Halloran Jonathan, Lalande Alexandre, Zang Mandy, Chodavarapu Harshita, Riera Céline E
Center for Neural Science and Medicine, Department of Biomedical Sciences, Board of Governors Regenerative Medicine Institute, Department of Neurology, Cedars-Sinai Medical Center, 127 South San Vicente Boulevard, Los Angeles, CA, 90048, USA.
University of California, Berkeley, USA.
Metabol Open. 2020 Oct 8;8:100060. doi: 10.1016/j.metop.2020.100060. eCollection 2020 Dec.
Calcitonin Gene-Related Peptide α (CGRPα) is a multifunctional neuropeptide found in the central and peripheral nervous system with cardiovascular, nociceptive, and gastrointestinal activities. CGRPα has been linked to obesity and insulin secretion but the role of this circulating peptide in energy metabolism remains unclear. Here, we thought to utilize a monoclonal antibody against circulating CGRPα to assess its ability to improve glucose homeostasis in mouse models of hyperglycemia and diabetes.
We examined the outcome of anti-CGRPα treatment in mouse models of diabetes and diet-induced obesity, using db/db mice, Streptozotocin (STZ) treatment to eliminate pancreatic islets, and high fat diet-fed mice. We also correlated these data with application of recombinant CGRPα peptide on cultured mature adipocytes to measure its impact on mitochondrial bioenergetics and fatty acid oxidation. Furthermore, we applied recombinant CGRPα to primary islets to measure glucose-stimulated insulin secretion (GSIS) and gene expression.
BL6-db diabetic mice receiving anti-CGRPα treatment manifested weight loss, reduced adiposity, improved glucose tolerance, insulin sensitivity, GSIS and reduced pathology in adipose tissue and liver. Anti-CGRPα failed to modulate weight or glucose homeostasis in STZ-treated animals. High fat diet-fed mice showed reduced adiposity but no benefit on glucose homeostasis. Considering these findings, we postulated that CGRPα may have dual effects on adipocytes to promote lipid utilization while acting on pancreatic β-cells to modulate insulin secretion. Analysis of CGRPα in the pancreas showed that the peptide localized to insulin-positive cells and perivascular nerves surrounding islets. Ex-vivo analysis of pancreatic islets determined that CGRPα blocked GSIS and reduced insulin-2 gene expression. Mechanistical analysis revealed that recombinant CGRPα was able to reduce glycolytic capacity as well as fatty acid oxidation in primary white adipocytes.
These results establish a multifaceted role in energy metabolism for circulating CGRPα, with the ability to modulate thermogenic pathways in adipose tissue, as well as pancreatic β-cell dependent insulin secretion. Reducing circulating CGRPα levels with monoclonal therapy presents therapeutic potential for type 2 diabetes as shown in BL6-db/db mice but has reduced potential for models of hyperglycemia resulting from loss of β-cells (STZ treatment).
降钙素基因相关肽α（CGRPα）是一种多功能神经肽，存在于中枢和外周神经系统中，具有心血管、伤害感受和胃肠道活性。CGRPα与肥胖和胰岛素分泌有关，但这种循环肽在能量代谢中的作用仍不清楚。在此，我们想利用一种针对循环CGRPα的单克隆抗体来评估其在高血糖和糖尿病小鼠模型中改善葡萄糖稳态的能力。
我们使用db/db小鼠、链脲佐菌素（STZ）处理以消除胰岛以及高脂饮食喂养的小鼠，研究了抗CGRPα治疗在糖尿病和饮食诱导肥胖小鼠模型中的结果。我们还将这些数据与重组CGRPα肽应用于培养的成熟脂肪细胞以测量其对线粒体生物能量学和脂肪酸氧化的影响相关联。此外，我们将重组CGRPα应用于原代胰岛以测量葡萄糖刺激的胰岛素分泌（GSIS）和基因表达。
接受抗CGRPα治疗的BL6-db糖尿病小鼠体重减轻、肥胖减轻、葡萄糖耐量改善、胰岛素敏感性提高、GSIS增加，并且脂肪组织和肝脏中的病理变化减轻。抗CGRPα未能调节STZ处理动物的体重或葡萄糖稳态。高脂饮食喂养的小鼠肥胖减轻，但对葡萄糖稳态无益处。考虑到这些发现，我们推测CGRPα可能对脂肪细胞有双重作用，既能促进脂质利用，又能作用于胰腺β细胞调节胰岛素分泌。胰腺中CGRPα的分析表明，该肽定位于胰岛素阳性细胞和胰岛周围的血管周围神经。胰腺胰岛的体外分析确定CGRPα阻断了GSIS并降低了胰岛素-2基因表达。机制分析表明，重组CGRPα能够降低原代白色脂肪细胞的糖酵解能力以及脂肪酸氧化。
这些结果确立了循环CGRPα在能量代谢中的多方面作用，它能够调节脂肪组织中的产热途径以及胰腺β细胞依赖性胰岛素分泌。如在BL6-db/db小鼠中所示，用单克隆疗法降低循环CGRPα水平对2型糖尿病具有治疗潜力，但对于因β细胞丧失（STZ处理）导致的高血糖模型，其潜力降低。
