Department of Neuroscience, Carleton University, 1125 Colonel By Drive, Ottawa, ON K1S 5B6, Canada.
Neuropeptides. 2024 Jun;105:102427. doi: 10.1016/j.npep.2024.102427. Epub 2024 Mar 30.
Obesity is a critical health condition worldwide that increases the risks of comorbid chronic diseases, but it can be managed with weight loss. However, conventional interventions relying on diet and exercise are inadequate for achieving and maintaining weight loss, thus there is significant market interest for pharmaceutical anti-obesity agents. For decades, receptor agonists for the gut peptide glucagon-like peptide 1 (GLP-1) featured prominently in anti-obesity medications by suppressing appetite and food reward to elicit rapid weight loss. As the neurocircuitry underlying food motivation overlaps with that for drugs of abuse, GLP-1 receptor agonism has also been shown to decrease substance use and relapse, thus its therapeutic potential may extend beyond weight management to treat addictions. However, as prolonged use of anti-obesity drugs may increase the risk of mood-related disorders like anxiety and depression, and individuals taking GLP-1-based medication commonly report feeling demotivated, the long-term safety of such drugs is an ongoing concern. Interestingly, current research now focuses on dual agonist approaches that include GLP-1 receptor agonism to enable synergistic effects on weight loss or associated functions. GLP-1 is secreted from the same intestinal cells as the anorectic gut peptide, Peptide YY (PYY), thus this review assessed the therapeutic potential and underlying neural circuits targeted by PYY when administered independently or in combination with GLP-1 to curb the appetite for food or drugs of abuse like opiates, alcohol, and nicotine. Additionally, we also reviewed animal and human studies to assess the impact, if any, for GLP-1 and/or PYY on mood-related behaviors in relation to anxiety and depression. As dual agonists targeting GLP-1 and PYY may produce synergistic effects, they can be effective at lower doses and offer an alternative approach for therapeutic benefits while mitigating undesirable side effects.
肥胖是全球范围内的一个严重健康问题，会增加合并慢性疾病的风险，但可以通过减肥来控制。然而，依靠饮食和运动的传统干预措施对于实现和维持体重减轻是不够的，因此，人们对用于治疗肥胖症的药物制剂有着极大的市场兴趣。几十年来，肠肽胰高血糖素样肽 1 (GLP-1) 的受体激动剂通过抑制食欲和食物奖励来引起快速减肥，在抗肥胖药物中占据重要地位。由于食物动机的神经回路与滥用药物的神经回路重叠，GLP-1 受体激动剂也已被证明可减少物质使用和复发，因此其治疗潜力可能不仅限于体重管理，还可用于治疗成瘾。然而，由于长期使用抗肥胖药物可能会增加与情绪相关的疾病（如焦虑和抑郁）的风险，并且服用 GLP-1 类药物的个体通常会感到缺乏动力，因此这些药物的长期安全性仍然是一个持续关注的问题。有趣的是，目前的研究重点是双重激动剂方法，包括 GLP-1 受体激动剂，以实现协同作用，从而达到减肥或相关功能。GLP-1 是与抑制食欲的肠肽 PYY 从相同的肠细胞分泌的，因此，本综述评估了 PYY 单独或与 GLP-1 联合给药时的治疗潜力和潜在神经回路，以抑制对食物或阿片类药物、酒精和尼古丁等滥用药物的食欲。此外，我们还回顾了动物和人体研究，以评估 GLP-1 和/或 PYY 对与焦虑和抑郁相关的情绪相关行为的影响（如果有的话）。由于针对 GLP-1 和 PYY 的双重激动剂可能会产生协同作用，因此它们可以在较低剂量下有效，同时提供一种替代方法，以获得治疗益处，同时减轻不良副作用。
