Phenotypes Associated with This Genotype

Genotype
MGI:2654708

• Allelic Composition: Lepr^db/Lepr^db
• Genetic Background: involves: C57BLKS/J

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

Neural-specific STAT3 deletion results in severe obesity in Stat3^tm1Flv/Stat3^tm1Flv Tg(Nes-cre)1Kln/0 mice similar to that seen in Lepr^db/Lepr^db mice

hematopoietic system

increased glycosylated hemoglobin level ( J:104790 )

• significant increase in the percentage of plasma glycosylated hemoglobin

liver/biliary system

increased liver weight ( J:232827 )

cellular

abnormal aerobic respiration ( J:106871 , J:107138 )

• elevation of fatty acids in perfused hearts causes an increase in fatty acid oxidation combined with a reduction in glucose oxidation rates (J:106871)

• carbohydrate oxidation becomes reduced (J:107138)

• palmitate oxidation is elevated (J:107138)

abnormal respiratory electron transport chain ( J:106871 )

• state 3 respiration is elevated in cardiac mitochondria incubated with palmitoyl-carnitine but not with pyruvate

muscle

abnormal myocardium layer morphology ( J:107138 )

• myocardial triacylglycerol content 2X that of controls at 10-18 weeks of age

decreased cardiac muscle contractility ( J:106871 )

• hearts show a significant increase in the slope of the MV_O2-PVA (pressure volume area) regression line after elevation of fatty acids, suggesting a reduction in contractile efficiency

increased vasoconstriction ( J:106597 )

• hypercontractility of smooth muscle in aortic strips due to either phenylephrine or serotonin

• hypercontractility corrollated with the levels of obesity, hyperglycemia, and hyperinsulinemia

• maximal contractions increase with age rather than decrease as in controls

homeostasis/metabolism

abnormal response to cardiac infarction ( J:104790 )

• homozygotes subjected to 45 min of ischemia display an increase in diastolic dimensions, significant dilatation of left ventricular end-systolic dimensions, a 30% reduction in fractional shortening, and an increase in cardiac hypertrophy, 28 days postreperfusion, indicating decreased tolerance to myocardial infarction

abnormal vascular wound healing ( J:135034 )

• reduced neointimal area relative to controls 4 weeks after femoral artery injury

• vascular smooth muscle proliferation significantly reduced

increased glycosylated hemoglobin level ( J:104790 )

• significant increase in the percentage of plasma glycosylated hemoglobin

impaired adaptive thermogenesis ( J:89242 )

• mutants become hypothermic after a 12 hour fast

• mutants housed at 4 degrees C for 3.5 hours cannot maintain their body temperature like wild-type and drop about 1 degree in body temperature every 30 min until they reach 34 degrees C, at which point they stabilize this temperature, indicating decreased sympathetic activity

increased circulating corticosterone level ( J:89242 )

increased circulating leptin level ( J:89242 , J:232827 )

increased circulating cholesterol level ( J:232827 )

increased circulating free fatty acids level ( J:106871 , J:232827 )

increased circulating triglyceride level ( J:232827 )

hyperlipidemia ( J:96047 )

decreased body temperature ( J:96047 )

abnormal glucose homeostasis ( J:80996 , J:107138 )

• diabetic phenotype appears earlier in males than in females (J:107138)

decreased circulating glucose level ( J:117919 )

• mice treated with adenovirus expressing Adipor1 (1.5-fold increase in liver expression), show decreased plasma glucose compared to wild-type

• mice treated with an adenovirus expressing Adipor2 (5-fold increase in liver expression), show decreased plasma glucose compared to wild-type

increased circulating glucose level ( J:5010 , J:80996 , J:89242 )

• plasma fasting glucose is increased (J:89242)

hyperglycemia ( J:96047 , J:104790 , J:106597 , J:106871 , J:117919 , J:210493 , J:232827 )

• by 8 weeks (J:106597)

• diabetes is improved after treatment with an adenovirus expressing Adipor1 or Adipor2 (J:117919)

• at 12 weeks (J:210493)

decreased circulating insulin level ( J:117919 )

• mice treated with an adenovirus expressing Adipor 2 show improved glucose resistance and decreased plasma insulin level

increased circulating insulin level ( J:5010 , J:80996 , J:89242 , J:104790 , J:106597 , J:232827 )

• fasting insulin is increased (J:89242)

• hyperinsulinemia by 8 weeks (J:106597)

impaired glucose tolerance ( J:89242 )

insulin resistance ( J:117919 )

• mice treated with an adenovirus expressing Adipor1 or Adipor 2 show improved insulin resistance

increased urine protein level ( J:5257 )

• in females when compared to female controls

• levels of protein in urine similar in males and females but levels in males lower than in male controls

abnormal nucleotide metabolism ( J:260830 )

• subcutaneous white adipose tissue (sWAT) has less uridine content than in wild-type mice

• however, epididymal white adipose tissue (eWAT), interscapular brown adipose tissue (BAT), and liver uridine content are not different

mortality/aging

increased susceptibility to induced morbidity/mortality ( J:104790 )

• homozygotes subjected to 30, 45, and 60 min of left coronary artery ischemia-reperfusion exhibit survival rates of 71%, 53%, and 18%, respectively, at 24 h after reperfusion, much lower than in controls

• homozygotes subjected to 30 and 45 min of left coronary artery occlusion show survival rates of 58% and 44%, respectively, at 28 days after reperfusion, compared to 100% and 88% in controls

growth/size/body

increased body weight ( J:5010 , J:80996 , J:106597 )

• by four weeks of age (J:80996)

• overweight by 4 weeks of age (J:106597)

obese ( J:89242 , J:96047 , J:104790 , J:106871 , J:232827 )

decreased body length ( J:89242 )

• mutants are about 5% shorter than controls

increased kidney weight ( J:232827 )

increased liver weight ( J:232827 )

reproductive system

abnormal uterus morphology ( J:80996 )

♀

abnormal endometrium morphology ( J:80996 )

♀ • increased volume and density of lipid inclusion vacuoles

♀ • basal membrane of epithelial cells displays a folded contour at locations where lipid accumulates

♀ • tissue norepinephrin levels elevated by 4 weeks of age and remain elevated

decreased uterus weight ( J:80996 )

♀ • decreased relative to controls by 4 weeks of age

♀ • 1/3 normal tissue weight by 12 weeks

vision/eye

abnormal intraocular pressure ( J:82879 )

• modest but significant elevation of intraocular pressure

behavior/neurological

abnormal conditioned taste aversion behavior ( J:85127 )

• aversion response is more strongly generalized from saccharin to sucrose

• lower aversion threshold for sucrose than in controls

• recovery from conditioned taste aversion is more rapid than in controls

polydipsia ( J:5010 )

polyphagia ( J:5010 , J:96047 )

renal/urinary system

increased kidney weight ( J:232827 )

increased urine protein level ( J:5257 )

• in females when compared to female controls

• levels of protein in urine similar in males and females but levels in males lower than in male controls

abnormal renal glomerulus morphology ( J:5257 )

• basement membrane becomes thickened with age

renal glomerular protein deposits ( J:30970 )

• large quantites of immunoglobulin and complement are found in the mesangium

renal glomerular immunoglobulin deposits ( J:30970 )

abnormal kidney papilla morphology ( J:5257 )

• eventually becomes flattened

abnormal kidney calyx morphology ( J:5257 )

• calyceal dilation eventually develops

polyuria ( J:5010 )

immune system

increased susceptibility to autoimmune diabetes ( J:7005 )

• T cells from homozygous mice but not those from heterozygous mice suppressed the beta cell response to glucose + theophylline

nervous system

abnormal hypothalamus physiology ( J:1325 )

• hypothalamic uptake of norepinephrine is decreased in males

adipose tissue

abnormal adipose tissue morphology ( J:232827 )

• increase in adipose tissue weight in both males and females

increased total body fat amount ( J:89242 )

• increase in total fat content

abnormal white adipose tissue morphology ( J:260830 )

• subcutaneous white adipose tissue (sWAT) has less uridine content than in wild-type mice

cardiovascular system

abnormal myocardium layer morphology ( J:107138 )

• myocardial triacylglycerol content 2X that of controls at 10-18 weeks of age

abnormal cardiovascular system physiology ( J:106871 , J:107138 )

• at low fatty acid supply, hearts consume 86% more oxygen (MV_O2) for noncontractile purposes compared with control hearts and a further increase in fatty acid supply has no effect on the already elevated unloaded MV_O2, indicating reduced cardiac efficiency in unloaded hearts (J:106871)

abnormal blood circulation ( J:107138 )

• reduced aortic flow

decreased cardiac output ( J:106871 , J:107138 )

• cardiac output is reduced in fatty acid perfused hearts (J:106871)

cardiac ischemia ( J:107138 )

• reduced recovery of mechanical function after 13 minutes of ischemia and reperfusion

decreased cardiac muscle contractility ( J:106871 )

• hearts show a significant increase in the slope of the MV_O2-PVA (pressure volume area) regression line after elevation of fatty acids, suggesting a reduction in contractile efficiency

increased left ventricle diastolic pressure ( J:106871 )

• hearts show a significant increase in the slope of the MV_O2-PVA (pressure volume area) regression line after elevation of fatty acids, suggesting a reduction in contractile efficiency

decreased heart rate ( J:106871 , J:107138 )

• intrinsic heart rates are reduced at all workloads (J:106871)

abnormal response to cardiac infarction ( J:104790 )

• homozygotes subjected to 45 min of ischemia display an increase in diastolic dimensions, significant dilatation of left ventricular end-systolic dimensions, a 30% reduction in fractional shortening, and an increase in cardiac hypertrophy, 28 days postreperfusion, indicating decreased tolerance to myocardial infarction

decreased systemic arterial blood pressure ( J:135034 )

decreased systemic arterial systolic blood pressure ( J:107138 )

• decreased peak systolic pressure

• decreased peak systolic pressure X cardiac output

• decreased peak systolic pressure X heart rate

increased vasoconstriction ( J:106597 )

• hypercontractility of smooth muscle in aortic strips due to either phenylephrine or serotonin

• hypercontractility corrollated with the levels of obesity, hyperglycemia, and hyperinsulinemia

• maximal contractions increase with age rather than decrease as in controls

abnormal vascular wound healing ( J:135034 )

• reduced neointimal area relative to controls 4 weeks after femoral artery injury

• vascular smooth muscle proliferation significantly reduced

endocrine/exocrine glands

abnormal pancreatic islet morphology ( J:96047 )

• islet mass and density are significantly increased compared to wild-type mice

abnormal pancreatic beta cell morphology ( J:96047 )

• individual beta cell size is increased

abnormal pancreatic beta cell physiology ( J:210493 )

• beta cells exhibit DNA damage unlike control cells

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
obesity		DOID:9970	OMIM:601665	J:96047 , J:104790 , J:106871
type 2 diabetes mellitus		DOID:9352	OMIM:125853 OMIM:601283 OMIM:601407 OMIM:603694 OMIM:608036	J:104790