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Ski transgenic mice are resistant to diet-induced obesity and have altered skeletal muscle metabolic gene expression
Oral Abstracts appear that rewards limit the effectiveness of taste exposure either in the short or medium-term. doi:10.1016/j.orcp.2010.09.122 O57 Ski transgenic mice are resistant to dietinduced obesity and have altered skeletal muscle metabolic gene expression Marianne Diaz 1,2 , Nick Martel 1,2 , Steve Myers 1 , Rebecca Fitzsimmons 1 , Michael Pearen 1 , George E.O. Muscat 1 , Gary M. Leong 1,2,∗ 1 Institute
for Molecular Bioscience, University of Queensland, Brisbane, Australia 2 Department of Paediatric Endocrinology and Diabetes, Mater Children’s Hospital, South Brisbane, Australia Transgenic mice over-expressing chicken Ski (c-Ski) develop marked muscle hypertrophy, and decrease in body fat. The underlying mechanisms for the decreased fat mass in the c-Ski mice are unclear. Previous studies in our laboratory suggest that the skeletal muscle expression of the master lipogenic regulator SREBP1c and the nuclear receptor, LXR␣ are suppressed in the Ski mice (Leong GM, et al. Int J Obesity 2010; 34:524—36). Based on these and other findings, we hypothesized that c-Ski mice are resistant to diet-induced obesity. Wild type (WT) and Ski mice were challenged on a high fat (HF) diet from 6 weeks old for 12 weeks, and glucose tolerance testing performed and skeletal muscle nuclear hormone receptor (NR) and metabolic gene expression assessed by qRT-PCR using ABI Taqman Low Density Arrays (TLDAs). At 18—20 weeks of age, HF-fed WT mice compared to chow-fed WT mice were significantly heavier by 25%. By contrast, body weights of HFand chow-fed Ski mice were not significantly different, despite Ski mice having a lower rate of physical activity and the same amount of food consumption than WT mice. Moreover, in HF-fed Ski mice, the fat pads were significantly smaller and the muscle mass larger than in HF-fed WT littermate controls. Glucose tolerance tests revealed HF-fed Ski mice had unaltered glucose tolerance compared to chow-fed Ski mice, whilst as expected, WT mice on HF-diet compared to chow-fed WT mice had significantly worse glucose tolerance. Analysis of NR and metabolic mRNA gene expression in Ski mice revealed significant changes in several key NR genes and gene pathways involved in glucose and lipid metabolism that in part provide explanation for the body composition and metabolic phenotype of the Ski mice. In conclusion, these studies suggest that
S63 c-Ski transgenic mice are resistant to diet-induced obesity and glucose-intolerance and that Ski targets several key NR and metabolic gene pathways to modulate body composition and metabolism. doi:10.1016/j.orcp.2010.09.123 O58 Microarray analysis of adipocytes and stromal vascular cells from lean Klf3 deficient mice Alex Rigg, Helen Williams, Hanapi Mat Jusoh, Kim Bell-Anderson ∗ School of Molecular Bioscience, University of Sydney, Sydney, Australia Krüppel-like factor 3 (Klf3) is a zinc finger transcription factor that has recently been implicated in adipogenesis. In vitro experiments in 3T3-L1 cells, overexpression of Klf3 inhibits adipogenesis through repression of core adipogenic transcription factor C/EBP-␣. However, Klf3−/− mice have smaller and fewer adipocytes and are leaner than wildtype mice (Sue et al., 2008). Furthermore, Klf3−/− mice are more glucose tolerant than wildtype mice (Unpublished work, Williams, H., 2010). In vivo, the phenotype is inconsistent with de-repression of C/EBP-␣ and adipogenic pathways, implicating systemic effects of Klf3-deficiency in the regulation of adipose tissue mass. To gain clues as to which genes and pathways are differentially expressed in Klf3−/− white adipose tissue, Affymetrix GeneChip® Gene 1.0st Arrays of epididymal and subcutaneous adipocytes and stromal vascular fractions were performed on male Klf3−/− mice. FunNet® analysis of GO and KEGG annotations identified enriched gene clusters in differentially regulated genes. In adipocytes from Klf3−/− mice, pathways associated with metabolism including glycolysis, citrate cycle, lipid biosynthesis and oxidation were upregulated. Genes associated insulin, Jak-STAT and adipocytokine signalling pathways were also elevated. Gene clusters that were down-regulated were associated with cell adhesion, immune response and proteolysis. Genes of the adipogenic pathways were not significantly affected by Klf3 deficiency in vivo, suggesting that Klf3 is not a regulator of adipogenesis in vivo. The microarray data instead suggests that the adipose tissue is more metabolically active and less inflammatory than adipose tissue from wildtype mice. doi:10.1016/j.orcp.2010.09.124
for Molecular Bioscience, University of Queensland, Brisbane, Australia 2 Department of Paediatric Endocrinology and Diabetes, Mater Children’s Hospital, South Brisbane, Australia Transgenic mice over-expressing chicken Ski (c-Ski) develop marked muscle hypertrophy, and decrease in body fat. The underlying mechanisms for the decreased fat mass in the c-Ski mice are unclear. Previous studies in our laboratory suggest that the skeletal muscle expression of the master lipogenic regulator SREBP1c and the nuclear receptor, LXR␣ are suppressed in the Ski mice (Leong GM, et al. Int J Obesity 2010; 34:524—36). Based on these and other findings, we hypothesized that c-Ski mice are resistant to diet-induced obesity. Wild type (WT) and Ski mice were challenged on a high fat (HF) diet from 6 weeks old for 12 weeks, and glucose tolerance testing performed and skeletal muscle nuclear hormone receptor (NR) and metabolic gene expression assessed by qRT-PCR using ABI Taqman Low Density Arrays (TLDAs). At 18—20 weeks of age, HF-fed WT mice compared to chow-fed WT mice were significantly heavier by 25%. By contrast, body weights of HFand chow-fed Ski mice were not significantly different, despite Ski mice having a lower rate of physical activity and the same amount of food consumption than WT mice. Moreover, in HF-fed Ski mice, the fat pads were significantly smaller and the muscle mass larger than in HF-fed WT littermate controls. Glucose tolerance tests revealed HF-fed Ski mice had unaltered glucose tolerance compared to chow-fed Ski mice, whilst as expected, WT mice on HF-diet compared to chow-fed WT mice had significantly worse glucose tolerance. Analysis of NR and metabolic mRNA gene expression in Ski mice revealed significant changes in several key NR genes and gene pathways involved in glucose and lipid metabolism that in part provide explanation for the body composition and metabolic phenotype of the Ski mice. In conclusion, these studies suggest that
S63 c-Ski transgenic mice are resistant to diet-induced obesity and glucose-intolerance and that Ski targets several key NR and metabolic gene pathways to modulate body composition and metabolism. doi:10.1016/j.orcp.2010.09.123 O58 Microarray analysis of adipocytes and stromal vascular cells from lean Klf3 deficient mice Alex Rigg, Helen Williams, Hanapi Mat Jusoh, Kim Bell-Anderson ∗ School of Molecular Bioscience, University of Sydney, Sydney, Australia Krüppel-like factor 3 (Klf3) is a zinc finger transcription factor that has recently been implicated in adipogenesis. In vitro experiments in 3T3-L1 cells, overexpression of Klf3 inhibits adipogenesis through repression of core adipogenic transcription factor C/EBP-␣. However, Klf3−/− mice have smaller and fewer adipocytes and are leaner than wildtype mice (Sue et al., 2008). Furthermore, Klf3−/− mice are more glucose tolerant than wildtype mice (Unpublished work, Williams, H., 2010). In vivo, the phenotype is inconsistent with de-repression of C/EBP-␣ and adipogenic pathways, implicating systemic effects of Klf3-deficiency in the regulation of adipose tissue mass. To gain clues as to which genes and pathways are differentially expressed in Klf3−/− white adipose tissue, Affymetrix GeneChip® Gene 1.0st Arrays of epididymal and subcutaneous adipocytes and stromal vascular fractions were performed on male Klf3−/− mice. FunNet® analysis of GO and KEGG annotations identified enriched gene clusters in differentially regulated genes. In adipocytes from Klf3−/− mice, pathways associated with metabolism including glycolysis, citrate cycle, lipid biosynthesis and oxidation were upregulated. Genes associated insulin, Jak-STAT and adipocytokine signalling pathways were also elevated. Gene clusters that were down-regulated were associated with cell adhesion, immune response and proteolysis. Genes of the adipogenic pathways were not significantly affected by Klf3 deficiency in vivo, suggesting that Klf3 is not a regulator of adipogenesis in vivo. The microarray data instead suggests that the adipose tissue is more metabolically active and less inflammatory than adipose tissue from wildtype mice. doi:10.1016/j.orcp.2010.09.124