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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., Competing Interests: Declaration of interests A family member of R.M.S. holds Novo Nordisk stocks. S.M. is on advisory boards of AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, and Sanofi Aventis; receives lecture fees from AstraZeneca, Boehringer Ingelheim, Merck Sharp & Dohme, Novo Nordisk, and Sanofi Aventis; and is a research grant recipient from Novo Nordisk and Boehringer Ingelheim. J.J.H. is on the advisory board of Novo Nordisk. S.S.T. is a research grant recipient and receives lecture fees from Novo Nordisk., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)