Phenotypes Associated with This Genotype

Genotype
MGI:3028851

• Allelic Composition: Tg(aP2-SREBF1c)9884Reh/0
• Genetic Background: involves: C57BL/6J * SJL

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

mortality/aging

postnatal lethality ( J:50770 )

• ~20% of mice fail to thrive and die within the first 3 weeks of life

cellular

abnormal cellular respiration ( J:249664 )

• 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

abnormal aerobic respiration ( J:249664 )

• in the fed state, hepatic tricarboxylic acid (TCA) cycle-linked respiration is increased at 18 weeks, but not 36 weeks, of age

abnormal lipid oxidation ( J:249664 )

• impaired lipid oxidation, with an inability to switch from glucose to lipid oxidation

oxidative stress ( J:249664 )

• systemic and muscle-specific oxidative stress develops after a long-standing insulin resistance

integument

decreased subcutaneous adipose tissue amount ( J:249664 )

• subcutaneous fat depots are decreased by 90%

growth/size/body

enlarged pancreas ( J:50770 )

• at 7-12 weeks of age, mutant pancreata are significantly enlarged

increased body weight ( J:249664 )

• 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

decreased body size ( J:50770 )

• 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

distended abdomen ( J:50770 )

• during the first week of life mice exhibit a distended abdomen due to liver enlargement

enlarged liver ( J:50770 , J:249664 )

• 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)

increased liver weight ( J:50770 )

• at 12 weeks of age, mutant liver weighs twice as much as wild-type liver (3.9 g versus 1.5 g, respectively)

enlarged spleen ( J:50770 )

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

adipose tissue

adipose tissue phenotype ( J:125992 )

N • despite adipose tissue defects, adipogenesis is normal in embryonic fibroblasts

abnormal brown adipose tissue morphology ( J:50770 )

• brown fat is hypertrophic and contains fat-laden cells that resemble immature white fat

increased brown adipose tissue amount ( J:50770 )

• at P7, mice display enlarged interscapular and submandibular brown fat depots relative to control mice

abnormal brown fat cell morphology ( J:50770 )

• 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

increased brown fat cell lipid droplet size ( J:50770 )

• at P40, most mutant brown adipocytes contain a prominent unilocular fat droplet

increased brown fat cell size ( J:50770 )

• at P8, mutant brown adipocytes are dramatically enlarged and stain palely

• at P40, most mutant brown adipocytes remain significantly enlarged

abnormal epididymal fat pad morphology ( J:50770 )

• 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

decreased epididymal fat pad weight ( J:50770 )

• 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)

abnormal interscapular fat pad morphology ( J:50770 )

• 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

increased interscapular fat pad weight ( J:50770 )

• at 12 weeks of age, mutant interscapular fat weighs nearly twice as much as wild-type (110 mg versus 58 mg, respectively)

abnormal white adipose tissue morphology ( J:50770 )

• white fat fails to differentiate fully, and the size of white fat depots is significantly reduced

decreased subcutaneous adipose tissue amount ( J:249664 )

• subcutaneous fat depots are decreased by 90%

decreased white adipose tissue amount ( J:50770 , J:249664 )

• 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

abnormal muscle morphology ( J:249664 )

• mice show increased intramyocellular lipids

abnormal skeletal muscle morphology ( J:249664 )

• 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

abnormal lipid oxidation ( J:249664 )

• impaired lipid oxidation, with an inability to switch from glucose to lipid oxidation

increased fasting circulating glucose level ( J:249664 )

• fasting blood glucose levels are increased in 18 week old mice

• from 18 to 36 weeks, fasting blood glucose further rises

hyperglycemia ( J:50770 )

• mice exhibit a significant increase in nonfasting plasma glucose levels, with a mean value 305 mg/dl

increased circulating insulin level ( J:50770 , J:249664 )

• 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)

increased respiratory quotient ( J:249664 )

• mice exhibit high respiratory quotients during light versus dark phases, indicating impaired metabolic flexibility

increased hepatic glucose production ( J:249664 )

• basal endogenous glucose production is increased in 18 and 36 week old mice

insulin resistance ( J:50770 , J:249664 )

• 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)

abnormal lipid level ( J:249664 )

• mice show increased intramyocellular lipids

increased circulating cholesterol level ( J:50770 )

• at 7 weeks of age, plasma cholesterol levels are mildly, but significantly, increased

increased circulating triglyceride level ( J:50770 )

• 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)

increased unsaturated fatty acids level ( J:249664 )

• livers show higher monounsaturated fatty acid content

decreased ceramide level ( J:249664 )

• 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

increased ceramide level ( J:249664 )

• C20:0 ceramides are increased in 18 week old liver

increased liver triglyceride level ( J:50770 )

• at 7 weeks of age, the hepatic content of triglycerides is significantly increased

abnormal lipolysis ( J:249664 )

• increase in adipose tissue lipolysis

liver/biliary system

liver inflammation ( J:249664 )

• 18 and 36 week old mice exhibit portal and lobular inflammation without hepatocellular ballooning or fibrosis

abnormal liver morphology ( J:249664 )

• 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

enlarged liver ( J:50770 , J:249664 )

• 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)

increased liver weight ( J:50770 )

• at 12 weeks of age, mutant liver weighs twice as much as wild-type liver (3.9 g versus 1.5 g, respectively)

increased liver triglyceride level ( J:50770 )

• at 7 weeks of age, the hepatic content of triglycerides is significantly increased

abnormal liver lobule morphology ( J:50770 )

• at P8, mutant livers display uniform vacuolar changes throughout the hepatic lobule

abnormal hepatocyte morphology ( J:50770 )

• 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

hepatic steatosis ( J:50770 , J:249664 )

• 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)

pale liver ( J:50770 )

• at P7, mutant livers are markedly pale

• mutant livers remain pale at 7-12 weeks of age

endocrine/exocrine glands

enlarged pancreas ( J:50770 )

• at 7-12 weeks of age, mutant pancreata are significantly enlarged

hematopoietic system

enlarged spleen ( J:50770 )

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

immune system

enlarged spleen ( J:50770 )

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

abnormal abdominal lymph node morphology ( J:50770 )

• at 7-12 weeks of age, mutant abdominal lymph nodes are significantly enlarged

decreased interleukin-6 secretion ( J:249664 )

• inerleukin-6 is decreased in the liver of 18 and 36 week old mice

decreased tumor necrosis factor secretion ( J:249664 )

• TNF-alpha is decreased in the liver of 18 and 36 week old mice

• however, circulating cytokines are unchanged

liver inflammation ( J:249664 )

• 18 and 36 week old mice exhibit portal and lobular inflammation without hepatocellular ballooning or fibrosis

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
congenital generalized lipodystrophy type 2		DOID:0111136	OMIM:269700	J:50770
metabolic dysfunction-associated steatotic liver disease		DOID:0080208	OMIM:613282 OMIM:613387	J:249664
type 2 diabetes mellitus		DOID:9352	OMIM:125853 OMIM:601283 OMIM:601407 OMIM:603694 OMIM:608036	J:50770