Celastrol Reduces Obesity in MC4R Deficiency and Stimulates Sympathetic Nerve Activity Affecting Metabolic and Cardiovascular Functions

Kenji Saito; Kevin C Davis; Donald A Morgan; Brandon A Toth; Jingwei Jiang; Uday Singh; Eric D Berglund; Justin L Grobe; Kamal Rahmouni; Huxing Cui

doi:10.2337/db18-1167

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Celastrol Reduces Obesity in MC4R Deficiency and Stimulates Sympathetic Nerve Activity Affecting Metabolic and Cardiovascular Functions

Journal article

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Celastrol Reduces Obesity in MC4R Deficiency and Stimulates Sympathetic Nerve Activity Affecting Metabolic and Cardiovascular Functions

Kenji Saito, Kevin C Davis, Donald A Morgan, Brandon A Toth, Jingwei Jiang, Uday Singh, Eric D Berglund, Justin L Grobe, Kamal Rahmouni and Huxing Cui

Diabetes (New York, N.Y.), Vol.68(6), pp.1210-1220

06/2019

DOI: 10.2337/db18-1167

PMCID: PMC6610022

PMID: 30894367

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Abstract

Leptin resistance is a hallmark of obesity with unclear etiology. Celastrol, a compound found in the roots of the 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.

Triterpenes - pharmacology

Receptors, Leptin - genetics

Sympathetic Nervous System - drug effects

Body Weight - drug effects

Basal Metabolism - drug effects

Weight Loss - drug effects

Endoplasmic Reticulum Stress - genetics

Obesity - genetics

Adipose Tissue, Brown - innervation

Diet, High-Fat

Arterial Pressure - drug effects

Cytokines - genetics

Disease Models, Animal

Kidney - drug effects

Endoplasmic Reticulum Stress - drug effects

Inflammation

Receptor, Melanocortin, Type 4 - genetics

Mice, Knockout

Obesity - metabolism

Eating - drug effects

Animals

Cytokines - drug effects

Energy Metabolism

Kidney - innervation

Adipose Tissue, Brown - drug effects

Mice

Details

Title: Subtitle: Celastrol Reduces Obesity in MC4R Deficiency and Stimulates Sympathetic Nerve Activity Affecting Metabolic and Cardiovascular Functions
Creators: Kenji Saito - Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA
Kevin C Davis - Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA
Donald A Morgan - Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA
Brandon A Toth - Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA
Jingwei Jiang - Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA
Uday Singh - Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA
Eric D Berglund - Advanced Imaging Research Center and Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX
Justin L Grobe - Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA
Kamal Rahmouni - Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA
Huxing Cui - Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA
Resource Type: Journal article
Publication Details: Diabetes (New York, N.Y.), Vol.68(6), pp.1210-1220
DOI: 10.2337/db18-1167
PMID: 30894367
PMCID: PMC6610022
NLM abbreviation: Diabetes
ISSN: 0012-1797
eISSN: 1939-327X
Publisher: United States
Grant note: R21 MH109920 / NIMH NIH HHS P01 HL084207 / NHLBI NIH HHS R01 HL127673 / NHLBI NIH HHS T32 HL007344 / NHLBI NIH HHS R01 HL134850 / NHLBI NIH HHS I01 BX004249 / BLRD VA
Language: English
Date published: 06/2019
Academic Unit: Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984070612902771

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