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

Diabetes. 2019 Jun;68(6):1210-1220. doi: 10.2337/db18-1167. Epub 2019 Mar 20.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

  • Cytokines
  • MC4R protein, mouse
  • Pentacyclic Triterpenes
  • Receptor, Melanocortin, Type 4
  • Receptors, Leptin
  • Triterpenes
  • leptin receptor, mouse
  • celastrol