Rapamycin Normalizes Serum Leptin by Alleviating Obesity and Reducing Leptin Synthesis in Aged Rats

Area of Science:

• Gerontology
• Metabolic Science
• Pharmacology

Background:

• Obesity in aged populations is linked to metabolic dysfunction, including hyperlipidemia and diabetes.
• Rapamycin treatment can reduce body weight and adiposity but is associated with adverse effects like hyperlipidemia.
• The precise mechanisms by which rapamycin affects leptin levels and body composition require further elucidation.

Purpose of the Study:

• To determine if a low intermittent dose of rapamycin can reduce body weight and adiposity in aged obese rats without inducing hyperlipidemia or diabetes-like symptoms.
• To investigate whether rapamycin-induced decreases in serum leptin result from reduced adiposity, diminished leptin synthesis, or both.
• To compare the effects of peripheral rapamycin administration with central infusion.

Main Methods:

• Aged obese rats (3 and 24 months old) were administered rapamycin (1mg/kg) three times weekly.
• Evaluated parameters included body weight, food intake, body composition, mTORC1 signaling, metabolic markers, serum leptin levels, and adipose tissue leptin synthesis.
• Compared outcomes to those observed following central rapamycin infusion.

Main Results:

• Intermittent, low-dose rapamycin inhibited peripheral mTORC1 signaling, preferentially reducing adiposity while sparing lean mass in aged obese rats.
• This dosing regimen led to favorable outcomes, including improved blood triglycerides, an increased lean/fat ratio, and normalized age-related elevations in serum leptin.
• Rapamycin's effects appeared to be mediated by peripheral targets, potentially signaling the hypothalamus to reduce food consumption and decrease adiposity and leptin synthesis.

Conclusions:

• A specific intermittent dosing schedule of rapamycin offers a potential therapeutic strategy for managing obesity and metabolic dysfunction in aged individuals.
• Peripheral rapamycin administration can effectively reduce adiposity and improve metabolic parameters without the adverse effects associated with continuous or higher doses.
• The findings suggest a peripheral mechanism of action for rapamycin in regulating appetite and body composition, with implications for treating age-related metabolic diseases.