Synergistic Intervention for Obesity: Integrating Central Appetite Regulation and Peripheral Energy Expenditure.

PURPOSE OF REVIEW: Obesity stems from a chronic imbalance between energy intake and expenditure. Current therapeutic strategies primarily focus on reducing caloric intake, yet their long-term efficacy is often limited by compensatory metabolic adaptations that lead to weight regain. This review outlines the neural mechanisms through which the central nervous system regulates appetite and the peripheral metabolic pathways that drive adipose thermogenesis. Furthermore, it examines how integrated approaches-spanning from approved to preclinical and clinical-stage investigational agents (e.g., dual- or multi-target agonists), microbiome-targeted interventions (e.g., probiotics), and exercise therapy-can synergistically overcome the limitations of single-pathway strategies. Ultimately, this review provides a theoretical foundation for designing next-generation, personalized, multimodal obesity management regimens.

RECENT FINDINGS: Traditional weight-loss drugs primarily act by centrally suppressing appetite, reducing food intake through modulation of neural circuits in regions such as the hypothalamus. However, studies show that relying on appetite suppression often triggers compensatory metabolic adaptation, ultimately leading to weight regain. Current anti-obesity drug development is therefore shifting toward integrated central-peripheral dual mechanisms. GLP‑1/glucagon dual-receptor agonists and triple-receptor agonists (such as retatrutide) have exhibited unprecedented weight-loss efficacy in clinical trials. These novel agents overcome the limitations of single-target appetite suppression by synergistically integrating central anorexigenic signaling with peripherally mediated increases in energy expenditure, thereby achieving more potent and durable weight reduction. The sustainability of obesity treatment relies on a dual-pronged intervention strategy: suppressing appetite to reduce energy intake while actively promoting energy expenditure, thereby overcoming the metabolic adaptation and weight rebound associated with monotherapy.