Inserm UMRS 1124 T3S, Paris University, Paris, France.
Department of Immunology, School of Medicine, Shenzhen University, Shenzhen, China.
Front Endocrinol (Lausanne). 2021 Oct 8;12:739287. doi: 10.3389/fendo.2021.739287. eCollection 2021.
Obesity is a major public health problem of our time as a risk factor for cardiometabolic disease and the available pharmacological tools needed to tackle the obesity pandemic are insufficient. Neurotensin (NTS) is a 13 amino acid peptide, which is derived from a larger precursor hormone called proneurotensin or Long Form NTS (LF NTS). NTS modulates neuro-transmitter release in the central system nervous, and facilitates intestinal fat absorption in the gastrointestinal tract. Mice lacking LF NTS are protected from high fat diet (HFD) induced obesity, hepatic steatosis and glucose intolerance. In humans, increased levels of LF NTS strongly and independently predict the development of obesity, diabetes mellitus, cardiovascular disease and mortality. With the perspective to develop therapeutic tools to neutralize LF NTS, we developed a monoclonal antibody, specifically inhibiting the function of the LF NTS (LF NTS mAb). This antibody was tested for the effects on body weight, metabolic parameters and behavior in mice made obese by high-fat diet.
C57bl/6j mice were subjected to high-fat diet (HFD) until they reached an obesity state, then food was switched to chow. Mice were treated with either PBS (control therapy) or LF NTS mAb at the dose of 5 mg/kg once a week (i.v.). Mice weight, plasma biochemical analysis, fat and muscle size and distribution and behavioral tests were performed during the losing weight period and the stabilization period.
Obese mice treated with the LF NTS mAb lost weight significantly faster than the control treated group. LF NTS mAb treatment also resulted in smaller fat depots, increased fecal cholesterol excretion, reduced liver fat and larger muscle fiber size. Moreover, mice on active therapy were also less stressed, more curious and more active, providing a possible explanation to their weight loss.
Our results demonstrate that in mice subjected to HFD-induced obesity, a blockade of LF NTS with a monoclonal antibody results in reduced body weight, adipocyte volume and increased muscle fiber size, possibly explained by beneficial effects on behavior. The underlying mechanisms as well as any future role of LF NTS mAb as an anti-obesity agent warrants further studies.
肥胖是我们这个时代的一个主要公共健康问题，是心血管代谢疾病的一个风险因素，而现有的治疗肥胖的药物工具还远远不够。神经降压素（NTS）是一种 13 个氨基酸的肽，它来源于一种叫做前神经降压素或长形式 NTS（LF NTS）的较大前体激素。NTS 调节中枢神经系统的神经递质释放，并促进胃肠道的脂肪吸收。缺乏 LF NTS 的小鼠可以防止高脂肪饮食（HFD）引起的肥胖、肝脂肪变性和葡萄糖不耐受。在人类中，LF NTS 水平的升高强烈且独立地预测肥胖、糖尿病、心血管疾病和死亡率的发生。为了开发中和 LF NTS 的治疗工具，我们开发了一种单克隆抗体，专门抑制 LF NTS 的功能（LF NTS mAb）。该抗体在高脂肪饮食诱导肥胖的小鼠中进行了体重、代谢参数和行为的测试。
C57bl/6j 小鼠接受高脂肪饮食（HFD）直至肥胖状态，然后改为普通饮食。用 PBS（对照治疗）或 LF NTS mAb（5mg/kg，每周一次，iv）治疗小鼠。在减肥期和稳定期进行小鼠体重、血浆生化分析、脂肪和肌肉大小和分布以及行为测试。
用 LF NTS mAb 治疗的肥胖小鼠体重减轻速度明显快于对照组。LF NTS mAb 治疗还导致脂肪沉积减少、粪便胆固醇排泄增加、肝脂肪减少和肌肉纤维大小增加。此外，接受主动治疗的小鼠压力也较小，好奇心和活动度更高，这可能解释了它们的体重减轻。
我们的结果表明，在高脂肪饮食诱导肥胖的小鼠中，用单克隆抗体阻断 LF NTS 可导致体重减轻、脂肪细胞体积减小和肌肉纤维大小增加，这可能是由于行为方面的有益影响。LF NTS mAb 作为一种抗肥胖药物的潜在作用及其潜在机制需要进一步研究。
