Inhibition of mTOR improves malnutrition induced hepatic metabolic dysfunction

Area of Science:

• Biochemistry
• Cell Biology
• Pediatric Nutrition

Background:

• Severe malnutrition causes significant child mortality, with high inpatient mortality linked to metabolic dysfunction.
• Hepatic metabolic dysfunction and impaired autophagy are correlated in malnutrition.
• Existing World Health Organization (WHO) guidelines have not fully addressed inpatient mortality in severe malnutrition.

Purpose of the Study:

• To investigate the role of mechanistic target of rapamycin complex 1 (mTORC1) inhibition in a mouse model of malnutrition-induced liver dysfunction.
• To determine if inhibiting mTORC1 can ameliorate hepatic steatosis and mitochondrial dysfunction caused by severe protein deficiency.

Main Methods:

• Wild type weanling mice were fed either an 18% or 1% protein diet for two weeks.
• A low-protein group received daily rapamycin injections to inhibit mTORC1.
• Hepatic function was assessed using histology, immunofluorescence, gene expression, metabolomics, and protein analysis.

Main Results:

• Low-protein diet induced malnutrition characteristics: weight loss, hypoalbuminemia, hypoglycemia, hepatic steatosis, and cholestasis.
• Mice on the low-protein diet exhibited reduced mitochondrial content and impaired mitochondrial function.
• Rapamycin treatment prevented hepatic steatosis, restored ATP levels, and normalized fasted plasma glucose, correlating with increased LC3-II and decreased PINK1.

Conclusions:

• Inhibition of mTORC1 partially prevents hepatic steatosis and mitochondrial dysfunction in a murine model of severe malnutrition.
• Stimulating autophagy via mTORC1 inhibition shows potential as a novel therapeutic strategy for improving metabolic function in severely malnourished children.