Objective

PPARα/γ dual agonists have been in clinical development for the treatment of metabolic diseases including type 2 diabetes and dyslipidemia. However, severe adverse side effects led to complications in clinical trials. As most of the beneficial effects rely on the compound activity in adipocytes, the selective targeting of this cell type is a cutting-edge strategy to develop safe anti-diabetic drugs. The goal of this study was to strengthen the adipocyte-specific uptake of the PPARα/γ agonist tesaglitazar via NPY₁R-mediated internalization.

Methods

NPY₁R-preferring peptide tesaglitazar-[F⁷, P³⁴]-NPY (tesa-NPY) was synthesized by a combination of automated SPPS and manual couplings. Following molecular and functional analyses for proof of concept, cell culture experiments were conducted to monitor the effects on adipogenesis. Mice treated with peptide drug conjugates or vehicle either by gavage or intraperitoneal injection were characterized phenotypically and metabolically. Histological analysis and transcriptional profiling of the adipose tissue were performed.

Results

In vitro studies revealed that the tesaglitazar-[F⁷, P³⁴]-NPY conjugate selectively activates PPARγ in NPY₁R-expressing cells and enhances adipocyte differentiation and adiponectin expression in adipocyte precursor cells. In vivo studies using db/db mice demonstrated that the anti-diabetic activity of the peptide conjugate is as efficient as that of systemically administered tesaglitazar. Additionally, tesa-NPY induces adipocyte differentiation in vivo.

Conclusions

The use of the tesaglitazar-[F7, P34]-NPY conjugate is a promising strategy to apply the beneficial PPARα/γ effects in adipocytes while potentially omitting adverse effects in other tissues.

中文翻译：

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NPY1R靶向肽介导的PPARα/γ双重激动剂向脂肪细胞的输送增强了脂肪形成并阻止了糖尿病的发展。

客观的

PPARα/γ双重激动剂已经在临床开发中用于治疗代谢性疾病，包括2型糖尿病和血脂异常。但是，严重的不良副作用导致临床试验复杂化。由于大多数有益作用都依赖于脂肪细胞中的化合物活性，因此这种细胞类型的选择性靶向是开发安全抗糖尿病药物的前沿策略。这项研究的目的是通过NPY ₁ R介导的内在化作用来增强PPARα/γ激动剂替格列扎的脂肪细胞特异性摄取。

方法

NPY ₁ R优先肽tesaglitazar- [F ⁷，P ³⁴ ] -NPY（tesa-NPY）是通过自动SPPS和手动偶联的组合合成的。在进行分子和功能分析以验证概念后，进行了细胞培养实验以监测对脂肪形成的影响。通过肽管法或腹膜内注射用肽药物缀合物或运载体处理的小鼠在表型和代谢上得到表征。进行脂肪组织的组织学分析和转录谱分析。

结果

体外研究表明，tesaglitazar- [F ⁷，P ³⁴ ] -NPY共轭物可选择性激活NPY ₁ R表达细胞中的PPARγ，并增强脂肪细胞分化和脂肪细胞前体细胞中脂联素的表达。使用db / db小鼠进行的体内研究表明，肽缀合物的抗糖尿病活性与全身给药的替格列他扎的抗糖尿病活性一样有效。另外，tesa-NPY在体内诱导脂肪细胞分化。

结论

tesaglitazar- [F7，P34] -NPY共轭物的使用是一种有前景的策略，可在脂肪细胞中应用有益的PPARα/γ效应，同时有可能忽略其他组织的不利影响。