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

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.

Neural Underpinnings of Obesity: The Role of Oxidative Stress and Inflammation in the Brain

“…The corrected body weight can be largely explained by increased leptin sensitivity in the hypothalamus since celastrol was not effective in leptin-deficient ob/ob mice or leptin receptor-deficient db/db mice. In contrast to the study by Saito and colleagues [ 132 ], the anti-obesity action of celastrol was associated with reduced ER stress in the hypothalamus. Kyriakou and colleagues [ 134 ] have recently shown that deletion of hypothalamic leptin signaling inhibitors—PTP1B and TCPTP—successfully lowers body weight in diet-induced obese mice, supporting the concept that celastrol restores the control of energy balance through enhancing hypothalamic leptin sensitivity.…”

“…A compound found in the root extracts of Tripterygium wilfordii , celastrol is reported to exhibit antioxidant, anti-inflammatory, anti-cancer, and anti-neurodegenerative activity [ 130 , 131 ]. Saito and colleagues [ 132 ] have demonstrated that only 10 days of systemic celastrol injection is sufficient to significantly reduce food intake and body weight in both HFD-fed obese mice and MC4R-deficient obese mice. However, inflammatory mediators including TNF-α and IL-1β were upregulated without any changes in ER stress markers in the hypothalamus of celastrol-treated mice.…”

Celastrol mitigates high glucose‐induced inflammation and apoptosis in rat H9c2 cardiomyocytes via miR‐345‐5p/growth arrest‐specific 6

“…6,7 Accumulating evidence has suggested that Cel promotes cardiomyocyte survival and leads to the reduction of ischaemic-induced myocardial damage and cardiac fibrosis. [8][9][10] Intriguingly, Cel can protect against high glucose (HG)-induced podocyte injury. 11 A randomized controlled trial indicates that Cel, as an effective and safe adjuvant drug, cooperates with oral nifedipine to alleviate hypertension in patients with pre-eclampsia.…”

Celastrol inhibits intestinal lipid absorption by reprofiling the gut microbiota to attenuate high-fat diet-induced obesity

“…Celastrol (also known as tripterine), a compound isolated from Tripterygium wilfordii or other members of the Celastraceae family, has been reported to have antiinflammatory and anticancer effects ( Allison et al., 2001 ; Kashyap et al., 2018 ; Lee et al., 2006 ; Pang et al., 2010 ). In recent years, celastrol has been proven to have a strong anti-obesity effect and has the potential to be an anti-obesity drug ( Chellappa et al., 2019 ; Feng et al., 2019 ; Kyriakou et al., 2018 ; Liu et al., 2015 ; Ma et al., 2015 ; Pfuhlmann et al., 2018 ; Saito et al., 2019 ; Wang et al., 2014 ). The possible mechanisms of its weight-loss effect have also been reported.…”