Overview

Mutant mice on this background will be useful in studies to establish the nature of diabesity modifier genes in the DBA/2 genome as well as the development of diabetic complications, notably diabetic nephropathy and glaucoma.

Donating Investigator

T1DR Colony, The Jackson Laboratory

Genetic overview

Genetic Background	Generation
000671 DBA/2J

Lepr^db

Allele Type	Gene Symbol	Gene Name
Spontaneous	Lepr	leptin receptor

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Research Applications

Diabetes and Obesity Research
Endocrine Deficiency Research
Immunology, Inflammation and Autoimmunity Research
Internal/Organ Research
Reproductive Biology Research
Mouse/Human Gene Homologs
Metabolism Research

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Base Price

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$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

Recessive mutations in the leptin receptor produce massive obesity regardless of the strain background on which they are studied. However, development of obesity-induced and insulin resistant diabetes ("diabesity") is strongly influenced by inbred strain background modifier genes and by sex. A comparison of this mutation on multiple inbred backgrounds showed that the congenic transfer of the mutation from the diabesity-susceptible C57BLKS/J background onto the DBA/2J background produced an even more severe diabesity syndrome (Leiter et al., 1981). This is noteworthy because C57BLKS/J is thought to differ from the diabesity-resistant C57BL/6J strain by the presence of DBA/2 genetic contamination in a B6-like genome (Naggert et al., 1995). Unfortunately, this D2.BKS-Lepr^db stock was not maintained. Because diabetic DBA/2J males have been shown to be more susceptible to development of diabetic nephropathy (Gurley et al., 2010), speed congenic methodology was used to regenerate this mutant stock. Mutant mice on this background will be useful in studies to establish the nature of diabesity modifier genes in the DBA/2 genome (Davis et al., 2012) as well as the development of diabetic complications, notably diabetic nephropathy and glaucoma.

Heterozygous mice are either grey or dilute in appearance .

Development

The spontaneous autosomal recessive diabetes (Lepr^db) mutation was discovered at The Jackson Laboratory, Bar Harbor, Maine USA in 1966 on the inbred strain C57BLKS/J (BKS). Using marker assisted technology, the Type 1 Diabetes Resource and Genetic Resource Sciences established the "D2-db" congenic strain by introducing the Lepr^db allele from the BKS.Cg-m +/+ Lepr^db/J repulsion stock (see Stock No. 000642) onto the DBA/2J (see Stock No. 000671) background. In 2012, "D2-db" mice generated using speed congenic technology were rederived into the Repository and are at the 6th backcross generation.

Control Suggestions

+/+ from the colony
000671 DBA/2J

Additional Information

Considerations for Choosing Controls

Genetics

Lepr^db

Allele Symbol: Lepr^db

Allele Name	diabetes
Allele Type	Spontaneous
Allele Synonym(s)	db; db/db; Lep^db; Lepr-; Lepr^db-1J; leprdb
Gene Symbol and Name	Lepr, leptin receptor
Gene Synonym(s)
Strain of Origin	C57BLKS/J
Chromosome	4
General Note	Phenotypic Similarity to Human Syndrome: Gestational Diabetes J:219658
Molecular Note	An intronic G-to-T transversion in this allele created a donor splice site that causes abnormal splicing and the inclusion of 106 nt of intronic sequence in the transcript, leading to premature termination of the long cellular domain of the Ob-Rb splice form and loss of its signal transducing function.

Disease/Phenotype

Disease Terms

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

Models with phenotypic similarity to human diseases where etiology is unknown or involving genes where ortholog is unknown.

non-alcoholic fatty liver disease

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Genotype: Lepr^db related

Diabetes and Obesity Research
- Obesity With Diabetes
- Impaired Wound Healing
- Hyperinsulinemia
- Insulin Resistance
Endocrine Deficiency Research
- Hypothalamus/Pituitary Defects
- Pancreas Defects
- Adipose Defects
Immunology, Inflammation and Autoimmunity Research
- Immunodeficiency Associated with Other Defects
Internal/Organ Research
- Adipose Defects
Reproductive Biology Research
- Fertility Defects
Mouse/Human Gene Homologs
- obesity, morbid, with hypogonadism (rare)
Metabolism Research

Diabetes and Obesity Research
- Hyperglycemia
- Type 2 Diabetes (NIDDM)

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Lepr^db/Lepr^db
C57BLKS/J-Lepr

behavior/neurological phenotype

polyphagia

homeostasis/metabolism phenotype

hyperglycemia

increased circulating leptin level

increased circulating insulin level

increased circulating cholesterol level

increased circulating triglyceride level

increased circulating free fatty acids level

decreased body temperature

hyperlipidemia

liver/biliary system phenotype

increased liver weight

renal/urinary system phenotype

increased kidney weight

cardiovascular system phenotype

decreased cardiac output

decreased heart rate

abnormal cardiovascular system physiology

growth/size/body region phenotype

obese

increased kidney weight

increased liver weight

Genotype: Lepr^db/Lepr^db
B6.BKS(D)-Lepr/J

behavior/neurological phenotype

abnormal behavior
- faster in food finding trials relative to controls

hypoactivity
- during the dark phase

homeostasis/metabolism phenotype

decreased oxygen consumption

decreased body temperature

insulin resistance

decreased carbon dioxide production

abnormal response/metabolism to endogenous compounds
- mice treated with leptin fail to exhibit a decrease in food intake unlike similarly treated wild-type mice

impaired glucose tolerance

renal/urinary system phenotype

glomerulosclerosis
- homozygotes develop significant glomerulosclerosis by 18 weeks of age

Genotype: Lepr^db/Lepr^db
involves: C57BL/6

cellular phenotype

abnormal osteoclast differentiation
- increased numbers of osteoclasts

hematopoietic system phenotype

abnormal osteoclast differentiation
- increased numbers of osteoclasts

immune system phenotype

abnormal osteoclast differentiation
- increased numbers of osteoclasts

skeleton phenotype

abnormal osteoclast differentiation
- increased numbers of osteoclasts

increased bone volume
- 3 fold increase in bone volume

abnormal skeleton development
- rate of new bone formation increased at both 3 and 6 months

Genotype: Lepr^db/Lepr^db
BKS.Cg-Dock7 +/+ Lepr/OlaHsd

digestive/alimentary phenotype

abnormal digestive system physiology
- transepithelial resistance in the epithelium is reduced, indictive of a disrupted mucosal barrier function

abnormal intestinal epithelium morphology
- zonula occludens 1 has a discontinuous distribution
- reduced levels of occludin in intestinal sections

immune system phenotype

abnormal acute inflammation
- higher levels of endotoxin are found in portal blood (entotoxemia)

increased susceptibility to endotoxin shock
- increased succeptibility of hepatic stellate cells to LPS

liver inflammation

increased interleukin-6 secretion
- increased release by hepatic stellate cells

abnormal chemokine secretion
- increased release of monocyte chemo attractant protein by hepatic stellate cells

liver/biliary system phenotype

liver inflammation

Genotype: Lepr^db/Lepr^db
involves: C57BLKS/J

muscle phenotype

increased vasoconstriction
- maximal contractions increase with age rather than decrease as in controls
- hypercontractility corrollated with the levels of obesity, hyperglycemia, and hyperinsulinemia
- hypercontractility of smooth muscle in aortic strips due to either phenylephrine or serotonin

decreased cardiac muscle contractility
- 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

abnormal myocardium layer morphology
- myocardial triacylglycerol content 2X that of controls at 10-18 weeks of age

nervous system phenotype

abnormal hypothalamus physiology
- hypothalamic uptake of norepinephrine is decreased in males

renal/urinary system phenotype

abnormal kidney papilla morphology
- eventually becomes flattened

polyuria

renal glomerular immunoglobulin deposits

renal glomerular protein deposits
- large quantites of immunoglobulin and complement are found in the mesangium

abnormal renal glomerulus morphology
- basement membrane becomes thickened with age

increased kidney weight

abnormal kidney calyx morphology
- calyceal dilation eventually develops

increased urine protein level
- 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

reproductive system phenotype

abnormal endometrium morphology
- basal membrane of epithelial cells displays a folded contour at locations where lipid accumulates
- increased volume and density of lipid inclusion vacuoles
- tissue norepinephrin levels elevated by 4 weeks of age and remain elevated

decreased uterus weight
- decreased relative to controls by 4 weeks of age
- 1/3 normal tissue weight by 12 weeks

abnormal uterus morphology

vision/eye phenotype

abnormal intraocular pressure
- modest but significant elevation of intraocular pressure

adipose tissue phenotype

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

abnormal adipose tissue morphology
- increase in adipose tissue weight in both males and females

increased total body fat amount
- increase in total fat content

cardiovascular system phenotype

decreased heart rate
- intrinsic heart rates are reduced at all workloads

decreased cardiac output
- cardiac output is reduced in fatty acid perfused hearts

decreased systemic arterial blood pressure

abnormal cardiovascular system physiology
- 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

increased vasoconstriction
- 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

cardiac ischemia
- reduced recovery of mechanical function after 13 minutes of ischemia and reperfusion

decreased systemic arterial systolic blood pressure
- decreased peak systolic pressure X cardiac output
- decreased peak systolic pressure X heart rate
- decreased peak systolic pressure

abnormal myocardium layer morphology
- myocardial triacylglycerol content 2X that of controls at 10-18 weeks of age

abnormal vascular wound healing
- reduced neointimal area relative to controls 4 weeks after femoral artery injury
- vascular smooth muscle proliferation significantly reduced

abnormal blood circulation
- reduced aortic flow

decreased cardiac muscle contractility
- 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

abnormal response to cardiac infarction
- 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

increased left ventricle diastolic pressure
- 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

cellular phenotype

abnormal aerobic respiration
- elevation of fatty acids in perfused hearts causes an increase in fatty acid oxidation combined with a reduction in glucose oxidation rates
- carbohydrate oxidation becomes reduced
- palmitate oxidation is elevated

abnormal respiratory electron transport chain
- state 3 respiration is elevated in cardiac mitochondria incubated with palmitoyl-carnitine but not with pyruvate

endocrine/exocrine gland phenotype

abnormal pancreatic beta cell morphology
- individual beta cell size is increased

abnormal pancreatic beta cell physiology
- beta cells exhibit DNA damage unlike control cells

abnormal pancreatic islet morphology
- islet mass and density are significantly increased compared to wild-type mice

behavior/neurological phenotype

abnormal conditioned taste aversion behavior
- 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

polyphagia

polydipsia

growth/size/body region phenotype

obese

increased body weight
- by four weeks of age
- overweight by 4 weeks of age

increased liver weight

decreased body length
- mutants are about 5% shorter than controls

increased kidney weight

hematopoietic system phenotype

increased glycosylated hemoglobin level
- significant increase in the percentage of plasma glycosylated hemoglobin

homeostasis/metabolism phenotype

abnormal response to cardiac infarction
- 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

hyperglycemia
- diabetes is improved after treatment with an adenovirus expressing Adipor1 or Adipor2
- at 12 weeks
- by 8 weeks

increased circulating glucose level
- plasma fasting glucose is increased

decreased body temperature

decreased circulating glucose level
- mice treated with an adenovirus expressing Adipor2 (5-fold increase in liver expression), show decreased plasma glucose compared to wild-type
- mice treated with adenovirus expressing Adipor1 (1.5-fold increase in liver expression), show decreased plasma glucose compared to wild-type

impaired adaptive thermogenesis
- 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
- sympathetic activity
- mutants become hypothermic after a 12 hour fast

abnormal vascular wound healing
- vascular smooth muscle proliferation significantly reduced
- reduced neointimal area relative to controls 4 weeks after femoral artery injury

abnormal nucleotide metabolism
- 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

abnormal glucose homeostasis
- diabetic phenotype appears earlier in males than in females

increased circulating free fatty acids level

increased circulating insulin level
- fasting insulin is increased
- hyperinsulinemia by 8 weeks

increased glycosylated hemoglobin level
- significant increase in the percentage of plasma glycosylated hemoglobin

increased circulating triglyceride level

hyperlipidemia

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

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

increased circulating leptin level

increased urine protein level
- 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

increased circulating corticosterone level

impaired glucose tolerance

increased circulating cholesterol level

immune system phenotype

increased susceptibility to autoimmune diabetes
- T cells from homozygous mice but not those from heterozygous mice suppressed the beta cell response to glucose + theophylline

liver/biliary system phenotype

increased liver weight

mortality/aging

increased sensitivity to induced morbidity/mortality
- 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

Genotype: Lepr^db/Lepr^db
FVB.BKS-Lepr

renal/urinary system phenotype

abnormal renal glomerulus morphology
- at 7 months of age, obese mice show an increased mesangial matrix in most glomeruli compared to lean controls, resembling diabetic nephropathy; some small glomeruli have separated from the capsule with nearly obliterated microtubules

endocrine/exocrine gland phenotype

pancreatic islet hyperplasia
- some islets in obese mice have more than 1000 cells per cross section; such islets are absent in lean mice

increased pancreatic beta cell number
- obese mice show massive expansion of beta cells (744 insulin +ve cells/islet cross-section in obese vs 165 +ve cells in lean mice); there are 4.5-fold more cells per islet cross-section in obese mice

growth/size/body region phenotype

obese
- mice of both sexes are obese

homeostasis/metabolism phenotype

abnormal circulating glucose level
- Background Sensitivity - after a 2-day fast on refeeding with carbohydrate-free diet, female obese mice show a rise in glucose

increased circulating insulin level
- Background Sensitivity - /ml)
- Background Sensitivity - at 3 months of age, females show a trend toward higher insulin levels compared to obese B6.BKS-Lepr^db females; at 5-7 months insulin levels (~500 ng/ml) are ~10-fold higher than levels in obese female obese B6.BKS-Lepr^db mice (~50 ng/ml)

impaired glucose tolerance
- Background Sensitivity - obese mice show a rapid increase of blood glucose above 400 mg/dl with diminished rate of glucose clearance
- Background Sensitivity - at 7 months of age obese males are severely glucose intolerant with glucose levels of >400 mg/dl 90 minutes after glucose load compared to obese B6.BKS-Lepr^db mice clear glucose load by 90 min

insulin resistance
- circulating insulin levels in the fed state show that obese mice have exteme insulin resistance
- at 7 months of age, 3U/kg of insulin does not alter circulating glucose levels, while in B6.BKS-Lepr mice, glucose decreases by 50% by 40 minutes; 12U/kg insulin does not cause a decrease in glucose in obese female mice on the FVB background
- at a dose of 3U/kg 6-week old mice show a diminished response to insulin

hyperglycemia
- levels increase from 5 to 7 months in obese females to ~500 ng/ml, significantly higher than the males (~40 ng/ml) or obese B6.BKS-Lepr^db females (~50 ng/ml)
- fasting mice are hyperglycemic at 3 months of age, while obese B6.BKS-Lepr^db fasted mice are euglycemic
- Background Sensitivity - obese mice have a prolonged period of hyperglycemia compared to obese B6.BKS-Lepr^db mice where glucose levels rarely exceed 250 mg/dl

Genotype: Lepr^db/Lepr^db
BKS.Cg-Dock7 +/+ Lepr/J

cellular phenotype

abnormal axon extension
- axonal growth cone extension fails to occur for neurons treated in culture with 100ng/ml of leptin

endocrine/exocrine gland phenotype

increased glucagon secretion
- increased secreation of glucagon by pancreatic cells in culture

growth/size/body region phenotype

increased body weight

weight loss
- body weight drops after 6 days on feeding restriction during the dark phase

obese
- become progressively obese starting at 5 weeks of age
- weight reaches 2.5X that of control mice by 3 months of age

homeostasis/metabolism phenotype

decreased prostaglandin level
- in diabetic wounds, PGE2 level is consistently less than 50% of wild-type wounds at all times

increased glucagon secretion
- increased secreation of glucagon by pancreatic cells in culture

decreased urine albumin level
- mutants treated with sRAGE do not show the increased albumin excretion seen in untreated mutants (0.11 ug albumin/ug creatinine vs 0.20 ug albumin/ ug creatinine); levels are not significantly different from control animals (0.08 ug albumin/ ug creatinine)
- )

decreased circulating glucose level
- affect of BDNF on blood glucose becomes progressively less as mice age
- neurotrophin 3 also causes a drop in blood glucose but the glucose levels return to normal by 24 hours after treatment
- glucose levels are reduced at all times tested when mice are placed on feeding restriction during the dark phase
- brain derived neurotrophic factor (BDNF) causes a drop in blood glucose relative to controls 8 weeks after treatment

albuminuria
- moderate albuminuria is observed at 26 weeks of age

abnormal circulating lipid level
- Background Sensitivity - but have significantly higher plasma triglyceride levels
- Background Sensitivity - plasma lipid levels differ between young and old mutants unlike on the C57BL/6J background where levels are similar at both ages; 14-month old mice have lower triglycerides, HDL cholesterol and combined VLDL + LDL cholesterol levels than 14-week old mice, but have significantly higher plasma triglyceride levels

increased circulating cholesterol level
- fasting plasma total cholesterol concentration is increased 2 fold over controls

hyperglycemia
- fasting blood glucose level is significantly higher than control at 26 weeks of age

decreased circulating insulin level
- morning insulin levels lowered when feeding is restricted during the dark phase
- BDNF causes a 50% reduction in plasma insulin relative to controls

decreased circulating triglyceride level
- triglyceride levels are reduced at all times tested when mice are placed on feeding restriction during the dark phase

increased circulating HDL cholesterol level

increased circulating VLDL cholesterol level

increased circulating LDL cholesterol level

increased circulating glucose level
- blood glucose shows a progressive increase from 5 through 33 weeks

improved glucose tolerance
- BDNF treatment causes a lower blood glucose level response in a glucose tolerance test

abnormal enzyme/coenzyme activity
- Lypla1 (APT-1) enzyme activity is decreased in lung endothelial cells

abnormal circulating cholesterol level

abnormal circulating glucose level

delayed wound healing
- wound healing is impaired, with an average wound closure time of 22 days, 7 days longer than in controls
- T26A, a prostaglandin transporter inhibitor, topically applied to wounds shortened wound closure to 16 days in mutants, similar to untreated controls; T26A increased re-epithelialization, neovascularization, and blood flow in wounds

increased circulating triglyceride level
- triglyceride levels are elevated 1.5- to 2-fold

muscle phenotype

abnormal myocardial fiber morphology
- dense bodies present in places normally occupied by mitochondria
- disrupted sarcomeres sometimes
- presence of many lipid droplets

behavior/neurological phenotype

abnormal locomotor circadian rhythm
- daily locomotor rhythmicity restored by feeding restriction during dark phase
- daily locomotor activity rhythmicity severely diminished at 13-14 weeks, 75% fail to show significant rhythmicity
- daily locomotor pattern becomes attenuated in 6-8 week old mice but rhythmicity is retained

abnormal learning/memory/conditioning

abnormal food intake
- food intake is about 60% of control level

abnormal spatial learning
- longer swimming distances than control mice in a Morris water maze test

abnormal spatial reference memory
- cross the original platform location less frequently than do controls in a Morris water maze test

nervous system phenotype

abnormal CNS synaptic transmission

decreased motor neuron number
- myelinated fibers reduced in numbers at 25 weeks in the sural nerve
- unmyelinated fiber density increase in the sural, peroneal, and vagus nerves
- myelinated fiber density increases in most nerves (not the peroneal and phrenic nerves)
- unmyelinated fibers reduced in numbers at 25 weeks in the vagus nerve

reduced long term potentiation
- CA1 hippocampal slices indicate brief post tetanic potentiation but no long term potentiation on recordings of excitatory post-synaptic potentials

abnormal axon extension
- axonal growth cone extension fails to occur for neurons treated in culture with 100ng/ml of leptin

abnormal nervous system morphology

abnormal axon morphology
- smaller diameter nerve fibers in peroneal, phrenic and vagus nerves at 25 weeks but not significant
- non significant shift toward smaller fiber diameter at 15 weeks of age
- small numbers of very large unmyelinated fibers (up to 1.6 micrometers)
- significantly shifted to smaller diameter fibers by 25 weeks in ventral roots, dorsal roots, sural nerve
- shift of unmyelinated fibers to smaller diameters

abnormal nerve conduction
- no conductance improvement is seen in mice over 23 weeks in age due to insulin treatment
- motor nerve conductance significantly lower than controls from 7 weeks of age onward
- velocity returns to and is maintained at prediabetic levels by 15 weeks of age whereas control mice show a continuous increase in velocity
- insulin treatment results in improved conductance but only for the duration of treatment and control levels of conductance are never restored

abnormal myelin sheath morphology
- number of myelin lamellae relative to nerve diameter is increased

absent long term depression
- CA1 hippocampal slices indicate no long term depression on recordings of excitatory post-synaptic potentials

renal/urinary system phenotype

albuminuria
- moderate albuminuria is observed at 26 weeks of age

decreased urine albumin level
- )
- mutants treated with sRAGE do not show the increased albumin excretion seen in untreated mutants (0.11 ug albumin/ug creatinine vs 0.20 ug albumin/ ug creatinine); levels are not significantly different from control animals (0.08 ug albumin/ ug creatinine)

expanded mesangial matrix
- moderate mesangial expansion is observed in glomeruli at 26 weeks

increased creatinine clearance
- ght)
- male mutants treated with sRAGE to achieve RAGE blockade display increased creatinine clearance (~5.1 ml/hour/100 x g body weight) compared to PBS-treated mutants (~3 ml/hour/100 x g body weight), approaching wild-type levels (6.7 ml/hour/100 x g body weight)

vision/eye phenotype

abnormal eye electrophysiology
- prolonged latency of the b-wave in the retina
- delays in oscillatory potentials 1, 2, 3 although only the delay in "OP1" is significant

cardiovascular system phenotype

abnormal aorta morphology
- aortic tissue shows increased retention of insoluble fibronectin

abnormal myocardial fiber morphology
- disrupted sarcomeres sometimes
- dense bodies present in places normally occupied by mitochondria
- presence of many lipid droplets

abnormal vascular development
- dense bodies found in the smooth muscle of intramyocardial arteries

Genotype: Lepr^db/Lepr^db
involves: C57BL/6 * C57BLKS/J

adipose tissue phenotype

increased percent body fat/body weight

growth/size/body region phenotype

obese
- early onset obesity starting from 4 weeks of age

decreased body length

decreased lean body mass

increased body weight

homeostasis/metabolism phenotype

hyperglycemia

increased circulating leptin level

insulin resistance

impaired glucose tolerance

abnormal oxygen consumption
- oxygen consumption normalized to lean mass is increased compared to wild-type controls but oxygen consumption normalized to metabolic size is decreased compared to wild-type controls

increased circulating insulin level

impaired adaptive thermogenesis
- thermoregulation in response to cold exposure is severely impaired compared to wild-type controls

increased circulating glucose level

limbs/digits/tail phenotype

short femur

reproductive system phenotype

abnormal female reproductive system morphology

absent estrus

female infertility

absent estrous cycle

skeleton phenotype

short femur

behavior/neurological phenotype

polyphagia

hypoactivity
- decreased activity in both the light and dark cycle

abnormal eating behavior

Genotype: Lepr^db/Lepr⁺
involves: C57BLKS/J

adipose tissue phenotype

increased total body fat amount
- 20% greater adipose tissue mass during pregnancy than in controls

growth/size/body region phenotype

increased susceptibility to weight gain
- maternal body weight at term 24% greater than controls
- birth weights significantly heavier than controls and unaffected by maternal leptin treatment unlike controls where maternal leptin treatment causes a decrease in birth weights
- 33% greater maternal weight gain

increased body weight
- male and female heterozygous offspring from both normal and complicated pregnancies, are heavier than wild-type littermates at 3 and 6 months of age
- heterozygous pregnant dams are heavier than wild-type mothers at E18.5

increased birth weight
- Normal - however, wild-type pups from heterozygous mothers are no bigger than wild-type fetuses carried by wild-type mothers
- heterozygous fetuses carried by wild-type dams exhibit a 5% higher birth weight than wild-type littermates
- heterozygous fetuses from heterozygous mothers are 3% bigger than wild-type littermates

homeostasis/metabolism phenotype

increased circulating leptin level
- mothers exhibit higher circulating leptin levels than wild-type mothers
- heterozygous offspring exhibit an increase in leptin levels at 6 months of age

impaired glucose tolerance
- both male and female heterozygous offspring have impaired glucose tolerance irrespective of maternal environment (heterozygous or wild-type mothers)
- profound glucose intolerance during pregnancy
- females exhibit impaired glucose tolerance during pregnancy
- 45-55% higher glucose levels after a glucose challenge but dramatically improved by leptin treatment and glucose levels reduced 33 and 30% in glucose tolerance tests at 30 and 60 minute time points
- glucose levels 41% higher in a glucose tolerance test at 30 and at 60 minute time points

abnormal glucose homeostasis

abnormal hormone level
- elevated placental leptin levels in pregnant females

abnormal circulating insulin level
- 2.2X increase in fasting insulin during pregnancy compared to a 3X increase in controls
- leptin treatment results in a 14% reduction in insulin levels compared to a 45% reduction in controls

increased circulating glucose level
- fasting glucose levels elevated 25% during pregnancy

decreased circulating insulin level
- pregnant dams exhibit lower fasting insulin levels than wild-type mothers

behavior/neurological phenotype

increased food intake
- leptin treatment suppresses food intake to near control levels
- food intake 11% greater than controls during pregnancy

cellular phenotype

maternal effect
- wild-type males born to heterozygous mothers are heavier than wild-type mice born to wild-type mothers, but postnatal weight gain of female offspring is not affected by the maternal environment
- offspring born from heterozygous mothers with gestational diabetes have lower fasting insulin levels and worse glucose tolerance than offspring born from wild-type mothers

embryo phenotype

enlarged placenta
- placentas from heterozygous fetuses are larger than those of wild-type fetuses, irrespective of maternal genotype

Genotype: Lepr^db/Lepr^db
B6.Cg-Dock7 +/+ Lepr/J

behavior/neurological phenotype

polyphagia

reduced male mating frequency

hematopoietic system phenotype

increased neutrophil cell number
- increased numbers in bronchoalveolar lavage

decreased leukocyte cell number
- decrease blood leukocyte numbers

abnormal leukocyte morphology

homeostasis/metabolism phenotype

increased circulating cholesterol level
- fasting plasma total cholesterol concentration is increased 2 fold over controls

abnormal glucose homeostasis

increased circulating HDL cholesterol level

increased circulating triglyceride level
- triglyceride levels are elevated 1.5- to 2-fold

increased circulating glucose level

hyperglycemia

abnormal circulating cholesterol level

increased circulating leptin level

increased circulating LDL cholesterol level

abnormal interleukin level
- elevated levels of IL-6 in bronchoalveolar lavage fluid

abnormal circulating lipid level
- Background Sensitivity - plasma lipid levels are similar at 3.5 and 14 months of age on the C57BL/6J background unlike on a C57BL/KsJ background
- HDL cholesterol and glucose levels increase concurrently

increased circulating VLDL cholesterol level

decreased circulating adiponectin level
- decreased adiponectin levels in serum

abnormal chemokine level
- elevated levels of eotaxin, keratinocyte cytokine, and monocyte chemotactic protein-1 (also elevated in serum) in bronchoalveolar lavage fluid

increased circulating interleukin-6 level
- elevated levels of IL-6 in serum

increased circulating insulin level

abnormal hormone level
- female mice exhibit an increase in hypothalamic gonadotrophin releasing hormone compared to in wild-type mice

immune system phenotype

abnormal interleukin level
- elevated levels of IL-6 in bronchoalveolar lavage fluid

lung inflammation
- elevated pulmonary levels of TNF mRNA 24 hours after ozone exposure but to a lesser extent than in controls
- elevated pulmonary levels of Il1beta mRNA 24 hours after ozone exposure
- elevated levels of eotaxin, Il6, keratinocyte cytokine, monocyte chemotactic protein-1, and neutrophiles in bronchoalveolar lavage as a result of ozone exposure
- ozone induces significantly elevated levels of TNFR1
- ozone induces a nonsignificant elevation of TNFR2 levels

abnormal leukocyte morphology

increased neutrophil cell number
- increased numbers in bronchoalveolar lavage

decreased leukocyte cell number
- decrease blood leukocyte numbers

abnormal chemokine level
- elevated levels of eotaxin, keratinocyte cytokine, and monocyte chemotactic protein-1 (also elevated in serum) in bronchoalveolar lavage fluid

increased circulating interleukin-6 level
- elevated levels of IL-6 in serum

cardiovascular system phenotype

heart left ventricle hypertrophy
- 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 myocardial fiber morphology
- exhibit myocyte hypertrophy

muscle phenotype

heart left ventricle hypertrophy
- 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 myocardial fiber morphology
- exhibit myocyte hypertrophy

neoplasm

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

nervous system phenotype

abnormal hypothalamus physiology

reproductive system phenotype

female infertility
- all females fail to reproduce

constricted vagina orifice

absent estrous cycle
- mice exhibit diestrous vaginal acyclicity or occasional metestrous acyclicity

anovulation

abnormal female reproductive system morphology
- atrophy of the reproductive organs

small uterus

absent estrus
- females never show signs of vaginal oestrous

respiratory system phenotype

abnormal lung compliance
- total lung resistance increases much more in response to ozone than in control mice
- responsiveness to methacholine and serotonin is much greater than controls

lung inflammation
- elevated pulmonary levels of Il1beta mRNA 24 hours after ozone exposure
- ozone induces a nonsignificant elevation of TNFR2 levels
- elevated pulmonary levels of TNF mRNA 24 hours after ozone exposure but to a lesser extent than in controls
- elevated levels of eotaxin, Il6, keratinocyte cytokine, monocyte chemotactic protein-1, and neutrophiles in bronchoalveolar lavage as a result of ozone exposure
- ozone induces significantly elevated levels of TNFR1

abnormal functional residual capacity
- reduced
- pressure volume curves shifted to the right

decreased pulmonary ventilation
- ventilation volumes decline with ozone exposure but to a lesser degree than for controls

abnormal respiratory mechanics
- end-expiratory pause increases considerably less than in controls after ozone exposure

growth/size/body region phenotype

heart left ventricle hypertrophy
- induced weight loss via leptin infusion, but not via caloric restriction, partially resolves the hypertrophy
- increase in left ventricle wall thickness and mass is seen by 6 months of age but not at 2 months of age

obese
- body weight is 10% and 20% more in males and females, respectively, compared to Leprr^tm1Mgmj homozygotes
- body weight is 2- to 3-fold more than in wild-type mice by 10 weeks of age
- develop progressive obesity
- increase in body weight becomes apparent at 4-6 weeks of age

decreased body length
- snout to anus length is decreased by about 5% compared to wild-type mice

Genotype: Lepr^db/Lepr^db
B6.BKS(D)-Lepr/JOrlRj

cellular phenotype

increased hepatocyte apoptosis
- some hepatocyte apoptosis is seen in mice fed the standard diet and apoptosis is not increased by a high-calorie diet and even reduced after 3 months of a high-calorie diet

liver/biliary system phenotype

hepatic steatosis
- severity of steatosis is enhanced by the high-calorie diet after 1 month, but is subsequently reduced after 3 months on this diet
- mice develop steatosis, with steatosis mainly localized in the centrilobular and mediolobular areas; fatty change is milder than in Lep^ob homozygotes

liver inflammation
- hepatic necroinflammation is not prominent, however it is aggravated after 1 month of high-calorie diet compared to standard diet and tends to alleviate with time
- non-alcoholic steatohepatitis is seen occasionally after 3 months of a standard diet and is seen in 3 of 9 mice after 3 months of the high-calorie diet

liver fibrosis
- some portal and perisinusoidal fibrosis is seen in standard diet fed mice at 3 months and is increased when mice are fed the high-calorie diet

microvesicular hepatic steatosis
- microvesicular steatosis is more frequently seen than in Lep^ob homozygotes

increased hepatocyte apoptosis
- some hepatocyte apoptosis is seen in mice fed the standard diet and apoptosis is not increased by a high-calorie diet and even reduced after 3 months of a high-calorie diet

macrovesicular hepatic steatosis
- macrovacuolar steatosis is similar to that seen in Lep^ob homozygotes

growth/size/body region phenotype

increased body weight
- mice exhibit increased body weight at 3 months, but not 1 month, of standard chow diet

increased susceptibility to diet-induced obesity
- mice exhibit increased body weight when fed a high-calorie diet for 1 or 3 months

homeostasis/metabolism phenotype

increased cholesterol level
- total cholesterol levels are increased in mice fed a high-calorie diet for 1 month and increased further when fed for 3 months

increased susceptibility to diet-induced obesity
- mice exhibit increased body weight when fed a high-calorie diet for 1 or 3 months

increased circulating ketone body level
- plasma beta-hydroxybutyrate levels are greatly increased after 3 months of the high-calorie diet

immune system phenotype

liver inflammation
- non-alcoholic steatohepatitis is seen occasionally after 3 months of a standard diet and is seen in 3 of 9 mice after 3 months of the high-calorie diet
- hepatic necroinflammation is not prominent, however it is aggravated after 1 month of high-calorie diet compared to standard diet and tends to alleviate with time

Genotype: Lepr^db/Lepr^db
involves: 129S2/SvPas * C57BL/6 * C57BLKS/J

renal/urinary system phenotype

abnormal kidney morphology
- total kidney collagen is increased in females by 96%

abnormal renal glomerulus morphology
- glomerular extracellular matrix (ECM) area in females is increased by 31% compared to wild-type female controls and female single Serpine1-deficient animals; however, when expressed as fractional glomerular ECM area, little difference is observed between any genotype
- any genotype

Genotype: Lepr^db/Lepr^db
BKS.Cg-Dock7 +/+ Lepr/Jcl

adipose tissue phenotype

abnormal epididymal fat pad morphology
- the epididymal fat pad exhibits macrophage infiltration unlike in wild-type mice

cellular phenotype

increased pancreatic islet cell apoptosis
- pancreatic islet cell apoptosis is increased compared to in heterozygous mice

endocrine/exocrine gland phenotype

increased pancreatic beta cell mass

abnormal pancreas physiology
- Normal - however, pancreatic islet cell proliferation by 16 weeks is normal
- at 8 weeks, pancreatic islet cell proliferation is increased compared to in heterozygous mice

increased pancreatic islet cell apoptosis
- pancreatic islet cell apoptosis is increased compared to in heterozygous mice

homeostasis/metabolism phenotype

hyperglycemia

increased circulating insulin level

Genotype: Lepr^db/Lepr⁺
B6.Cg-Dock7 +/+ Lepr/J

growth/size/body region phenotype

increased body weight
- slight but significant increase in body weight compared to wild-type mice

mortality/aging

extended life span
- Background Sensitivity - survival when deprived of food is not as long as when in a C57BLKsS background
- increased survival when totally deprived of food than wild-type controls

Genotype: Dock7^m/Dock7⁺ Lepr^db/Lepr⁺
BKS.Cg-Dock7 +/+ Lepr/J

mortality/aging

extended life span
- Background Sensitivity - survival when deprived of food is longer rhan when in a C57BL/6 background
- increased survival when totally deprived of food than wild-type controls

References

Additional - Lepr^db related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Restriction Enzyme Digest:Lepr
- End Point Analysis:Lepr
- Genotyping resources and troubleshooting
Breeding Considerations

This colony is maintained as segregating heterozygous and wildtype.
- Additional Breeding and Husbandry Support
Citation
When using the D2.BKS(D)-Lepr^db/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #012666 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Pricing & Availability

Cryo Recovery

Domestic
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Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
> >	Heterozygous or wildtype for Lepr<db>

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Frozen Mouse Embryo	D2.BKS(D)-Lepr<db>/J Frozen Embryo	$2595.00
Frozen Mouse Embryo	D2.BKS(D)-Lepr<db>/J Frozen Embryo	$2595.00
Frozen Mouse Embryo	D2.BKS(D)-Lepr<db>/J Frozen Embryo	$3373.50
Frozen Mouse Embryo	D2.BKS(D)-Lepr<db>/J Frozen Embryo	$3373.50

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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

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Genetic overview

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Detailed Description

Development

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Additional Information

Leprdb

Allele Symbol: Leprdb

Disease Terms

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

Models with phenotypic similarity to human diseases where etiology is unknown or involving genes where ortholog is unknown.

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Genotype: Leprdb related

Mammalian Phenotype Terms by Genotype

Genotype: Leprdb/LeprdbC57BLKS/J-Lepr

behavior/neurological phenotype

homeostasis/metabolism phenotype

liver/biliary system phenotype

renal/urinary system phenotype

cardiovascular system phenotype

growth/size/body region phenotype

Genotype: Leprdb/LeprdbB6.BKS(D)-Lepr/J

behavior/neurological phenotype

homeostasis/metabolism phenotype

renal/urinary system phenotype

Genotype: Leprdb/Leprdbinvolves: C57BL/6

cellular phenotype

hematopoietic system phenotype

immune system phenotype

skeleton phenotype

Genotype: Leprdb/LeprdbBKS.Cg-Dock7 +/+ Lepr/OlaHsd

digestive/alimentary phenotype

immune system phenotype

liver/biliary system phenotype

Genotype: Leprdb/Leprdbinvolves: C57BLKS/J

muscle phenotype

nervous system phenotype

renal/urinary system phenotype

reproductive system phenotype

vision/eye phenotype

adipose tissue phenotype

cardiovascular system phenotype

cellular phenotype

endocrine/exocrine gland phenotype

behavior/neurological phenotype

growth/size/body region phenotype

hematopoietic system phenotype

homeostasis/metabolism phenotype

immune system phenotype

liver/biliary system phenotype

mortality/aging

Genotype: Leprdb/LeprdbFVB.BKS-Lepr

renal/urinary system phenotype

endocrine/exocrine gland phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

Genotype: Leprdb/LeprdbBKS.Cg-Dock7 +/+ Lepr/J

cellular phenotype

endocrine/exocrine gland phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

muscle phenotype

behavior/neurological phenotype

nervous system phenotype

renal/urinary system phenotype

vision/eye phenotype

cardiovascular system phenotype

Genotype: Leprdb/Leprdbinvolves: C57BL/6 * C57BLKS/J

adipose tissue phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

limbs/digits/tail phenotype

reproductive system phenotype

skeleton phenotype

behavior/neurological phenotype

Genotype: Leprdb/Lepr+involves: C57BLKS/J

adipose tissue phenotype

Lepr^db

Allele Symbol: Lepr^db

Genotype: Lepr^db related

Genotype: Lepr^db/Lepr^db
C57BLKS/J-Lepr

Genotype: Lepr^db/Lepr^db
B6.BKS(D)-Lepr/J

Genotype: Lepr^db/Lepr^db
involves: C57BL/6

Genotype: Lepr^db/Lepr^db
BKS.Cg-Dock7 +/+ Lepr/OlaHsd

Genotype: Lepr^db/Lepr^db
involves: C57BLKS/J

Genotype: Lepr^db/Lepr^db
FVB.BKS-Lepr

Genotype: Lepr^db/Lepr^db
BKS.Cg-Dock7 +/+ Lepr/J

Genotype: Lepr^db/Lepr^db
involves: C57BL/6 * C57BLKS/J

Genotype: Lepr^db/Lepr⁺
involves: C57BLKS/J

Genotype: Lepr^db/Lepr^db
B6.Cg-Dock7 +/+ Lepr/J

Genotype: Lepr^db/Lepr^db
B6.BKS(D)-Lepr/JOrlRj

Genotype: Lepr^db/Lepr^db
involves: 129S2/SvPas * C57BL/6 * C57BLKS/J

Genotype: Lepr^db/Lepr^db
BKS.Cg-Dock7 +/+ Lepr/Jcl

Genotype: Lepr^db/Lepr⁺
B6.Cg-Dock7 +/+ Lepr/J

Genotype: Dock7^m/Dock7⁺ Lepr^db/Lepr⁺
BKS.Cg-Dock7 +/+ Lepr/J

Additional - Lepr^db related