Lysosomal dysfunction results in altered energy balance.

The mucopolysaccharidosis (MPS) type VII mouse was originally described as the adipose storage deficiency mouse because of its extreme lean phenotype of unknown etiology. Here, we show that adipose storage deficiency and lower leptin levels are common to five different lysosomal storage diseases (LSDs): MPSI, MPSIIIB, MPSVII, Niemann-Pick type A/B, and infantile neuronal ceroid lipofuscinosis. Elevated circulating pro-inflammatory proteins (VCAM1 and MCP1) were found in multiple LSDs. Multiple anti-inflammatory strategies (dexamethasone, MCP1 deficiency, M3 expression) failed to alter adiposity in LSD animals. All of the models had normal or greater caloric intake and lower to normal metabolic rate, fasting plasma glucose, non-esterified fatty acids, cholesterol, and triglycerides. Triglycerides were lower in the livers of MPSI mice, and the trend was lower in the muscle. Lipid absorption and processing in MPSI mice were indistinguishable from those in normal mice following oral gavage of olive oil. The increased lean mass of MPSI and MPSIIIB mice suggests a shift in adipose triglycerides to lysosomal storage. In agreement, MPSI livers had a similar total caloric content but reduced caloric density, indicating a shift in energy from lipids to proteins/carbohydrates (lysosomal storage). Enzyme replacement therapy normalized the caloric density within 48 h without reducing total caloric content. This was due to an increase in lipids. Recycling of stored material is likely reduced or nonexistent. Therefore, to maintain homeostasis, energy is likely diverted to synthesis at the expense of typical energy storage depots. Thus, these diseases will serve as important tools in studying the role of lysosome function in metabolism and obesity.