Monoclonal therapy against calcitonin gene-related peptide lowers hyperglycemia and adiposity in type 2 diabetes mouse models.

ABSTRACT: Objective:Calcitonin Gene-Related Peptide ? (CGRP?) is a multifunctional neuropeptide found in the central and peripheral nervous system with cardiovascular, nociceptive, and gastrointestinal activities. CGRP? 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 CGRP? to assess its ability to improve glucose homeostasis in mouse models of hyperglycemia and diabetes. Methods:We examined the outcome of anti-CGRP? 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 CGRP? peptide on cultured mature adipocytes to measure its impact on mitochondrial bioenergetics and fatty acid oxidation. Furthermore, we applied recombinant CGRP? to primary islets to measure glucose-stimulated insulin secretion (GSIS) and gene expression. Results:BL6-db diabetic mice receiving anti-CGRP? treatment manifested weight loss, reduced adiposity, improved glucose tolerance, insulin sensitivity, GSIS and reduced pathology in adipose tissue and liver. Anti-CGRP? 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 CGRP? may have dual effects on adipocytes to promote lipid utilization while acting on pancreatic ?-cells to modulate insulin secretion. Analysis of CGRP? 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 CGRP? blocked GSIS and reduced insulin-2 gene expression. Mechanistical analysis revealed that recombinant CGRP? was able to reduce glycolytic capacity as well as fatty acid oxidation in primary white adipocytes. Conclusions:These results establish a multifaceted role in energy metabolism for circulating CGRP?, with the ability to modulate thermogenic pathways in adipose tissue, as well as pancreatic ?-cell dependent insulin secretion. Reducing circulating CGRP? 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 ?-cells (STZ treatment).

SUBMITTER: Halloran J 

PROVIDER: S-EPMC7566843 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature