Phenotypes Associated with This Genotype

Genotype
MGI:3623749

• Allelic Composition: Lep^ob/Lep^ob
• Genetic Background: B6.Cg-Lep^ob/J

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

Lep^ob/Lep^ob

growth/size/body

heart left ventricle hypertrophy ( J:103063 )

• increase in left ventricle wall thickness and mass is seen by 6 months of age but not at 2 months of age

• induced weight loss via leptin infusion, but not via caloric restriction, partially resolves the hypertrophy

abnormal body weight ( J:22025 , J:29075 )

• treatment with triiodothyronine significantly reduces body weight relative to the reduction seen in controls (J:22025)

• body weight reduced by treatment with Leptin (J:29075)

increased body weight ( J:185261 )

obese ( J:103063 , J:104171 )

• develop progressive obesity (J:103063)

• 12-week old males are obese (J:104171)

increased growth rate ( J:5400 )

• mice reach 60-70 g by 10 months of age

homeostasis/metabolism

decreased insulin secretion ( J:145998 )

• leptin-treated islet cells exhibit decreased insulin secretion compared to similarly treated wild-type islets

increased insulin secretion ( J:145998 )

• insulin content in the pancreata is increased compared to in wild-type mice

abnormal circulating glucose level ( J:5400 )

decreased circulating glucose level ( J:129554 , J:145998 , J:189019 )

• 4 weeks' treatment with Adipor2-ASO (antisense oligonucleotide) significantly reduces plasma glucose levels in fed mice (J:129554)

• after feeding, serum glucose levels are more than 30% lower than in wild-type mice (J:145998)

• when treated with AdipoR2-ASO, mice exhibit a decrease in plasma glucose level (J:189019)

hypoglycemia ( J:5400 )

• older mice are usually hypoglycemic

hyperglycemia ( J:5400 , J:65486 , J:122746 )

• transient hyperglycemia (J:5400)

• blood sugar peaks at 2-3 months (J:5400)

• returns to normal by 4-5 months of age (J:5400)

• Background Sensitivity: homozygotes exhibit a mild, transient hyperglycemia between 10-14 weeks of age as compared to the severe, progressive hyperglycemia observed on the BTBR background (J:65486)

• mice infrequently transition to severe hyperglycemia (J:65486)

• serum glucose is 320 mg/dl compared to 134 mg/dl in wild-type controls (J:122746)

increased circulating insulin level ( J:5400 , J:104171 , J:122746 )

• insulin levels increase rapidly to over 50X normal controls (J:5400)

• seen in 12-week old males (J:104171)

• serum insulin is 41.5 ng/ml compared to 0.8 ng/ml in wild-type (J:122746)

abnormal circulating cholesterol level ( J:18161 )

increased circulating cholesterol level ( J:18161 )

• fasting plasma total cholesterol concentration is increased 2-3 fold over controls

increased circulating HDL cholesterol level ( J:18161 )

increased circulating LDL cholesterol level ( J:18161 )

increased circulating VLDL cholesterol level ( J:18161 )

increased circulating triglyceride level ( J:18161 , J:104171 )

• triglyceride levels are elevated 1.5- to 2-fold (J:18161)

• seen in 12-week old males (J:104171)

decreased body temperature ( J:129662 )

• body temperature is maintained a basal level when the ambient temperature is gradually reduced to 4C

abnormal oxygen consumption ( J:22025 , J:22377 )

• oxygen consumption about 2/3 that observed in controls (J:22025)

• increased by treatment with triiodothyronine (J:22025)

• insulin stimulated oxygen consumption by the soleus muscle is little affected by triiodothyronine (J:22377)

decreased oxygen consumption ( J:22377 )

• in the epididymal and brown fat pads

increased oxygen consumption ( J:22377 )

• in the liver

impaired glucose tolerance ( J:104171 , J:107486 )

• glucose intolerance which improved when treated with rosiglitazone (J:107486)

• following an acute intraperitoneal glucose injection, the post-challenge glucose level remained elevated up to 120 min compared to controls, indicating glucose intolerance (J:107486)

insulin resistance ( J:104171 )

abnormal protein level ( J:22025 )

• total body protein lower than in controls

• total body protein increased by treatment with triiodothyronine

abnormal urine homeostasis ( J:4033 )

• males show elevated levels of serotonin and 5'hydroxyindolineacetic acid in urine

abnormal urine catecholamine level ( J:4033 )

• less epinephrine in the urine of ad libitum fed mice

• urine levels of norepinephrine only slightly elevated

• males show elevated levels of dopamine in urine

decreased physiological sensitivity to xenobiotic ( J:344866 )

• mice exhibit a resistance to the insulin-sensitizing effects of the drug auranofin

• epididymal white adipose tissue is unresponsive to isoproterenol, a nonselective beta-adrenergic receptor agonist

cardiovascular system

abnormal myocardial fiber morphology ( J:103063 , J:104171 , J:111488 )

• exhibit myocyte hypertrophy, with increased myocyte diameter and distorted nuclear architecture (J:103063)

• exhibit extensive focal damage in myocardial tissue, showing an abundance of lipid droplets in myocytes and damaged mitochondria that are swelled, have disorganized cristae and show loss of integrity (J:104171)

• cardiomyocytes exhibit a significantly enlarged cross-sectional area (J:111488)

increased myocardial fiber size ( J:104171 )

• cardiomyocytes display larger resting cell length and cross-sectional area

heart left ventricle hypertrophy ( J:103063 )

• increase in left ventricle wall thickness and mass is seen by 6 months of age but not at 2 months of age

• induced weight loss via leptin infusion, but not via caloric restriction, partially resolves the hypertrophy

decreased cardiac muscle contractility ( J:104171 , J:111488 )

• exhibit cardiac contractile dysfunction that is due to leptin deficiency and not obesity as high fat diet-induced obese controls show normal cardiomyocyte morphology and contractile function (J:104171)

• cardiomyocytes exhibit a reduced contractile capacity (J:111488)

• decreased peak shortening (J:111488)

• prolonged relengthening (J:111488)

• elevated resting peak calcium ion concentration (J:111488)

• slowed intracellular calcium ion decay (J:111488)

abnormal myocardial fiber physiology ( J:104171 )

• cardiomyocytes exhibit decreased peak shortening and maximal velocity of shortening/relengthening, prolonged time-to-90% relengthening, reduced intracellular calcium release upon electrical stimulus associated with a slowed intracellular calcium decay rate, and significantly higher oxygen levels

muscle

decreased cardiac muscle contractility ( J:104171 , J:111488 )

• exhibit cardiac contractile dysfunction that is due to leptin deficiency and not obesity as high fat diet-induced obese controls show normal cardiomyocyte morphology and contractile function (J:104171)

• cardiomyocytes exhibit a reduced contractile capacity (J:111488)

• decreased peak shortening (J:111488)

• prolonged relengthening (J:111488)

• elevated resting peak calcium ion concentration (J:111488)

• slowed intracellular calcium ion decay (J:111488)

abnormal muscle morphology ( J:151518 )

• muscle protein content is reduced

abnormal myocardial fiber morphology ( J:103063 , J:104171 , J:111488 )

• exhibit myocyte hypertrophy, with increased myocyte diameter and distorted nuclear architecture (J:103063)

• exhibit extensive focal damage in myocardial tissue, showing an abundance of lipid droplets in myocytes and damaged mitochondria that are swelled, have disorganized cristae and show loss of integrity (J:104171)

• cardiomyocytes exhibit a significantly enlarged cross-sectional area (J:111488)

increased myocardial fiber size ( J:104171 )

• cardiomyocytes display larger resting cell length and cross-sectional area

heart left ventricle hypertrophy ( J:103063 )

• increase in left ventricle wall thickness and mass is seen by 6 months of age but not at 2 months of age

• induced weight loss via leptin infusion, but not via caloric restriction, partially resolves the hypertrophy

decreased skeletal muscle fiber size ( J:151518 )

• cross-sectional area of muscle fibers is generally smaller

abnormal skeletal muscle fiber type ratio ( J:151518 )

• lower proportion of faster myosin heavy chain isoforms

decreased skeletal muscle mass ( J:151518 )

• mean muscle mass consistently less than controls but magnitude of difference is muscle specific

adipose tissue

decreased white fat cell number ( J:22377 )

• treatment with triiodothyronine significantly reduces adipocyte numbers relative to the degree of reduction seen in controls

• treatment with triiodothyronine reduces adipocyte numbers

increased fat cell size ( J:189019 )

abnormal epididymal fat pad morphology ( J:22377 )

• treatment with triiodothyronine significantly reduces epididymal fat pad weight relative to the degree of reduction seen in controls

• adipocyte size remains larger after treatment with triiodothyronine relative to controls

increased interscapular fat pad weight ( J:22377 )

• greater weight than for controls

• affected less by treatment with triiodothyronine than controls

• brown adipocyte numbers are normal

increased percent body fat/body weight ( J:122746 )

• mice have fat mass of ~42 g compared to ~3 g in wild-type at 16 weeks

behavior/neurological

abnormal food intake ( J:122746 )

decreased food intake ( J:29075 )

• food intake is reduced by Leptin treatment

increased food intake ( J:129662 )

• increased food intake when ambient temperature drops from 28 to 21C

polyphagia ( J:122746 )

• mice eat 70% more than wild-type controls

decreased locomotor activity ( J:115771 , J:122746 )

• less wheel running activity (J:115771)

• more wheel running activity in light phase and less in dark phase (J:115771)

• significantly reduced activity relative to wild-type controls (J:122746)

abnormal sleep pattern ( J:115771 )

• increased total sleep time in a 24 hour period

• additional sleep primarily in the dark phase

• increased non-REM sleep time

• recovery from sleep deprivation involves increased duration of non-REM bouts rather than increased number of bouts as seen in controls

abnormal frequency of paradoxical sleep ( J:115771 )

• reduced REM in light phase

• increased REM in dark phase

fragmentation of sleep/wake states ( J:115771 )

• sleep more fragmented

• more arousals

• shorter wake periods

abnormal pain threshold ( J:152019 )

allodynia ( J:152019 )

• resistant to tactile allodynia caused by partial sciatic nerve ligation

• epineural application of leptin treated peritoneal macrophage induces tactile allodynia

hyperalgesia ( J:152019 )

• display thermal hyperalgesia after partial sciatic nerve ligation

reproductive system

female infertility ( J:122746 )

♀ • females do not produce litters

respiratory system

lung inflammation ( J:115772 )

• ozone induces significantly elevated levels of TNFR1

• ozone induces a nonsignificant elevation of TNFR2 levels

endocrine/exocrine glands

enlarged pancreatic islets ( J:5400 )

abnormal pancreatic beta cell physiology ( J:5400 )

• Background Sensitivity: less beta cell degranulation than seen on the "BKS" background

decreased insulin secretion ( J:145998 )

• leptin-treated islet cells exhibit decreased insulin secretion compared to similarly treated wild-type islets

increased insulin secretion ( J:145998 )

• insulin content in the pancreata is increased compared to in wild-type mice

renal/urinary system

abnormal urine homeostasis ( J:4033 )

• males show elevated levels of serotonin and 5'hydroxyindolineacetic acid in urine

abnormal urine catecholamine level ( J:4033 )

• less epinephrine in the urine of ad libitum fed mice

• urine levels of norepinephrine only slightly elevated

• males show elevated levels of dopamine in urine

immune system

decreased NK cell number ( J:117826 )

• reduced numbers can be restored by treatment with leptin

lung inflammation ( J:115772 )

• ozone induces significantly elevated levels of TNFR1

• ozone induces a nonsignificant elevation of TNFR2 levels

neoplasm

increased metastatic potential ( J:117826 )

• increased metastasis to the lung of both melanoma cell lines and lung cancer cell lines initially injected in the tail vein

• leptin reduces the level of metastasis

hematopoietic system

decreased NK cell number ( J:117826 )

• reduced numbers can be restored by treatment with leptin

nervous system

abnormal sympathetic nervous system physiology ( J:145998 )

liver/biliary system

abnormal liver weight ( J:22377 )

• treatment with triiodothyronine significantly reduces relative and absolute liver weight

skeleton

abnormal bone marrow morphology ( J:189019 )

• bone marrow is almost completely replaced with mature adipocytes

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
obesity		DOID:9970	OMIM:601665	J:103063 , J:104171