Weight-loss maintenance is accompanied by interconnected alterations in circulating FGF21-adiponectin-leptin and bioactive sphingolipids

Weight loss is often followed by weight regain. Characterizing endocrine alterations accompanying weight reduction and regain may disentangle the complex biology of weight-loss maintenance. Here, we profile energy-balance-regulating metabokines and sphingolipids in adults with obesity undergoing an initial low-calorie diet-induced weight loss and a subsequent weight-loss maintenance phase with exercise, glucagon-like peptide-1 (GLP-1) analog therapy, both combined, or placebo. We show that circulating growth differentiation factor 15 (GDF15) and C16:0-C18:0 ceramides transiently increase upon initial diet-induced weight loss. Conversely, circulating fibroblast growth factor 21 (FGF21) is downregulated following weight-loss maintenance with combined exercise and GLP-1 analog therapy, coinciding with increased adiponectin, decreased leptin, and overall decrements in ceramide and sphingosine-1-phosphate levels. Subgroup analyses reveal differential alterations in FGF21-adiponectin-leptin-sphingolipids between weight maintainers and regainers. Clinically, cardiometabolic health outcomes associate with selective metabokine-sphingolipid remodeling signatures. Collectively, our findings indicate distinct FGF21, GDF15, and ceramide responses to diverse phases of weight change and suggest that weight-loss maintenance involves alterations within the metabokine-sphingolipid axis. [Display omitted] •Diet-induced weight loss (WL) transiently increases GDF15 and C16:0-C18:0 ceramides•Sustained WL leads to reduced FGF21, leptin, ceramides, and S1P and increased adiponectin•Weight maintainers and regainers exhibit distinct metabokine-sphingolipid alterations•Clinically, these alterations associate with changes in cardiometabolic health outcomes Fiorenza et al. reveal selective and dynamic alterations in energy-balance-regulating metabokines and sphingolipids throughout weight loss, weight-loss maintenance, and weight regain in adults with obesity. Weight-loss maintenance elicits distinct remodeling patterns within the FGF21-adiponectin-leptin-sphingolipid axis as compared with weight regain, and these changes are associated with cardiometabolic health outcomes.