Osborne Brenna, Patel Rekha S, Krause-Hauch Meredith, Lui Ashley, Vidyarthi Gitanjali, Patel Niketa A
Research Service, James A. Haley Veteran's Hospital, 13000 Bruce B Downs Blvd, Tampa, FL 33612, USA.
Department of Molecular Medicine, University of South Florida, Tampa, FL 33612, USA.
Biology (Basel). 2024 Nov 18;13(11):943. doi: 10.3390/biology13110943.
Obesity promotes metabolic diseases such as type 2 diabetes and cardiovascular disease. PKCδI is a serine/threonine kinase which regulates cell growth, differentiation, and survival. Caspase-3 cleavage of PKCδI releases the C-terminal catalytic fragment (PKCδI_C), which promotes inflammation and apoptosis. We previously demonstrated an increase in PKCδI_C in human obese adipose tissue (AT) and adipocytes. Subsequently, we designed a small molecule drug called NP627 and demonstrated that NP627 specifically inhibited the release of PKCδI_C in vitro. Here, we evaluate the in vivo safety and efficacy of NP627 in a diet-induced obese (DIO) mouse model. The results demonstrate that NP627 treatment in DIO mice increased glucose uptake and inhibited the cleavage of PKCδI_C in the AT as well as in the kidney, spleen, and liver. Next, RNAseq analysis was performed on the AT from the NP627-treated DIO mice. The results show increases in ADIPOQ and CIDEC, upregulation of AMPK, PI3K-AKT, and insulin signaling pathways, while inflammatory pathways were decreased post-NP627 administration. Further, levels of lncRNAs associated with metabolic pathways were affected by NP627 treatment. In conclusion, the study demonstrates that NP627, a small-molecule inhibitor of PKCδI activity, is not toxic and that it improves the metabolic function of DIO mice in vivo.
肥胖会引发2型糖尿病和心血管疾病等代谢性疾病。蛋白激酶CδI（PKCδI）是一种丝氨酸/苏氨酸激酶，可调节细胞生长、分化和存活。PKCδI的半胱天冬酶-3切割会释放C端催化片段（PKCδI_C），该片段会促进炎症和细胞凋亡。我们之前证明了人肥胖脂肪组织（AT）和脂肪细胞中PKCδI_C的增加。随后，我们设计了一种名为NP627的小分子药物，并证明NP627在体外能特异性抑制PKCδI_C的释放。在此，我们评估NP627在饮食诱导肥胖（DIO）小鼠模型中的体内安全性和疗效。结果表明，用NP627处理DIO小鼠可增加葡萄糖摄取，并抑制AT以及肾脏、脾脏和肝脏中PKCδI_C的切割。接下来，对用NP627处理的DIO小鼠的AT进行了RNA测序分析。结果显示，脂联素（ADIPOQ）和细胞死亡诱导DFFA样效应因子C（CIDEC）增加，AMPK、PI3K-AKT和胰岛素信号通路上调，而在给予NP627后炎症通路减少。此外，与代谢途径相关的长链非编码RNA（lncRNA）水平受到NP627处理的影响。总之，该研究表明，PKCδI活性的小分子抑制剂NP627无毒，且能在体内改善DIO小鼠的代谢功能。
