Orexin-A neural networks integrate feeding, energy, and anxiety-obesity comorbidity regulation

The complex comorbidity of obesity and anxiety significantly exacerbates metabolic burden and compromises psychological well-being. Neurons in the lateral hypothalamus (LH) synthesize neuropeptides orexin-A and orexin-B, which are critical for orchestrating feeding behavior and energy expenditure, thereby directly regulating energy homeostasis. These orexins function as integrative modulators, coordinating autonomic, neuroendocrine, arousal, reward, and stress circuits. Dysregulation of orexin signaling is strongly implicated in both metabolic disorders like obesity and psychiatric conditions including anxiety and depression, highlighting its central role in their comorbidity.

This comprehensive review synthesizes recent advances in understanding orexin-A neural circuits, specifically focusing on their role in feeding regulation. The authors critically evaluate mechanistic insights into the intricate interplay between orexin signaling, energy balance, and the comorbidity of anxiety and obesity. The review also assesses sources of heterogeneous therapeutic outcomes observed in current research and outlines future strategies for precise modulation of the orexin system to restore metabolic and emotional homeostasis.

The review highlights the profound role of orexins as integrative modulators that coordinate diverse physiological and psychological circuits, including autonomic function, neuroendocrine responses, arousal, reward processing, and stress responses. Dysregulation of orexin signaling is strongly implicated in the pathogenesis of metabolic disorders, particularly obesity, as well as in psychiatric conditions such as anxiety and depression, underscoring its pivotal role in their comorbidity. The authors emphasize that orexin-A neural circuits are crucial for orchestrating feeding behavior and energy expenditure, directly regulating energy homeostasis. > The review identifies the central role of orexin-A in linking energy balance with emotional states, providing a mechanistic framework for understanding the complex interplay in anxiety-obesity comorbidity. It also points to the need for targeted therapeutic approaches.