Catestatin Inhibits Obesity-Induced Macrophage Infiltration and Inflammation in the Liver and Suppresses Hepatic Glucose Production Leading to Improved Insulin Sensitivity
Abstract
The activation of Kupffer cells (KCs) and monocyte (Mc)-derived recruited macrophages (McMΦs) in the liver contributes to obesity-induced insulin resistance and type 2 diabetes. Diet-induced obese (DIO) mice treated with Chromogranin A (CgA) peptide catestatin (CST) showed several positive results. These included decreased hepatic/plasma lipids and plasma insulin, diminished expression of gluconeogenic genes, attenuated expression of pro-inflammatory genes, increased expression of anti-inflammatory genes in McMΦs, and inhibition of the infiltration of McMΦs resulting in improvement of insulin sensitivity. Systemic CST knockout (CST-KO) mice on normal chow diet (NCD) ate more food, gained weight, and displayed elevated blood glucose and insulin levels. Supplementation of CST normalized glucose and insulin levels. To verify that the CST deficiency caused macrophages to be very pro-inflammatory in CST-KO-NCD mice and produced glucose intolerance, we tested the effects of FACS-sorted F4/80+Ly6C- cells (representing KCs) and F4/80-Ly6C+ cells (representing McMΦs) on hepatic glucose production (HGP). Both basal and glucagon-induced HGP was markedly increased in hepatocytes co-cultured with KCs and McMΦs from NCD-fed CST-KO mice, and the effect was abrogated upon pre-treatment of CST-KO-MΦs with CST. Thus, we provide a novel mechanism of HGP suppression through CST-mediated inhibition of macrophage infiltration and function.
Additional Information
© 2018 by the American Diabetes Association. Received July 5, 2017. Accepted January 28, 2018.Attached Files
Supplemental Material - DB170788SupplementaryData.pdf
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Additional details
- Eprint ID
- 84884
- Resolver ID
- CaltechAUTHORS:20180220-082141564
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2018-02-22Created from EPrint's datestamp field
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2021-11-15Created from EPrint's last_modified field