These findings suggest that, in a healthy population, inflammatory regulation is influenced by interactions between sex and adiposity. Finally, chapter 2 showed for the first time that adipose tissue contains functional T cells recognising viruses including Cytomegalovirus, Epstein Barr Virus, Varicella Zoster Virus, and SARS-CoV-2. This finding demonstrates that adipose tissue is an immunologically active organ that might contribute towards immunological memory, but these cells might also impact adipose tissue inflammation, possibly contributing towards inflammageing.

Chapter 3 examined the effects of a six-month intervention comprising either met form in administration, brisk walking, or both, on circulating inflammatory markers in men (age 66.916± 7.1 years, BMI 28.2 ± 6.2 kg/m²) with localised or locally advanced prostate cancer who were under active surveillance or who had undergone either radical prostatectomy or radiotherapy. The results showed no statistically significant changes in inflammatory cytokine levels across intervention groups compared with the others. Within the context of a heterogeneous clinical population, a feasibility study design, modest sample size and variable adherence to the interventions, these findings suggest that systemic inflammatory markers in men with prostate cancer are unlikely to change following six months of behavioural or pharmacological intervention when adherence is inconsistent.

Chapter 4 investigated the effects of four weeks of ketone ester supplementation in healthy older adults (age 68 ± 5 years, BMI 24.5 ± 3.2 kg/m²) on cytokine production and activation marker expression and the number of monocytes and T cells in peripheral blood mononuclear cells (PBMCs) and in adipose tissue-derived macrophages and T cells. The results demonstrated that four weeks of ketone ester supplementation, reported to decrease the systemic levels of inflammation in human did not significantly alter cytokine production or activation marker expression in circulating monocytes, T cells, or adipose tissue macrophages and T cells. However, adipose tissue resident macrophage counts decreased in the ketone ester supplementation group whilst it increased in the placebo group. In addition, there was a significant increase in adipocyte cytokine secretion, including IL-8,resistin, and RANTES, in the placebo group only. In addition, ex vivo β-hydroxybutyrate(BHB) suppresses the secretion of the pro-inflammatory cytokines IFN-γ and IL-1β in LPS stimulated 3-hour whole blood cultures and also limited TNF-α secretion under basal unstimulated conditions. These findings suggest that although the four-week ketone ester supplementation did not substantially alter the immune phenotype and inflammation levels among healthy older adults, it could limit adipocyte-derived cytokines that contribute towards in flammageing.

In summary the findings reported in this thesis, deepens understanding of how inflammation, adipose tissue characteristics, and related immune–metabolic processes vary across individual and population characteristics such as sex, age, and disease. It also examines whether lifestyle, dietary, and pharmacological interventions can modify these processes. Overall, the findings suggest that intervention effects are generally modest and strongly influenced by participant characteristics, intervention type, and duration. This work highlights the complexity of factors shaping human inflammation and adipose tissue biology. Collectively, these studies provide an important foundation for future research aimed at clarifying the mechanisms driving variability in these physiological responses.

Date of Award	20 May 2026
Original language	English
Awarding Institution	University of Bath
Supervisor	Francoise Koumanov (Supervisor), James Turner (Supervisor), Jean-Philippe Walhin (Supervisor), Javier Gonzalez (Supervisor), Dylan Thompson (Supervisor) & John Campbell (Supervisor)