Silencing CCKBR Containing Neurons in the VMN Restrains Hepatic Glucose Production to Ameliorate Diabetes in Mice
Diabetes(2020)
摘要
Optimal glucose control remains elusive for many patients with diabetes despite current therapies, necessitating the development of novel therapeutic modalities. While the central nervous system (CNS) plays a crucial role in glucose homeostasis, specific CNS targets for therapeutic intervention in diabetes have remained elusive. We recently demonstrated that the cholecystokinin b receptor (CCKbR)-expressing subpopulation of ventromedial hypothalamic nucleus (VMN; VMNCCKBR) neurons not only mediate the counter-regulatory response, but also elevate blood glucose by insulin-independently modulating hepatic glucose production under normal physiologic conditions. To test the potential therapeutic utility of these neurons for the treatment of diabetes, we cre-dependently expressed tetanus toxin in the VMN of Cckbrcre mice to silence VMNCCKBR neurons in streptozotocin (STZ)-induced (insulinopenic; Type 1 model) and leptin-deficient (ob/ob; obese Type 2 model) mice. While STZ-treated control mice became hyperglycemic and lost approximately 20% of their body weight over two weeks, VMNCCKBR-silenced mice were protected from these effects of STZ, despite similar hormone levels in STZ-treated control and CCKBRTTmice. Similarly, silencing of VMNCCKBR neurons in ob/ob mice normalized fasting and ad libitum-fed blood glucose despite identical food intake, body weight and body composition in control and VMNCCKBR-silenced mice. While VMNCCKBR-silenced ob/ob mice exhibited no alterations in glucose or insulin tolerance compared to controls, glucose clamps demonstrated decreased hepatic glucose output in the VMNCCKBR-silenced animals. These data suggest that VMNCCKBR neurons represent potential targets to reduce hepatic glucose production and ameliorate hyperglycemia in diabetes. Disclosure A. Affinati: Research Support; Self; Novo Nordisk Inc. J. Flak: None. N. Bozadjieva: None. N. Kodur: None. C.M. Cras-Meneur: None. D.A. Sandoval: Research Support; Self; MedImmune, Novo Nordisk A/S. M.G. Myers: Research Support; Self; AstraZeneca, Novo Nordisk Inc. Funding National Institutes of Health (5T32DK7245-42, 1F32DK122660-01)
更多查看译文
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要