Next-Generation Targets in Metabolic Syndrome: Novel Hormones, Neural Circuits, and GLP-1–Era Therapeutics

The GLP-1 era has reshaped obesity treatment by validating gut–brain pharmacology as a scalable, clinically meaningful approach. Yet obesity remains a heterogeneous, relapsing neuroendocrine disease, and many patients experience variable response, tolerability limits, and weight regain after treatment cessation. Obesity is confounded by other metabolic syndrome attributes, including but not limited to diabetes, fatty liver condition, polycystic ovarian syndrome, and hypertension. In parallel, a new wave of endocrine signals and neuromodulators –asprosin, liver-expressed antimicrobial peptide 2 (LEAP2), fabkin, fibroblast growth factor 21 (FGF21), growth differentiation factor 15 (GDF15), N-lactoyl-phenylalanine (Lac-Phe), nesfatin, insulin-like peptide 5 (INSL5), glial-derived octadecaneuropeptide (ODN), adropin, neuropeptide 26RF, among others– is rapidly refining our understanding of how circulating hormones and neuropeptides contribute to energy-balance control. Building on the clinical momentum of GLP-1–based therapies, these targets offer concrete opportunities for next-generation therapeutics, biomarker development, and mechanism-driven combination strategies.Breakthrough outcomes with GLP-1 receptor agonists and related incretin-era drugs have accelerated clinical adoption and clarified the centrality of gut–brain signaling in obesity; however, major translational gaps persist –why some patients plateau or do not respond, how adverse effects constrain dosing, how to improve durability, and how to match mechanisms to specific obesity phenotypes. This Research Topic focuses on advancing obesity research from molecular and cellular endocrine mechanisms to applications in human biology and clinical medicine, with an emphasis on diagnostics, therapeutics, and clinical management. We aim to gather further insights into translational and clinical paths for obesity therapeutics, spanning hormones, neural circuits, and GLP-1–adjacent development.We therefore invite work that connects emerging endocrine and neuropeptide signals –asprosin, LEAP2, fabkin, FGF21, GDF15, Lac-Phe, nesfatin, INSL5, spexin, neuropeptide 26RF, neuropeptide FF, adropin, and ODN– to human-relevant endpoints and tractable therapeutic strategies, including GLP-1–era combination and sequencing approaches. We welcome original research, review, mini review and perspective articles addressing, but not limited to, the following themes: • Human and preclinical mechanistic studies of novel hormones/metabolites regulating appetite, energy expenditure, and nutrient partitioning• Circuit-level neurobiology of obesity (hypothalamic–brainstem integration, reward, interoception, vagal pathways) and glial contributions• Translational biomarkers (target engagement, imaging, omics) and experimental-medicine paradigms linking mechanisms to patient outcomes• Clinical development in the GLP-1 era: responder profiling, durability/weight regain, tolerability, and rational combination therapies• Therapeutic implications for obesity complications (e.g., cardiometabolic risk, liver disease) and special populations (e.g., aging, sarcopenic obesity)Dr. Mishra holds asprosin related patents. Dr. Geisler holds patents related to several targets for energy balance control. Dr. Geisler holds shares of a private company, Coronation Bio, that has licensed two of her patents. Topic editors: Ila Mishra, Caroline Geisler, Sayantan Sur Source: https://www.frontiersin.org/research-topics/79829/next-generation-targets-in-metabolic-syndrome-novel-hormones-neural-circuits-and-glp-1-era-therapeutics