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

Area of Science:

• Endocrinology
• Neuroscience
• Metabolic Research

Background:

• Leptin resistance is a key feature of obesity with unknown causes.
• Celastrol, derived from Tripterygium wilfordii, reduces endoplasmic reticulum (ER) stress and shows potential for treating obesity by enhancing leptin sensitivity.
• The neural pathways targeted by celastrol for obesity reduction are not well understood.

Purpose of the Study:

• To investigate the neural mechanisms underlying celastrol's anti-obesity effects.
• To determine if celastrol's effects are dependent on the melanocortin 4 receptor (MC4R) pathway.
• To explore celastrol's impact on energy homeostasis and physiological parameters.

Main Methods:

• Utilized three mouse models: diet-induced obesity (DIO), leptin receptor (LepR)-null, and MC4R-null mice.
• Administered celastrol systemically to assess effects on food intake, body weight, body composition, and gene expression.
• Monitored sympathetic nerve activity, resting metabolic rate, and arterial pressure.

Main Results:

• Celastrol significantly reduced food intake and body weight in MC4R-null mice, similar to DIO mice, demonstrating an MC4R-independent effect.
• Body weight loss resulted from reductions in both fat and lean mass.
• Celastrol increased proinflammatory cytokines, did not affect ER stress genes, and elevated sympathetic nerve activity to brown adipose tissue and kidneys, increasing metabolic rate and blood pressure.

Conclusions:

• Celastrol exerts anti-obesity effects through an MC4R-independent mechanism.
• The compound influences energy homeostasis by increasing sympathetic activity, metabolic rate, and arterial pressure.
• Further research is needed to evaluate the safety and efficacy of celastrol as an anti-obesity medication due to its complex physiological effects.