Mráziková Lucia, Neprašová Barbora, Mengr Anna, Popelová Andrea, Strnadová Veronika, Holá Lucie, Železná Blanka, Kuneš Jaroslav, Maletínská Lenka
Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech.
Institute of Physiology, Czech Academy of Sciences, Prague, Czech.
Front Pharmacol. 2021 Nov 18;12:779962. doi: 10.3389/fphar.2021.779962. eCollection 2021.
Obesity and type 2 diabetes mellitus (T2DM) are preconditions for the development of metabolic syndrome, which is reaching pandemic levels worldwide, but there are still only a few anti-obesity drugs available. One of the promising tools for the treatment of obesity and related metabolic complications is anorexigenic peptides, such as prolactin-releasing peptide (PrRP). PrRP is a centrally acting neuropeptide involved in food intake and body weight (BW) regulation. In its natural form, it has limitations for peripheral administration; thus, we designed analogs of PrRP lipidized at the N-terminal region that showed high binding affinities, increased stability and central anorexigenic effects after peripheral administration. In this review, we summarize the preclinical results of our chronic studies on the pharmacological role of the two most potent palmitoylated PrRP31 analogs in various mouse and rat models of obesity, glucose intolerance, and insulin resistance. We used mice and rats with diet-induced obesity fed a high-fat diet, which is considered to simulate the most common form of human obesity, or rodent models with leptin deficiency or disrupted leptin signaling in which long-term food intake regulation by leptin is distorted. The rodent models described in this review are models of metabolic syndrome with different severities, such as obesity or morbid obesity, prediabetes or diabetes and hypertension. We found that the effects of palmitoylated PrRP31 on food intake and BW but not on glucose intolerance require intact leptin signaling. Thus, palmitoylated PrRP31 analogs have potential as therapeutics for obesity and related metabolic complications.
肥胖症和2型糖尿病（T2DM）是代谢综合征发展的先决条件，代谢综合征在全球正达到流行程度，但目前可用的抗肥胖药物仍然很少。治疗肥胖症及相关代谢并发症的一种有前景的手段是厌食肽，如催乳素释放肽（PrRP）。PrRP是一种作用于中枢的神经肽，参与食物摄入和体重（BW）调节。以其天然形式，它在外周给药方面存在局限性；因此，我们设计了在N端区域脂化的PrRP类似物，这些类似物在外周给药后显示出高结合亲和力、增加的稳定性和中枢厌食作用。在这篇综述中，我们总结了我们对两种最有效的棕榈酰化PrRP31类似物在各种肥胖、葡萄糖不耐受和胰岛素抵抗的小鼠和大鼠模型中的药理作用进行的慢性研究的临床前结果。我们使用了喂食高脂饮食的饮食诱导肥胖小鼠和大鼠，这种饮食被认为模拟了人类最常见的肥胖形式，或者使用了瘦素缺乏或瘦素信号传导中断的啮齿动物模型，其中瘦素对食物摄入的长期调节被扭曲。本综述中描述的啮齿动物模型是不同严重程度的代谢综合征模型，如肥胖或病态肥胖、糖尿病前期或糖尿病以及高血压。我们发现棕榈酰化PrRP31对食物摄入和体重的影响，但对葡萄糖不耐受没有影响，需要完整的瘦素信号传导。因此，棕榈酰化PrRP31类似物有潜力作为肥胖症及相关代谢并发症的治疗药物。
