growth/size/body
• increased fat mass by 20 months of age
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• body weight is normal at 4 months but significantly increased by 20 months of age
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adipose tissue
• increased white adipose tissue amount (WAT) at 4 and 20 months of age
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• increased fat mass by 20 months of age
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• increased adipogenic gene expression in differentiated adipocyte-derived stem cells (ASCs) isolated from subcutaneous fat pads of mutant mice relative to wild-type controls
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• white fat cell hypertrophy at 4 and 20 months of age
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• significant increase in epididymal WAT by 20 months of age
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• significant increase in perirenal fat by 20 months of age
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• downregulation of adiponectin mRNA and protein expression in mutant adipocytes isolated from epididymal WAT
• upregulation of plasminogen activator inhibitor-1 (PAI-1) mRNA and protein expression in mutant adipocytes isolated from epididymal WAT
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cellular
• increased adipogenic gene expression in differentiated adipocyte-derived stem cells (ASCs) isolated from subcutaneous fat pads of mutant mice relative to wild-type controls
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• severe downregulation of mitochondrial proteins involved in oxidative phosphorylation and fatty acid metabolism in mutant adipocytes isolated from epididymal WAT relative to wild-type controls
• impaired mitochondrial biogenesis in mutant adipocytes as shown by a significant reduction in mtDNA and a trend towards downregulation of genes related to mitochondrial biosynthesis
• increased mitochondrial protein carbonylation in mutant subcutaneous, epididymal, and omental WAT relative to wild-type controls
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• downregulation of mitochondrial enzymes involved in fatty acid oxidation in mutant adipocytes, suggesting impaired ability to burn excessive fat
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• aberrant mitochondrial redox state resulting in abnormal adipocyte differentiation
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• increased mitochondrial oxidative stress as shown by downregulation of antioxidant genes, including manganese superoxide dismutase, heme oxygenase-1 and quinone oxidoreductase 1, in mutant adipocytes relative to wild-type controls
• increased oxidative stress as shown by increased plasma lipid peroxidation levels (measured as thiobarbituric acid reactive substance levels) and HSP60/nitrotyrosine staining in WAT relative to wild-type controls
• increased mitochondrial protein carbonylation in mutant subcutaneous, epididymal, and omental WAT relative to wild-type controls
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homeostasis/metabolism
• downregulation of mitochondrial enzymes involved in fatty acid oxidation in mutant adipocytes, suggesting impaired ability to burn excessive fat
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• increased plasma glucose levels in the fasted state, with no change in fed glucose levels, relative to wild-type controls
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• increased plasma insulin levels in the fasted state relative to wild-type controls
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• significantly increased total plasma cholesterol levels relative to wild-type controls
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• trend towards lower plasma triglyceride levels, likely due to increased level of Lpl mRNA levels in mutant adipocytes
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• significantly increased plasma plasminogen activator inhibitor-1 (PAI-1) levels at 20 months of age
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• mice are glucose intolerant in an oral glucose tolerance test
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• mice show significantly decreased sensitivity to insulin in an insulin tolerance test
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• downregulation of adiponectin mRNA and protein expression in mutant adipocytes isolated from epididymal WAT
• in contrast, adipocyte leptin levels remain normal
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• significantly decreased plasma adiponectin levels at 20 months of age
• in contrast, plasma leptin levels remain normal
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• increased lipid metabolism in mutant adipocytes as shown by upregulation of genes related to lipid homeostasis
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