Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia USA.
Expert Opin Drug Discov. 2021 Jul;16(7):777-790. doi: 10.1080/17460441.2021.1877654. Epub 2021 Jan 29.
: Obesity is a prevalent condition that accounts for significant morbidity and mortality across the globe. Despite substantial effort, most obesity pharmacotherapies have proven unsafe or ineffective. The use of obese mouse models provides unique insight into the hormones and mechanisms that regulate appetite and metabolism. Paramount among these models are the 'obese' and 'diabetic' mice that revealed the powerful satiety hormone leptin, revolutionizing obesity research. In this article, the authors discuss work on leptin therapy, and the clinical response to leptin in humans. The authors describe the use of modern mouse genetics to study targetable mechanisms for genetic forms of human obesity. Additionally, they describe mouse models of neuromodulation and their utility in unraveling neural circuits that govern appetite and metabolism. Combining past and present models of obesity is required for the development of safe, effective, and impactful obesity therapy. Current research in obesity can benefit from repositories of genetically engineered mouse models to discover interactions between appetitive systems and circuits. Combining leptin therapy with other satiety signals comprising the gut-brain axis is a promising approach to induce significant enduring weight loss.
肥胖是一种普遍存在的病症，在全球范围内导致了大量的发病率和死亡率。尽管付出了巨大的努力，但大多数肥胖症的药物治疗都被证明是不安全或无效的。肥胖小鼠模型的使用为调节食欲和新陈代谢的激素和机制提供了独特的见解。在这些模型中，最重要的是“肥胖”和“糖尿病”小鼠，它们揭示了强大的饱腹感激素瘦素，彻底改变了肥胖症的研究。在本文中，作者讨论了瘦素治疗的工作以及瘦素在人类中的临床反应。作者描述了使用现代小鼠遗传学来研究针对人类肥胖遗传形式的可靶向机制。此外，他们还描述了神经调节的小鼠模型及其在揭示控制食欲和新陈代谢的神经回路方面的效用。为了开发安全、有效和有影响力的肥胖症治疗方法，需要将过去和现在的肥胖症模型结合起来。目前肥胖症的研究可以从基因工程小鼠模型库中受益，以发现食欲系统和回路之间的相互作用。将瘦素治疗与包括肠道-大脑轴在内的其他饱腹感信号结合使用，是诱导显著持久减肥的一种很有前途的方法。
