3,5-Dimethyl-2,4,6-trimethoxychalcone Lessens Obesity and MAFLD in Leptin-Deficient ob/ob Mice

Area of Science:

• Natural Product Chemistry
• Metabolic Disease Research
• Pharmacology

Background:

• Chalcones are natural compounds found in plants, known for biological activities like anti-diabetic and anti-obesity effects.
• 2',4'-Dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC), a compound from Cleistocalyx operculatus, exhibits anti-hyperglycemic properties.
• Artificial chalcone derivatives offer potential for therapeutic development by modifying natural scaffolds.

Purpose of the Study:

• To synthesize and evaluate an artificial chalcone derivative, 3,5-dimethyl-2,4,6-trimethoxychalcone (TriMetChalc).
• To investigate the effects of TriMetChalc on energy balance, obesity, and related metabolic dysfunctions in a mouse model.
• To identify molecular mechanisms underlying TriMetChalc's effects, particularly in the liver.

Main Methods:

• Synthesis of TriMetChalc from DMC.
• Administration of TriMetChalc (per os) to ob/ob mice for 3 weeks.
• Assessment of food intake, body weight, glucose tolerance, and liver steatosis.
• Comprehensive liver lipidomic analysis to identify metabolic changes.

Main Results:

• TriMetChalc administration modulated food intake by activating brain regions regulating energy balance.
• Significant reductions in weight gain, glucose intolerance, and hepatic steatosis were observed.
• Lipidomic analysis revealed TriMetChalc-induced modifications in the liver, suggesting improved hepatic status.

Conclusions:

• TriMetChalc is a promising chalcone derivative with the capacity to reduce food intake, glucose intolerance, and hepatic steatosis in an obesity mouse model.
• The findings support further investigation of TriMetChalc for metabolic disorders, including longer treatment durations and combination therapies.