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Abstract

Systemic and cellular metabolism are increasingly recognized as key regulators of chronic inflammation, a process implicated in the pathogenesis of metabolic disease. The ketone body, 𝛃-hydroxybutyrate (BHB) has garnered interest, not only as a metabolic fuel, but also as an immunomodulatory molecule. However, the anti-inflammatory properties of BHB are incompletely characterized in humans and across populations of differing health status. This dissertation aims to 1) advance understanding of the differential immunometabolic responses to ketogenic interventions across a spectrum of metabolic disease, and 2) determine the immunomodulatory potential of BHB and the broader ketogenic metabolic state in humans. A series of studies examined these questions by systematically manipulating metabolism via: i) ex vivo BHB treatment of immune cells, ii) acute and repeated exogenous BHB treatment in vivo, and iii) endogenously elevating BHB through fasting. Furthermore, the differential immunomodulatory effects of such metabolic perturbations were explored at the cellular and systemic level in people living with obesity and/or type 2 diabetes (T2D). Study 1, in leukocytes from individuals living with obesity, found that ex vivo treatment with BHB dose-dependently suppressed LPS-stimulated pro-inflammatory cytokine secretion but increased anti-inflammatory IL-10. Study 2 extended these findings in vivo by exogenously elevating BHB via ingestion of a single dose of a ketone monoester supplement (KME) in individuals living with T2D. This increased plasma IL-10 90 minutes following ingestion, which corresponded to peak blood BHB. In Study 3, individuals living with T2D ingested KME thrice-daily for 14 days to repeatedly elevate BHB. While this did not alter plasma cytokines or leukocyte subsets, direct treatment of leukocytes ex vivo with BHB modulated inflammatory cytokine concentration in a time- and glucose- dependent manner. Study 4 found that individuals living with obesity exhibited a blunted immunometabolic response to a 48-hour fast compared to lean individuals. This was evidenced by blunted endogenous ketogenesis and impaired ability to upregulate T cell fat oxidation. Collectively, this dissertation suggests that while BHB may effectively reduce markers of inflammation in individuals living with obesity or T2D, this group may be less likely to experience these benefits from endogenous ketogenic interventions due to impaired metabolic adaptability.