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Biochemical, Molecular, and Genetic Mechanisms

Energy Restriction Lowers the Expression of Genes Linked to Inflammation, the Cytoskeleton, the Extracellular Matrix, and Angiogenesis in Mouse Adipose Tissue¹

Yoshikazu Higami^*,,**,2, Jamie L. Barger^,**,2, Grier P. Page, David B. Allison, Steven R. Smith, Tomas A. Prolla and Richard Weindruch^,**,#,3

^* Department of Pathology and Gerontology, Nagasaki University Graduate School of Biomedical Science, Nagasaki 852-8523, Japan; Wisconsin National Primate Research Center, Madison, WI 53715; ^** Department of Medicine, University of Wisconsin-Madison, WI 53705; Department of Biostatistics, Section on Statistical Genetics, University of Alabama, Birmingham, AL 35249; Pennington Biomedical Research Center, Baton Rouge, LA 70808; Departments of Genetics and Medical Genetics, University of Wisconsin-Madison, Madison, WI 53706; and ^# Geriatric Research, Education and Clinical Center, W.S. Middleton Memorial Veterans Administration Medical Center, Madison, WI 53705

³ To whom correspondence should be addressed. Email: rhweindr{at}wisc.edu.

Using high-density oligonucleotide microarrays, we examined the actions of energy restriction (ER) on the expression of >11,000 genes in epididymal white adipose tissue (WAT) of 10- to 11-mo-old male C57Bl6 mice. Four groups were studied: controls not subjected to food restriction (CO), food-restricted 18 h before being killed (FR), short-term ER for 23 d (SER), and long-term ER for 9 mo (LER). As we reported previously, compared with CO mice, FR and SER minimally influenced the gene expression profiles; however, 345 transcripts of 6266 genes determined to be expressed in WAT were significantly altered by LER. We focus here on the 109 (31%) of these genes that were involved in either inflammation (56 genes), cytoskeleton (16 genes), extracellular matrix (23 genes), or angiogenesis (14 genes). Among these 109 genes, 104 transcripts (95%) were downregulated by LER. Western blotting for heat shock protein 47 and osteonectin, and immunohistochemical staining for hypoxia inducible factor (HIF)-1), supported the microarray data that LER downregulated the expressions of these genes. Additionally, a 75% reduction in adipocyte size with LER reflected the change in the expression of genes involved in cell morphology. Our findings provide evidence that LER suppresses the expression of genes encoding inflammatory molecules in WAT while promoting structural remodeling of the cytoskeleton, extracellular matrix, and vasculature. These alterations may play an important role in the protection against WAT-derived inflammation and in lifespan extension by LER.

KEY WORDS: • microarray • energy restriction • dietary restriction • aging

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