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J. Biol. Chem., Vol. 282, Issue 49, 35765-35771, December 7, 2007

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Lysosomal Dysfunction Results in Altered Energy Balance^*

Josh C. Woloszynek, Trey Coleman^¶, Clay F. Semenkovich^¶, and Mark S. Sands¹

From the Departments of Medicine, Genetics, and ^¶Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110

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.

Received for publication, June 21, 2007 , and in revised form, September 11, 2007.

^* This work was supported by grants from the National MPS Society (to J. C. W. and M. S. S.), the Lauren's Hope Foundation (to J. C. W. and M. S. S.), and the Batten Disease Support and Research Association (to M. S. S.) and by National Institutes of Health Grants DK57586 and NS043205 (to M. S. S.) and Grants DK56341 and HL083762 (to C. F. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental "Experimental Procedures," Figs. 8-11, Table 1, and a reference.

¹ To whom correspondence should be addressed: Dept. of Medicine, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. Tel.: 314-362-5494; Fax: 314-362-9333; E-mail: msands{at}im.wustl.edu.

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