The Pharmacogenetics of Weight Cycling with GLP-1 Receptor Agonists - ABSTRACT Glucagon-like receptor agonist therapy (GLP-1RA) has revolutionized the care of individuals with obesity. Sustained therapy with GLP-1RA and its derivatives leads to substantial weight loss and mitigation of metabolic comorbidities. Unfortunately, a key limitation of GLP-1RA is weight regain after discontinuation, with ~30% and ~50% of individuals ceasing treatment after 6 months and 1 year (respectively), and with >60% regain by 1 year which is accompanied by re-emergence of metabolic risk. However, weight regain and attendant metabolic risk is highly heterogeneous. Given the divergence seen between weight and metabolic risk post-GLP-1RA therapy, this also raises the potential of a metabolic “memory” of the initial GLP-1RA exposure, similar to that observed with lifestyle weight loss therapy, cyclical weight loss/regain, and metabolic disease such as diabetes. This clinical trial utilizes physiologic, pharmacodynamic, and molecular studies before/after GLP-1RA to identify/prioritize mechanisms of potential metabolic memory in 100 obese adults. Here, we propose to 1) identify signatures of changes in weight and energy expenditure (EE) arising after GLP-1RA discontinuation through multi-omic abdominal subcutaneous adipose tissue (ASAT) studies, 2) identify signatures of changes in weight and EE arising after GLP-1RA discontinuation through multi-omic peripheral blood (PB) studies, and 3) uncover mechanisms of metabolic heterogeneity during GLP-1RA administration/withdrawal via dynamic responses to a mixed meal tolerance test. For these aims, we will study and measure GLP-1RA administration/withdrawal responses in a metabolically high-risk adult population. Procedures and relevant analyses include ASAT biopsies (RNA sequencing (RNAseq)) and methylome studies), indirect calorimetry (resting EE), whole body DXA scan (adipose tissue composition), mixed meal tolerance testing (metabolite profiling and insulin action), peripheral blood draws (RNAseq, methylome studies, metabolite profiling, biochemical measurements), visual analogue scales (subjective appetite measures), food and exercise questionnaires, and anthropometric measurements. Our central hypothesis is that heterogeneity in weight changes and metabolic responses on/off GLP-1RA will identify molecular pathways underlying therapeutic—and potentially memory—effects. The study is innovative as it is the first large human physiologic study utilizing integrative/perturbational studies of metabolism (across relevant tissues/physiologies) to delineate mechanisms and implications of weight regain after initial weight loss with GLP-1RA therapy. The study is highly significant as controlled molecular studies of GLP-1RA exposure and withdrawal are not reported, highlighting a gap in our understanding of pathways of weight regain and metabolic risk—a fruitful ground for new obesity target discovery. Our work will reveal mechanistic insights into inherent (e.g., epigenetic) and mutable (e.g., transcriptomic, metabolomic) factors that impact weight regain after GLP- RA discontinuation. We envision that successful completion will identify potentially novel targets for mitigating weight regain and metabolic risk for study as adjunctive targets for obesity pharmacotherapy.
