A Conserved Glucocorticoid-Linked Transcriptional Program Underlies Obesity, Weight Loss, and Monogenic Immune Dysregulation

Abstract

This thesis set out to address fundamental questions in obesity immunology: why immune cells adopt a persistently activated inflammatory state in obesity, whether that state is reversible, and what molecular circuitry governs the transition between disease and health. A consistent finding was that the gene TNFAIP3, that encodes the protein product (A20), a critical negative regulator of NF-κB, is significantly downregulated in lymphocytes across tissues and in humans and mice in obesity, with expression restored following weight loss. This pattern links obesity to chronic NF-κB activation and aligns with phenotypes observed in TNFAIP3 knockout systems and in A20 haploinsufficiency (HA20), a genetic disorder where uncontrolled inflammation is a hallmark. Multi-omic analyses, genetic associations, and cross-species comparisons converge on a model in which reduced A20 lowers the threshold for lymphocyte activation and promotes persistent inflammatory tone, while restoration with weight loss resets this immune setpoint toward health. A second central theme is the role of glucocorticoids and the glucocorticoid receptor. Weight loss and fasting induce transient rises in cortisol, which activate a glucocorticoid driven anti-inflammatory program including TNFAIP3, NFKBIA, DUSP1, ZFP36, TSC22D3, and DDIT4. This network of genes includes NF-κB and AP-1 members suggesting co-operation at shared enhancers to terminate inflammation, reprogram metabolism, and direct lymphocyte trafficking via CXCR4. In obesity, reduced enhancer accessibility, impaired cortisol regeneration through HSD11B1, and altered AP-1 composition degrade this network, likely explaining the failure of immune resolution. Finally, by comparing obesity to the genetic disorder A20 haploinsufficiency, I show that both states converge on a glucocorticoid receptor driven regulatory network, despite obesity being environmentally acquired and A20 haploinsufficiency being inherited. That convergence implies that obesity may phenocopy aspects of A20 haploinsufficiency at the gene-regulatory level. Overall, this thesis provides multiple insights into transcriptional signatures associated with obesity, weight loss, fasting and A20 haploinsufficiency and their effects on lymphocyte regulation and has implications for how we think about immunity, metabolic disease and weight loss interventions.