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Phenotypes Associated with This Genotype
Genotype
MGI:3028851
Allelic
Composition
Tg(aP2-SREBF1c)9884Reh/0
Genetic
Background
involves: C57BL/6J * SJL
Find Mice Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Tg(aP2-SREBF1c)9884Reh mutation (1 available)
phenotype observed in females
phenotype observed in males
N normal phenotype
mortality/aging
• ~20% of mice fail to thrive and die within the first 3 weeks of life

cellular
• hepatic mitochondrial respiration is transiently increased and declines with aging along with higher muscle reactive oxygen species production
• in the fed state, hepatic beta-oxidation-linked respiration is higher at 18 weeks, but not 36 weeks, of age
• in the fed state, hepatic tricarboxylic acid (TCA) cycle-linked respiration is increased at 18 weeks, but not 36 weeks, of age
• impaired lipid oxidation, with an inability to switch from glucose to lipid oxidation
• systemic and muscle-specific oxidative stress develops after a long-standing insulin resistance

integument
• subcutaneous fat depots are decreased by 90%

growth/size/body
• body weight is increased by 10% at 18 and 36 weeks of age
• however, energy expenditure and food intake are unchanged during light (fasted) and dark (fed) periods
• mice appear slightly runted during the first week of life
• although most mice consuming a chow diet gain weight and reach a similar weight to that of control littermates by P40, a few remain runted throughout life
• during the first week of life mice exhibit a distended abdomen due to liver enlargement

adipose tissue
N
• despite adipose tissue defects, adipogenesis is normal in embryonic fibroblasts
• brown fat is hypertrophic and contains fat-laden cells that resemble immature white fat
• at P7, mice display enlarged interscapular and submandibular brown fat depots relative to control mice
• at P8, the cytoplasm of mutant brown adipocytes displays large unilocular vacuoles similar to those of immature white adipocytes but unlike the small multilocular vacuoles observed in wild-type brown adipocytes
• at P40, most mutant brown adipocytes contain a prominent unilocular fat droplet
• at P8, mutant brown adipocytes are dramatically enlarged and stain palely
• at P40, most mutant brown adipocytes remain significantly enlarged
• at P8, the mutant epididymal fat pad consists predominantly of small immature adipocytes with brightly eosinophilic cytoplasm and a distinct unilocular vacuole
• at P40, the mutant epididymal white fat contains a mixture of mature and immature adipocytes with significant size heterogeneity; immature adipocytes with bright eosinophilic cytoplasm, a round nucleus, and a distinct unilocular vacuole are observed
• at P40, some epididymal fat pads exhibit histological evidence of mild inflammation and fibrosis
• at 12 weeks of age, the mutant epididymal fat pad weighs only ~35% of the wild-type fat pad (160 mg versus 510 mg, respectively)
• at P7, all mice exhibit enlarged interscapular brown fat pads, manifested as bilobed interscapular humps
• at 7-12 weeks of age, mutant interscapular fat pads appear significantly enlarged, very firm, and white
• at P40, mutant interscapular brown fat consists of enlarged adipocytes containing large unilocular fat droplets; the interstitium shows signs of mild chronic inflammation
• at 12 weeks of age, mutant interscapular fat weighs nearly twice as much as wild-type (110 mg versus 58 mg, respectively)
• white fat fails to differentiate fully, and the size of white fat depots is significantly reduced
• subcutaneous fat depots are decreased by 90%
• at 7-12 weeks of age, mutant white adipose tissue is atrophic (J:50770)
• at P40, epididymal, omental and perinephric white fat deposits are significantly reduced (J:50770)
• visceral fat depots are decreased by 56% (J:249664)

muscle
• mice show increased intramyocellular lipids
• total cytosolic and membrane diacylglycerol is increased in skeletal muscle of 18 week old mice
• both cytosolic and membrane C18:1/C16:0-, C18:1/C18:1-, and C18:1/C18:2-containing diacylglycerol are increased

homeostasis/metabolism
• impaired lipid oxidation, with an inability to switch from glucose to lipid oxidation
• fasting blood glucose levels are increased in 18 week old mice
• from 18 to 36 weeks, fasting blood glucose further rises
• mice exhibit a significant increase in nonfasting plasma glucose levels, with a mean value 305 mg/dl
• mice exhibit a 60-fold increase in nonfasting plasma insulin levels relative to control littermates (J:50770)
• fasting insulin levels are increased in 18 week old mice but insulin levels decline from 18-36 weeks of age (J:249664)
• insulin, but not glucose, remains higher in the fed state (J:249664)
• mice exhibit high respiratory quotients during light versus dark phases, indicating impaired metabolic flexibility
• basal endogenous glucose production is increased in 18 and 36 week old mice
• all mice are significantly resistant to the glucose-lowering effect of exogenous insulin (J:50770)
• however, there is no evidence for insulin resistance in skeletal muscle (J:50770)
• mice show total, whole-body insulin resistance (J:249664)
• insulin-induced suppression of endogenous glucose production is 65% lower, indicating hepatic insulin resistance (J:249664)
• insulin-stimulated Rd is 76% and 74% lower at 18 and 36 weeks of age, respectively, indicating peripheral insulin resistance (J:249664)
• mice show increased intramyocellular lipids
• at 7 weeks of age, plasma cholesterol levels are mildly, but significantly, increased
• at 7 weeks of age, plasma triglyceride levels are mildly, but significantly, increased
• at 9-11 months of age, plasma triglyceride levels are significantly higher (mean of 450 mg/dl; range, 367-565) than those of control littermates (mean of 97 mg/dl; range, 75-147)
• livers show higher monounsaturated fatty acid content
• total ceramides are decreased in the liver
• C22:0, C24:1 and C24:0 ceramides are decreased in 18 week old liver
• C16:0, C20:0, C22:0, C24:1 and C24:0 ceramides are decreased in 36 week old liver
• C18:0 ceramides are decreased in 18 week old muscle
• C20:0 ceramides are increased in 18 week old liver
• at 7 weeks of age, the hepatic content of triglycerides is significantly increased
• increase in adipose tissue lipolysis

liver/biliary system
• 18 and 36 week old mice exhibit portal and lobular inflammation without hepatocellular ballooning or fibrosis
• total cytosolic and membrane diacylglycerol are increased in the livers of 18 week old mice
• several species of cytosolic diacylglycerol (C18:1/C16:0, C18:1/C18:1), containing at last one unsaturated fatty acid, gradually increase in the liver
• membrane diacylglycerol C18:1/C16:0 is increased
• at 7 weeks of age, the hepatic content of triglycerides is significantly increased
• at P8, mutant livers display uniform vacuolar changes throughout the hepatic lobule
• at P8, mutant hepatocytes are dramatically swollen; the cytoplasm stains palely eosinophilic and contains numerous microvesicular vacuoles which, in rare cases, coalesce to form a unilocular vacuole that displaces the nucleus peripherally
• at P40, hepatocellular swelling is less severe than at P8, and it is confined to the centrolobular zone; no hepatitis or fibrosis is observed
• at P7, mutant livers are massively enlarged (J:50770)
• mutant livers remain enlarged at 7-12 weeks of age (J:50770)
• 36 week old mice exhibit large livers with 191% higher hepatic lipid levels (J:249664)
• at 12 weeks of age, mutant liver weighs twice as much as wild-type liver (3.9 g versus 1.5 g, respectively)
• as early as P8, mutant livers are overloaded with fat (J:50770)
• despite a markedly fatty liver, plasma levels of albumin, aspartate aminotransferase, and bilirubin remain normal at 7 weeks of age (J:50770)
• increase in hepatic lipid accumulation with 36 week old mice showing 191% higher hepatic lipid levels (J:249664)
• at P7, mutant livers are markedly pale
• mutant livers remain pale at 7-12 weeks of age

endocrine/exocrine glands
• at 7-12 weeks of age, mutant pancreata are significantly enlarged

hematopoietic system
• at 7-12 weeks of age, mutant spleens are significantly enlarged

immune system
• at 7-12 weeks of age, mutant spleens are significantly enlarged
• at 7-12 weeks of age, mutant abdominal lymph nodes are significantly enlarged
• inerleukin-6 is decreased in the liver of 18 and 36 week old mice
• TNF-alpha is decreased in the liver of 18 and 36 week old mice
• however, circulating cytokines are unchanged
• 18 and 36 week old mice exhibit portal and lobular inflammation without hepatocellular ballooning or fibrosis


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Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB), Gene Ontology (GO)
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last database update
05/12/2020
MGI 6.15
The Jackson Laboratory