The Neural Network of Orexin-A: Implications in Feeding Regulation and Obesity–Anxiety Comorbidity

The comorbidity of obesity and anxiety represents a complex condition with substantial health implications, exacerbating metabolic burden while compromising psychological well-being. Neurons in the lateral hypothalamus (LH) synthesize orexin-A and orexin-B, neuropeptides that orchestrate feeding behavior and energy expenditure, thereby directly regulating energy homeostasis and associated behaviors. Functioning as integrative modulators, orexins coordinate autonomic, neuroendocrine, arousal, reward, and stress circuits. Dysregulation of orexin signaling is strongly implicated in metabolic disorders, particularly obesity, as well as in psychiatric conditions including anxiety and depression, highlighting its central role in their comorbidity. This review provides a comprehensive overview of recent advances in understanding orexin-A neural circuits in feeding regulation, emphasizing mechanistic insights into the interplay between orexin signaling, energy balance, and anxiety–obesity comorbidity. Furthermore, it critically evaluates sources of heterogeneous therapeutic outcomes and outlines future strategies for precise modulation of the orexin system to restore metabolic and emotional homeostasis.