Research progress in neural regulatory mechanisms and targeted therapy of obesity (Review).

Obesity is a multifactorial chronic metabolic disease driven by disrupted energy homeostasis and excessive adipose tissue (AT) deposition under genetic, environmental and central neural regulation. Sustained energy surplus triggers AT hypertrophy, endocrine dysfunction and low‑grade inflammation, elevating risks of type 2 diabetes mellitus, cardiovascular diseases and multiple cancers while impairing physical‑mental well‑being. Hypothalamic central neural circuits integrate peripheral metabolic signals to govern feeding and systemic energy balance and serve as core pathological drivers of obesity. Conventional interventions including bariatric surgery, calorie restriction and exercise yield only transient weight loss with poor long‑term outcomes, as they fail to reverse obesity‑related neural‑circuit dysfunction and thus produce high weight‑regain rates. Translational obstacles remain for neuromodulatory therapies, including poorly defined cell‑type‑specific neural control and limited blood‑brain barrier penetration of candidate agents. The present review systematically outlined obesity‑associated hierarchical neural networks centered on hypothalamic arcuate nucleus pro‑opiomelanocortin and agouti‑related peptide neurons and the leptin‑melanocortin axis. The present review summarized recent progress in hypothalamic neurons, key neuro‑transmitters and downstream cascades controlling energy metabolism; characterized gut‑microbiota‑vagus‑nerve gut‑brain signaling and dual appetite‑regulatory roles of short‑chain fatty acids; and delineated pathological links between gut dysbiosis and hypothalamic pro‑opiomelanocortin neuronal injury, distinguishing confirmed mechanisms from unvalidated hypotheses. Three neural‑targeted anti‑obesity modalities (GLP‑1R agonists, MC4R agonists and NMU‑R2 small‑molecule candidates) are comparatively assessed, covering preclinical evidence for NMU‑R2, adverse‑effect profiles, target populations and animal‑to‑human translational gaps. The present study further addresses multimodal combined interventions and balanced pros‑and‑cons of neuromodulation techniques. This multi‑system overview provided theoretical support for developing novel precision anti‑obesity strategies.