Role of Pharmacotherapy in Counteracting Weight Regain in Adolescents with Severe Obesity

摘要 长期减肥维持很少实现的个人与肥胖，由于许多 生物适应发生在减肥后的设置，包括神经内分泌介导的变化， 食欲/饱腹感和能量消耗的减少。体重减轻后，外周和中枢 机制以类似于饥饿的方式做出反应，传递能量储备已经减少的感觉， 激活强烈的反反应以增加热量摄入。此外，代谢率下降，进一步 加重了体重反弹的倾向。患有严重肥胖症的青少年也不能免疫， 令人烦恼的体重恢复问题;因此，迫切需要有效和可扩展的治疗。 药物治疗有可能通过靶向靶向肿瘤细胞中的反调节机制来防止体重反弹。 减肥后的设置。不幸的是，只有一种肥胖药物是FDA批准的长期使用， 青少年和很少规定，由于适度的疗效和显着的副作用。的最 儿科管道中有希望的候选药物是芬特明和托吡酯的组合，这是 目前最有效的成人减肥药。作用机制被认为是 降低食欲，增强饱腹感，并可能增加能量消耗，使这种药物 特别适合于减肥维持的目的，因为它靶向许多生物 适应已知会导致复发和随后的体重反弹。我们小组已经初步 数据表明芬特明和托吡酯都能降低重度肥胖青少年的BMI， 具有可接受的安全性。在这项临床试验中，我们将利用芬特明/托吡酯靶向对抗- 负责膳食替代治疗后体重恢复的调节途径（已知的结构化膳食） 热量含量），目的是加强减肥维持， 改善共病结局。重要的是，我们将最大限度地发挥我们的临床效用和整体影响， 通过使用敏感措施全面表征芬特明/托吡酯的安全性的研究， 心脏自主神经功能、动脉僵硬度、认知和骨骼健康，以及检查 这种药物会抵消体重反弹的机制。

Abstract Long-term weight loss maintenance is seldom achieved by individuals with obesity owing to numerous biological adaptations occurring in the post-weight loss setting, including neuroendocrine-mediated changes in appetite/satiety and reduction of energy expenditure. Following weight loss, peripheral and central mechanisms respond in a way similar to starvation by conveying a sense that energy reserves have dwindled, activating a strong counter-response to increase caloric intake. Moreover, metabolic rate drops, further compounding the propensity for weight rebound. Adolescents with severe obesity are not immune to the vexing issue of weight regain; therefore, effective and scalable treatments are urgently needed. Pharmacotherapy has the potential to prevent weight regain by targeting counter-regulatory mechanisms in the post-weight loss setting. Unfortunately, only one obesity medication is FDA-approved for long-term use in adolescents and is seldom prescribed owing to modest efficacy and notable side effects. Among the most promising candidates in the pediatric pipeline is the combination of phentermine and topiramate, which is the most effective adult weight loss medication currently available. The mechanisms of action are thought to reduce appetite, enhance satiety, and potentially increase energy expenditure, making this medication particularly well-suited for the purpose of weight loss maintenance since it targets many of the biological adaptations known to induce relapse and subsequent weight regain. Our group has generated preliminary data demonstrating that both phentermine and topiramate reduce BMI in adolescents with severe obesity and have acceptable safety profiles. In this clinical trial, we will utilize phentermine/topiramate to target counter- regulatory pathways responsible for weight regain after meal replacement therapy (structured meals of known caloric content) in adolescents with severe obesity with a goal of enhancing weight loss maintenance and improving co-morbidity outcomes. Importantly, we will maximize the clinical utility and overall impact of our study by comprehensively characterizing the safety of phentermine/topiramate utilizing sensitive measures of cardiac autonomic function, arterial stiffness, cognition, and bone health, as well as examine the extent to which this medication counteracts mechanisms of weight regain.