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Celastrol Reduces Obesity in MC4R Deficiency and Stimulates Sympathetic Nerve Activity Affecting Metabolic and Cardiovascular Functions. Diabetes 2019 06;68(6):1210-1220

Date

03/22/2019

Pubmed ID

30894367

Pubmed Central ID

PMC6610022

DOI

10.2337/db18-1167

Scopus ID

2-s2.0-85066428424   18 Citations

Abstract

Leptin resistance is a hallmark of obesity with unclear etiology. Celastrol, a compound found in the roots of the Tripterygium wilfordii and known to reduce endoplasmic reticulum (ER) stress, has recently emerged as a promising candidate to treat obesity by improving leptin sensitivity. However, the underlying neural mechanisms by which celastrol reduces obesity remain unclear. Using three different mouse models of obesity-diet-induced obesity (DIO), leptin receptor (LepR)-null, and melanocortin 4 receptor (MC4R)-null mice-in this study, we show that systemic celastrol administration substantially reduces food intake and body weight in MC4R-null comparable to DIO, proving the MC4R-independent antiobesity effect of celastrol. Body weight reduction was due to decreases in both fat and lean mass, and modest but significant body weight reduction was also observed in nonobese wild-type and LepR-null mice. Unexpectedly, celastrol upregulated proinflammatory cytokines without affecting genes involved in ER stress. Importantly, celastrol steadily increased sympathetic nerve activity to the brown fat and kidney with concordant increases of resting metabolic rate and arterial pressure. Our results suggest a previously unappreciated mechanism of action of celastrol in the regulation of energy homeostasis and highlight the need for careful consideration of its development as a safe antiobesity medication.

Author List

Saito K, Davis KC, Morgan DA, Toth BA, Jiang J, Singh U, Berglund ED, Grobe JL, Rahmouni K, Cui H

Author

Justin L. Grobe PhD Associate Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adipose Tissue, Brown
Animals
Arterial Pressure
Basal Metabolism
Body Weight
Cytokines
Diet, High-Fat
Disease Models, Animal
Eating
Endoplasmic Reticulum Stress
Energy Metabolism
Inflammation
Kidney
Mice
Mice, Knockout
Obesity
Pentacyclic Triterpenes
Receptor, Melanocortin, Type 4
Receptors, Leptin
Sympathetic Nervous System
Triterpenes
Weight Loss