Lysosomal dysfunction results in altered energy balance.

Area of Science:

• Biochemistry
• Genetics
• Metabolic Disorders

Background:

• Lysosomal storage diseases (LSDs) are a group of genetic disorders affecting cellular waste disposal.
• Mucopolysaccharidosis (MPS) type VII mice, initially termed adipose storage deficiency mice, exhibit an unexplained lean phenotype.

Purpose of the Study:

• To investigate the common metabolic alterations in various LSDs, focusing on adipose tissue and leptin levels.
• To explore the potential of anti-inflammatory strategies and enzyme replacement therapy in managing metabolic dysfunction in LSDs.

Main Methods:

• Comparative analysis of five different LSD models (MPSI, MPSIIIB, MPSVII, Niemann-Pick A/B, infantile neuronal ceroid lipofuscinosis).
• Assessment of body composition, leptin levels, pro-inflammatory markers, caloric intake, metabolic rate, and plasma metabolites.
• Evaluation of lipid absorption and processing, liver and muscle triglyceride content.
• Testing of anti-inflammatory agents and enzyme replacement therapy (ERT).

Main Results:

• Adipose storage deficiency and low leptin levels are shared features across multiple LSDs.
• Elevated VCAM1 and MCP1 observed in LSD models; anti-inflammatory treatments were ineffective in altering adiposity.
• LSD models showed normal/high caloric intake, normal/low metabolic rate, and normal/low key metabolic markers.
• MPSI mice exhibited reduced liver triglycerides and normal lipid absorption, suggesting a shift from lipid to lysosomal storage.
• ERT normalized liver caloric density by increasing lipids, indicating impaired recycling and energy diversion to synthesis.

Conclusions:

• LSDs are characterized by a metabolic shift away from typical fat storage, potentially due to impaired lysosomal recycling.
• Energy homeostasis is maintained by diverting resources to synthesis, leading to lean phenotypes.
• LSD models provide valuable tools for studying the interplay between lysosome function, metabolism, and obesity.