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J Biol Chem. 2016 Mar 4;291(10):5185-98. doi: 10.1074/jbc.M115.705012. Epub 2015 Dec 23.

Small Molecular Allosteric Activator of the Sarco/Endoplasmic Reticulum Ca2+-ATPase (SERCA) Attenuates Diabetes and Metabolic Disorders.

Author information

1
From the Cardiovascular Research Institute and Diabetes Obesity and Metabolism Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
2
Department of Pharmaceutical Science, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064-3095.
3
Departments of Medicine and Neuroscience and Diabetes Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, and.
4
Celladon Corporation, San Diego, California 92130-3579.
5
From the Cardiovascular Research Institute and Diabetes Obesity and Metabolism Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, djamel.lebeche@mssm.edu.

Abstract

Dysregulation of endoplasmic reticulum (ER) Ca(2+) homeostasis triggers ER stress leading to the development of insulin resistance in obesity and diabetes. Impaired function of the sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) has emerged as a major contributor to ER stress. We pharmacologically activated SERCA2b in a genetic model of insulin resistance and type 2 diabetes (ob/ob mice) with a novel allosteric activator, CDN1163, which markedly lowered fasting blood glucose, improved glucose tolerance, and ameliorated hepatosteatosis but did not alter glucose levels or body weight in lean controls. Importantly, CDN1163-treated ob/ob mice maintained euglycemia comparable with that of lean mice for >6 weeks after cessation of CDN1163 administration. CDN1163-treated ob/ob mice showed a significant reduction in adipose tissue weight with no change in lean mass, assessed by magnetic resonance imaging. They also showed an increase in energy expenditure using indirect calorimetry, which was accompanied by increased expression of uncoupling protein 1 (UCP1) and UCP3 in brown adipose tissue. CDN1163 treatment significantly reduced the hepatic expression of genes involved in gluconeogenesis and lipogenesis, attenuated ER stress response and ER stress-induced apoptosis, and improved mitochondrial biogenesis, possibly through SERCA2-mediated activation of AMP-activated protein kinase pathway. The findings suggest that SERCA2b activation may hold promise as an effective therapy for type-2 diabetes and metabolic dysfunction.

KEYWORDS:

AMP-activated kinase (AMPK); Ca2+ homeostasis; SERCA2b; diabetes; endoplasmic reticulum stress (ER stress); glucose metabolism; hepatosteatosis; insulin sensitivity; lipid metabolism; mitochondria efficiency

PMID:
26702054
PMCID:
PMC4777852
DOI:
10.1074/jbc.M115.705012
[Indexed for MEDLINE]
Free PMC Article

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