Pharmacologic approaches to the treatment of obesity

治疗肥胖的药理学方法

• 批准号: 9549938
• 负责人: MARC L REITMAN
• 金额: $ 37.96万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9549938
• 关键词: Adipose tissue; Agonist; Anti-Obesity Agents; Biological Assay; Brain; Bupropion; CNR1 gene; Catecholamines; Combined Modality Therapy; Diet; Dose; Endocannabinoids; FDA approved; Fatty acid glycerol esters; Genetic; Goals; Human; Hypothalamic structure; Individual; Interleukin-4; Leptin; Macrophage Activation; Medical; Mus; Naltrexone; Obese Mice; Obesity; Paper; Patients; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Pharmacological Treatment; Pharmacology; Pharmacotherapy; Phentermine; Physiology; Pro-Opiomelanocortin; Production; Published Comment; Recruitment Activity; Reporting; Role; Series; Signal Transduction; Structure of nucleus infundibularis hypothalami; Therapeutic; Thermogenesis; United States; cost effective; editorial; liraglutide; macrophage; mouse model; obesity treatment; orlistat; topiramate

Obesity is a huge and increasing medical problem, with inadequate therapeutic options. One approach to the treatment of obesity is long-term pharmacotherapy. One modestly effective drug, orlistat, has been marketed in the United States since 1999. More recently four other drugs have been approved by the FDA: lorcaserin and Qsymia (a combination of phentermine and topiramate) in 2012 and Contrave (a combination of buproprion and naltrexone) and liraglutide (high dose) in 2014. The limited efficacy of single agents has led to the idea that additional agents and combination therapy are required. Progress in FY2017 includes the following: We wrote an editorial highlighting a remarkable study showing that treatment of patients with genetic deficiency of POMC (proopiomelanocortin) had their massive obesity revered by treatment with a melanocortin agonist, setmelanotide 1. We also wrote a commentary on a series of papers that individually appear well-done and convincing, yet fundamentally disagree. One group reported that interleukin-4 (IL-4) does not increase adipose thermogenesis and that activated macrophages do not synthesize catecholamines. This contrasts with prior findings that IL-4 activation of macrophages has been proposed to have a pivotal role in cold-induced thermogenesis by stimulating macrophage catecholamine production to recruit thermogenic beige or brite fat 2. We contributed to a study (in press) that examined the effect of a drug, JD5037, that is peripheral-acting (not acting in the brain) blocker of the endocannabinoid/CB1 receptor. The results demonstrated that peripheral CB1R blockade in diet-induced obese mice restored sensitivity to endogenous leptin. Thus, the leptin as able to elicit hypophagia via the activation of melanocortin signaling in the arcuate nucleus of the hypothalamus.

肥胖是一个巨大的和日益严重的医疗问题，治疗选择不足。 治疗肥胖症的一种方法是长期药物治疗。 奥利司他（orlistat）是一种效果温和的药物，自1999年以来已在美国上市。 最近，FDA批准了另外四种药物：2012年批准的lorcaserin和Qsymia（芬特明和托吡酯的组合）以及2014年批准的Contrave（安非他酮和纳洛酮的组合）和利拉鲁肽（高剂量）。 单一药剂的有限功效导致需要额外药剂和组合疗法的想法。 二零一七财政年度的进展包括以下各项： 我们写了一篇社论，强调了一项引人注目的研究，该研究表明，POMC（前阿黑皮素）遗传缺陷患者的治疗通过使用黑皮质素激动剂setmelanotide 1治疗而使其严重肥胖。 我们还对一系列论文写了评论，这些论文看起来做得很好，令人信服，但根本上不同意。 一个研究小组报告说，白细胞介素-4（IL-4）不增加脂肪产热，活化的巨噬细胞不合成儿茶酚胺。这与先前的研究结果形成对比，即巨噬细胞的IL-4活化已被提出通过刺激巨噬细胞儿茶酚胺产生以募集产热米色或棕色脂肪2而在冷诱导的产热中具有关键作用。 我们参与了一项研究（出版中），该研究检查了一种药物JD 5037的作用，该药物是内源性大麻素/CB 1受体的外周作用（不在大脑中起作用）阻滞剂。结果表明，饮食诱导的肥胖小鼠外周CB 1 R阻断恢复了对内源性瘦素的敏感性。 因此，瘦素能够通过激活下丘脑弓状核中的黑皮质素信号而引起食欲减退。