Strain Name:

B6.V-Lepob/J

Stock Number:

000632

Availability:

Level 2
Mice homozygous for the obese spontaneous mutation, (Lepob commonly referred to as ob or ob/ob), exhibit obesity, hyperphagia, a diabetes-like syndrome of hyperglycemia, glucose intolerance, elevated plasma insulin, subfertility, impaired wound healing and an increase in hormone production from both pituitary and adrenal glands. They are also hypometabolic and hypothermic. The obesity is characterized by an increase in both the number and the size of adipocytes. Although hyperphagia contributes to the obesity, homozygotes gain excess weight and deposit excess fat even when restricted to a diet sufficient for normal weight maintenance in lean mice.

Description

Strain Information

Type Congenic; Mutant Strain; Spontaneous Mutation;
Additional information on Genetically Engineered Mutant Mice.
Specieslaboratory mouse
Background Strain C57BL/6J
Donor Strain V
H2 Haplotypeb
GenerationN43 (11-JAN-08)

Appearance
black, fat
Related Genotype: a/a Lepob/Lepob

black, lean
Related Genotype: a/a Lepob/+ or a/a ?/+

Description
Mice homozygous for the obese spontaneous mutation, (Lepob; commonly referred to as ob or ob/ob), are first recognizable at about four weeks of age. Homozygous mutant mice gain weight rapidly and may reach three times the normal weight of wild-type controls. In addition to obesity, mutant mice exhibit hyperphagia, a diabetes-like syndrome of hyperglycemia, glucose intolerance, elevated plasma insulin, subfertility, impaired wound healing, and an increase in hormone production from both pituitary and adrenal glands. They are also hypometabolic and hypothermic. The obesity is characterized by an increase in both adipocyte number and size. Although hyperphagia contributes to the obesity, homozygotes gain excess weight and deposit excess fat even when restricted to a diet sufficient for normal weight maintenance in lean mice. Hyperinsulinemia does not develop until after the increase in body weight, and probably results from it. Homozygotes have an abnormally low threshold for stimulation of pancreatic islet insulin secretion even in very young pre-obese animals. Female homozygotes exhibit decreased uterine and ovarian weights, decreased ovarian hormone production and hypercytolipidemia in follicular granulosa and endometrial epithelial tissue layers (Garris et al., 2004).

As is the case with mice carrying the diabetes mutation (Leprdb), manifestation of the diabetic syndrome is strikingly dependent on genetic background. Hyperglycemia is only transient, (subsiding around 14 to 16 weeks) on the C57BL/6J background. On the C57BLKS background, obese homozygotes (Stock No. 000696) become severely diabetic with regression of islets and early death. Injection of recombinant leptin into obese homozygotes sharply reduces body weight, decreases food intake, increases energy expenditure, and restores fertility in male mice.

Leptin can regulate bone mass through a central, neuroendocrine signaling pathway. Similar to the effects of aging in humans, homozygotes exhibit muscle hypoplasia (quadriceps), increased marrow adipogenesis and decreased bone mass in the hindlimbs (Hamrick et al., 2004).

Control Information

  Control
   Heterozygote from the colony
   Untyped from the colony
   000664 C57BL/6J
 
  Considerations for Choosing Controls

Related Strains

Strains carrying   Lepob allele
006906   B6.Cg-Lepob Ldlrtm1Her/J
000696   BKS.V-Lepob/J
004824   BTBR.V(B6)-Lepob/WiscJ
View Strains carrying   Lepob     (3 strains)

Additional Web Information

Congenic Nomenclature
Genetic Quality Control Annual Report
JAX® NOTES, Fall 1992; 451. Variation in the severity and duration of hyperglycemia in the C57BL/6J-ob/ob (obese) mouse.
JAX® NOTES, Spring 2003; 489. Malocclusion in the Laboratory Mouse.
JAX® NOTES, Summer 2003; 490. Hydrocephalus in Laboratory Mice.

Phenotype

Phenotype Information

View Phenotypic Data

Phenotypic Data
Body Weight Information - JAX® Mice Strain B6.V-Lepob/J (000632)
(This chart reflects the typical correlation between body weight and age for mice maintained in production colonies at The Jackson Laboratory.)
Mouse Phenome Database
View Mammalian Phenotype Terms

Mammalian Phenotype Terms
      assigned by genotype

Lepob/Lep+

        involves: C57BL/6J
  • skeleton phenotype
  • increased bone mass (MGI Ref ID J:60001)
    • increased bone mass even on a low fat diet to delay obesity

Lepob/Lepob

        involves: C57BL/6J
  • skeleton phenotype
  • abnormal skeleton development (MGI Ref ID J:60001)
    • rate of new bone formation increased at both 3 and 6 months
    • abnormal osteoclast formation (MGI Ref ID J:60001)
      • increased numbers of osteoclasts
  • increased bone mass (MGI Ref ID J:60001)
    • denser vertebrae and long bones at 6 months
    • increased bone mass even on a low fat diet to delay obesity
    • osteopetrosis (MGI Ref ID J:60001)
      • increased numbers of thick trabeculae at 3 and 6 months
      • 2 fold increase in trabecular bone volume
  • homeostasis/metabolism phenotype
  • increased circulating corticosterone level (MGI Ref ID J:60001)
    • severe

Lepob/Lepob

        B6.V-Lepob/J
  • growth/size phenotype
  • obese (MGI Ref ID J:104171)
    • 12-week old males are obese
    • develop progressive obesity
  • homeostasis/metabolism phenotype
  • abnormal circulating cholesterol level (MGI Ref ID J:18161)
    • increased circulating cholesterol level (MGI Ref ID J:18161)
      • fasting plasma total cholesterol concentration is increased 2-3 fold over controls
      • increased circulating HDL cholesterol level (MGI Ref ID J:18161)
      • increased circulating LDL cholesterol level (MGI Ref ID J:18161)
      • increased circulating VLDL cholesterol level (MGI Ref ID J:18161)
  • hyperglycemia (MGI Ref ID J:122746)
    • serum glucose is 320 mg/dl compared to 134 mg/dl in wild-type controls
  • impaired glucose tolerance (MGI Ref ID J:104171)
    • glucose intolerance which improved when treated with rosiglitazone
    • following an acute intraperitoneal glucose injection, the post-challenge glucose level remained elevated up to 120 min compared to controls, indicating glucose intolerance
  • increased circulating insulin level (MGI Ref ID J:104171)
    • seen in 12-week old males
    • serum insulin is 41.5 ng/ml compared to 0.8 ng/ml in wild-type
  • increased circulating triglyceride level (MGI Ref ID J:104171)
    • seen in 12-week old males
    • triglyceride levels are elevated 1.5- to 2-fold
  • insulin resistance (MGI Ref ID J:104171)
  • cardiovascular system phenotype
  • abnormal myocardial fiber morphology (MGI Ref ID J:104171)
    • 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
    • exhibit myocyte hypertrophy, with increased myocyte diameter and distorted nuclear architecture
    • enlarged myocardial fiber (MGI Ref ID J:104171)
      • cardiomyocytes display larger resting cell length and cross-sectional area
  • abnormal myocardial fiber physiology (MGI Ref ID 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
  • decreased cardiac muscle contractility (MGI Ref ID J:104171)
    • 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
  • left ventricle hypertrophy (MGI Ref ID 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
  • muscle phenotype
  • abnormal myocardial fiber morphology (MGI Ref ID J:104171)
    • 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
    • exhibit myocyte hypertrophy, with increased myocyte diameter and distorted nuclear architecture
    • enlarged myocardial fiber (MGI Ref ID J:104171)
      • cardiomyocytes display larger resting cell length and cross-sectional area
  • decreased cardiac muscle contractility (MGI Ref ID J:104171)
    • 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
  • adipose tissue phenotype
  • increased adipose tissue amount (MGI Ref ID J:122746)
    • mice have fat mass of ~42 g compared to ~3 g in wild-type at 16 weeks
  • behavior/neurological phenotype
  • abnormal food intake (MGI Ref ID J:122746)
    • polyphagia (MGI Ref ID J:122746)
      • mice eat 70% more than wild-type controls
  • hypoactivity (MGI Ref ID J:122746)
    • significantly reduced activity relative to wild-type controls
  • reproductive system phenotype
  • female infertility (MGI Ref ID J:122746)
    • females do not produce litters
  • respiratory system phenotype
  • lung inflammation (MGI Ref ID J:115772)
    • ozone induces significantly elevated levels of TNFR1
    • ozone induces a nonsignificant elevation of TNFR2 levels
  • immune system phenotype
  • decreased NK cell number (MGI Ref ID J:117826)
    • reduced numbers can be restored by treatment with leptin
  • lung inflammation (MGI Ref ID J:115772)
    • ozone induces significantly elevated levels of TNFR1
    • ozone induces a nonsignificant elevation of TNFR2 levels
  • tumorigenesis
  • increased metastatic potential (MGI Ref ID 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 phenotype
  • decreased NK cell number (MGI Ref ID J:117826)
    • reduced numbers can be restored by treatment with leptin

Lepob/Lepob

        C57BL/6J-Lepob
  • homeostasis/metabolism phenotype
  • decreased circulating glucose level (MGI Ref ID J:129554)
    • when treated with AdipoR2-ASO, mice exhibit a decrease in plasma glucose level

Lepob/Lepob

        B6.V-Lepob/OlaHsd
  • digestive/alimentary phenotype
  • abnormal digestive system physiology (MGI Ref ID J:124815)
    • transepithelial resistance in the epithelium is reduced, indictive of a disrupted mucosal barrier function
  • abnormal intestinal epithelium morphology (MGI Ref ID J:124815)
    • reduced levels of occludin in intestinal sections
    • zonula occludens 1 has a discontinuous distribution
  • immune system phenotype
  • abnormal acute inflammation (MGI Ref ID J:124815)
    • higher levels of endotoxin are found in portal blood (entotoxemia)
    • increased susceptibility to endotoxin shock (MGI Ref ID J:124815)
      • increased succeptibility of hepatic stellate cells to LPS
  • abnormal chemokine secretion (MGI Ref ID J:124815)
    • increased release of monocyte chemo attractant protein by hepatic stellate cells
  • increased interleukin-6 secretion (MGI Ref ID J:124815)
    • increased release by hepatic stellate cells
  • liver inflammation (MGI Ref ID J:124815)
  • liver/biliary system phenotype
  • liver inflammation (MGI Ref ID J:124815)

The following phenotype information may relate to a genetic background differing from this JAX® Mice strain.

Lepob/Lep+

        involves: 129X1/SvJ * C57BL/6
  • liver/biliary system phenotype
  • increased liver weight (MGI Ref ID J:76479)
    • mice show significant increase in relative and absolute hepatic weight compared to wild-type; otherwise, no differences from wild-type are noted

Lepob/Lepob

        D2.B6-Lepob
  • growth/size phenotype
  • obese (MGI Ref ID J:78850)
  • homeostasis/metabolism phenotype
  • hyperglycemia (MGI Ref ID J:78850)
    • at 3 months of age, males are hyperglycemic with blood glucose levels of ~574 mg/dl; females have levels of ~388 mg/dl
  • increased circulating insulin level (MGI Ref ID J:78850)
    • some mutant DBA/2J mice have high insulin levels compared to controls
  • endocrine/exocrine gland phenotype
  • abnormal islet of Langerhans morphology (MGI Ref ID J:78850)
    • there is a 5-fold increase in number of insulin-secreting cells per islet in obese mice with high insulin secretion
    • islets of mutants with low insulin levels are abnormal in appearance, being found in clusters of 1-4 cells, scattered within the ductal epithelium
    • decreased pancreatic beta cell number (MGI Ref ID J:78850)
      • mutants with low insulin secretion have a low number of insulin-secreting cells compared to controls or high-insulin secreting mutants
  • digestive/alimentary phenotype
  • abnormal islet of Langerhans morphology (MGI Ref ID J:78850)
    • there is a 5-fold increase in number of insulin-secreting cells per islet in obese mice with high insulin secretion
    • islets of mutants with low insulin levels are abnormal in appearance, being found in clusters of 1-4 cells, scattered within the ductal epithelium
    • decreased pancreatic beta cell number (MGI Ref ID J:78850)
      • mutants with low insulin secretion have a low number of insulin-secreting cells compared to controls or high-insulin secreting mutants

Lepob/Lepob

        FVB.B6-Lepob
  • homeostasis/metabolism phenotype
  • hyperglycemia (MGI Ref ID J:78850)
    • mice are hyperglycemic like congenic FVB Lepr mice
  • increased circulating insulin level (MGI Ref ID J:78850)
    • mice are hyperinsulinemic like congenic FVB Leprdb mice

Lepob/Lepob

        involves: 129X1/SvJ * C57BL/6
  • growth/size phenotype
  • decreased lean body mass (MGI Ref ID J:107169)
    • decreased (16.0 g, 33% of body weight) compared to wild-type (25.5 g 87% of body weight) or double mutants (19.8g)
  • increased body weight (MGI Ref ID J:107169)
    • higher than wild-type
  • homeostasis/metabolism phenotype
  • abnormal circulating hormone level (MGI Ref ID J:76479)
    • abnormal circulating pancreatic peptide level (MGI Ref ID J:76479)
      • plasma levels of pancreatic polypeptide (PP) are strongly reduced compared to wild-type
    • decreased circulating testosterone level (MGI Ref ID J:76479)
      • level is markedly decreased compared to wild-type or Lep heterozygotes
      • significantly lower (4.2 nmol/l) compared to wild-type (14.2 nmol/l)
    • increased circulating corticosterone level (MGI Ref ID J:76479)
      • mice display hypercorticosteronemia compared to wild-type
      • mice display hypercorticosteronemia compared to wild-type, Npy2rtm1.1Hhz homozygotes, or Npy2r, Lep double mutants
    • increased circulating insulin level (MGI Ref ID J:76479)
      • level is significantly increased over wild-type
      • hyperinsulinemic compared to wild-type
    • increased circulating leptin level (MGI Ref ID J:76479)
      • level is significantly increased over wild-type
  • hyperglycemia (MGI Ref ID J:107169)
  • increased circulating cholesterol level (MGI Ref ID J:107169)
    • 5.74 mmol/l vs 3.54 mmol/l in wild-type
  • increased circulating triglyceride level (MGI Ref ID J:107169)
    • 2.48 mmol/l vs 1.62 mmol/l in wild-type
  • endocrine/exocrine gland phenotype
  • abnormal branching of the mammary ductal tree (MGI Ref ID J:76479)
    • in virgin females, no ductal development occurs
  • abnormal ovarian folliculogenesis (MGI Ref ID J:76479)
    • ovaries have very few primary or secondary follicles
  • absent corpus luteum (MGI Ref ID J:76479)
    • no corpora lutea develops properly in ovary
  • decreased seminal gland weight (MGI Ref ID J:76479)
    • weight of gland is significantly lower than wild-type or heterozygotes
  • decreased testis weight (MGI Ref ID J:76479)
    • testis weight is significantly lower than in Lepob heterozygotes or Lep, Ppyr1 double null mice
    • testes weigh 0.19 g compared to 0.33 g in wild-type
  • enlarged pancreas (MGI Ref ID J:107169)
    • 0.41 g vs 0.29 in wild-type
  • adipose tissue phenotype
  • abnormal adipose tissue amount (MGI Ref ID J:107169)
    • combined white adipose tissue (WAT) mass is increased compared to wild-type
  • reproductive system phenotype
  • abnormal branching of the mammary ductal tree (MGI Ref ID J:76479)
    • in virgin females, no ductal development occurs
  • abnormal ovarian folliculogenesis (MGI Ref ID J:76479)
    • ovaries have very few primary or secondary follicles
  • abnormal vagina opening (MGI Ref ID J:76479)
    • vaginal opening is very small compared to wild-type
  • absent corpus luteum (MGI Ref ID J:76479)
    • no corpora lutea develops properly in ovary
  • decreased seminal gland weight (MGI Ref ID J:76479)
    • weight of gland is significantly lower than wild-type or heterozygotes
  • decreased testis weight (MGI Ref ID J:76479)
    • testis weight is significantly lower than in Lepob heterozygotes or Lep, Ppyr1 double null mice
    • testes weigh 0.19 g compared to 0.33 g in wild-type
  • female infertility (MGI Ref ID J:76479)
    • homozygous females produce no litters
  • male infertility (MGI Ref ID J:76479)
    • only one male tested was able to sire a litter
    • no males could produce offspring
  • prolonged diestrous (MGI Ref ID J:76479)
    • mice have diestrous-like swab until 9 weeks of age
  • prolonged estrous cycle (MGI Ref ID J:76479)
    • beginning at 9 weeks of age, estrous cycles last 11-15 days
  • prolonged estrous (MGI Ref ID J:76479)
    • beginning at 9 weeks of age, estrous-like cytology lasts 6-8 days
  • behavior/neurological phenotype
  • polyphagia (MGI Ref ID J:107169)
  • digestive/alimentary phenotype
  • abnormal intestine morphology (MGI Ref ID J:107169)
    • mice display intestinal hypertrophy compared to wild-type mice (intestine weight - 1.89 g vs 1.03 g in wild-type; intestine length 43 cm vs 33 cm in wild-type)
  • enlarged pancreas (MGI Ref ID J:107169)
    • 0.41 g vs 0.29 in wild-type
  • liver/biliary system phenotype
  • increased liver weight (MGI Ref ID J:107169)
    • 4.56 g vs 1.44 g in wild-type
  • renal/urinary system phenotype
  • increased kidney weight (MGI Ref ID J:107169)
    • 0.54 g vs 0.41 g in wild-type

Lepob/Lepob

        involves: 129/Sv * C57BL/6
  • homeostasis/metabolism phenotype
  • abnormal lipid level (MGI Ref ID J:121534)
    • sphingomeylin and antioxidant ethanolamine plasmlogen are markedly decreased
  • increased circulating insulin level (MGI Ref ID J:121534)
    • at 4 and 16 weeks of age
  • insulin resistance (MGI Ref ID J:121534)
    • at 16 weeks
  • endocrine/exocrine gland phenotype
  • abnormal islet of Langerhans morphology (MGI Ref ID J:121534)
    • increase in islet number and size
    • at 16 weeks, increased islet-to-pancreases volume ratios
    • at 16 weeks, islet insulin content is 30-fold greater than in Ppargtm1Avb Lepob homozygotes
  • increased insulin secretion (MGI Ref ID J:121534)
    • at 16 weeks of age
  • behavior/neurological phenotype
  • hypoactivity (MGI Ref ID J:121534)
    • at 20 weeks, mice have decreased locomotor activity compared to wild-type
  • polyphagia (MGI Ref ID J:121534)
    • hyperphagic
  • growth/size phenotype
  • increased body weight (MGI Ref ID J:121534)
    • mice quickly become heavier and have significantly elevated body weights at 4 and 6 weeks of age in females and males, respectively
  • adipose tissue phenotype
  • increased percent body fat (MGI Ref ID J:121534)
    • 40% increase compared to wild-type at 20 weeks
  • liver/biliary system phenotype
  • hepatic steatosis (MGI Ref ID J:121534)
  • digestive/alimentary phenotype
  • abnormal islet of Langerhans morphology (MGI Ref ID J:121534)
    • increase in islet number and size
    • at 16 weeks, increased islet-to-pancreases volume ratios
    • at 16 weeks, islet insulin content is 30-fold greater than in Ppargtm1Avb Lepob homozygotes
  • increased insulin secretion (MGI Ref ID J:121534)
    • at 16 weeks of age

Lepob/Lepob

        BKS.V-Lepob/J
  • homeostasis/metabolism phenotype
  • abnormal circulating cholesterol level (MGI Ref ID J:18161)
    • increased circulating cholesterol level (MGI Ref ID J:18161)
      • fasting plasma total cholesterol concentration is increased 2-3 fold over controls
      • increased circulating HDL cholesterol level (MGI Ref ID J:18161)
      • increased circulating LDL cholesterol level (MGI Ref ID J:18161)
      • increased circulating VLDL cholesterol level (MGI Ref ID J:18161)
  • increased circulating triglyceride level (MGI Ref ID J:18161)
    • triglyceride levels are elevated 1.5- to 2-fold
View Research Applications

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

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

Internal/Organ Research
Wound Healing (delayed/impaired)

Lepob related

Diabetes and Obesity Research
Hyperinsulinemia
Impaired Wound Healing
Insulin Resistance
Obesity With Diabetes

Endocrine Deficiency Research
Adipose Defects
Hypothalamus/Pituitary Defects
Pancreas Defects

Immunology and Inflammation Research
Immunodeficiency Associated with Other Defects

Internal/Organ Research
Adipose Defects

Metabolism Research

Mouse/Human Gene Homologs
obesity, severe, due to leptin deficiency (rare)

Reproductive Biology Research
Fertility Defects

Genes & Alleles

Gene & Allele Information

Allele Symbol Lepob
Allele Name obese
Allele Type Spontaneous
Common Name(s) ob;
Strain of OriginSTOCK Mlph a Tgfa Cdh23 Ednrb
Gene Symbol and Name Lep, leptin
Chromosome 6
Gene Common Name(s) FLJ94114; OB; OBS; ob; obese;
General Note Homozygous obese mice are first recognizable at about 4 weeks of age. They increase in weight rapidly and may reach three times normal weight (J:13066). In addition to obesity, mutant mice exhibit hyperphagia; a diabetes-like syndrome of hyperglycemia, glucose intolerance, and elevated plasma insulin; subfertility; and increased hormone production from both pituitary and adrenal. They also have difficulty maintaining body temperature under cold conditions (J:7702).

The obesity is characterized by both an increased number of adipocytes and an increase in their size (J:7702); this is in contrast to other genetic obesities in the mouse in which increase in fat depots is due entirely to cell enlargement (J:5253, J:5765).

Hyperphagia may contribute tothe obesity. However, homozygotes gain excess weight and deposit excess fat even when restricted to a diet sufficient for normal lean mice, thus demonstrating an increased metabolic efficiency (J:6236). In parabiosis with normal mice, Lepob homozygotes eat less and lose weight; in parabiosis with Leprdb homozygotes, they cease eating completely and die of starvation. This is taken to mean that they have a normal response to a 'satiety' factor, presumably the leptin protein, but are unable to produce enough of it to maintain normal food intake (J:5401).

Hyperinsulinemia does not develop until after the increase in food intake and is probably the result of it (J:5759). It has been shown, however, that homozygous Lepob mice have an abnormally low threshold for stimulation of pancreatic islet insulin secretion (J:14402), even in very young animals before obesity develops (J:22634). As is the case with the diabetes mutant Leprdb, manifestation of the diabetic syndrome is strikingly dependent on genetic background. On a C57BL/6 background, Lepob homozygotes develop a well compensated diabetes with only temporary and moderate hyperglycemia, marked hyperinsulinemia, and enlarged islets of Langerhans. Onthe C57BLKS background, however, they become severely diabetic with regression of the islets and early death (J:5400).

Lepob homozygous mice have an impaired capacity for non-shivering thermogenesis which can be demonstrated at low temperatures as early as 10 days of age (J:12010). At 4 degrees C they rapidly become hypothermic and die within a few hours (J:5958). It has been suggested that a reduction in the energy requirement normally used for thermoregulatory heat production could be responsible for the increased metabolic efficiency noted above. That is unlikely to be the major cause of the thermoregulatory problems, however, since brief exposure of obese mice to 10 degrees C produces cold adaptation and allows indefinite survival at 4degrees C with maintenance of nearly normal body temperature (J:6756).

Coleman has suggested that the hyperinsulinemia of obese mice, which increases synthetic processes and decreases degradation, might spare the energy normally spent on tissue turnover and account at least in part for the increased efficiency (J:6756). Some contribution to the effect may also come from a low basal Na+,K+ATPase activity, shown to occur in muscle of 14-day old mutants (J:6182).

Heterozygotes (Lepob/+) have normal body weight, blood glucose, and plasma insulin, but can survive a prolonged fast longer than congenic wild-type controls, suggesting that increased metabolic efficiency is expressed to some extent in heterozygotes (J:159).

Female homozygotes are always sterile, although their ovaries respond to exogenous pituitary hormones. About 20% of male homozygotes may be transiently fertile, particularly if maintained on a restricted diet (J:7702).

Cloning of the Lep gene has made possible the production of recombinant leptin. Injection of this protein into Lepob homozygotes sharply reduces body weight, decreases food intake, and increases energy expenditure. There is no effect in diabetic Leprdb homozygotes, who are resistant to effects of the Lepob mutation. Normal mice also decrease food consumption and lose weight, with an accompanying loss in body fat (J:29161). Other investigators have obtained congruent results in normal and in Lepob mice (J:29162, J:29075); leptin also reduces food intake in fasted normal mice (J:28578). Leptin treatment effects on behavior of Lepob mice suggest a direct effect on neuronal networks (J:29160). Interactions of leptin with effects of hypothalamic lesions and of the Lepr gene indicate that Lep is upstream in the pathway of adipose tissue mass regulation (J:27422). Mutant leptin produced by the Lepob mutation fails to self-regulate production of leptin mRNA, which rises to a level 4 times that in normal mice. Lean mice when fasted decrease in leptin mRNA levels, but obese animals do not (J:29081).

There is a vast literature on the biochemical and physiological changes in Lepob mice, which has been reviewed by Herberg and Coleman (J:5759) and more recently by Charlton (J:7702). Many of the studies performed in adult mice may involve secondary effects of obesity rather than primary causes of it.

Increased blood levels of corticosterone occur in Lepob/Lepob mice, and most of the symptoms of the obese syndrome are ameliorated by excision of the adrenal glands. The hypothalamus-pituitary-adrenal axis is dysregulated, with hyperactivity of pituitary synthesis and secretion of adrenocorticotropic hormone (ACTH), as well as hyperresponsiveness of the adrenal cortex to ACTH (J:13151). Adrenal medullary activity, on the other hand, may be decreased; a diminished urinary excretion of epinephrine in obese homozygous mice indicates reduced medullary production, although this may be a secondary effect of the obesity (J:4033). A low serum level of the thyroid hormone triiodothyronine (T3) is also characteristic of obese homozygotes. Early treatment of these mice with T3 increases oxygen consumption and temperature while reducing body fat (J:22025). T3 treatment increases oxidative metabolism in muscle, but not in brown adipose tissue or in liver (J:22377).

Plasma triglyceride levels are elevated in mouse mutants considered models of non-insulin-dependent diabetes,including Lepob mutants. Cholesterol is also elevated, but the increase is primarily in high-density lipoprotein cholesterol (J:18161), so that atherosclerotic lesions are not increased (J:19043).

Molecular Note Sequencing of RT-PCR products revealed a nonsense mutation in codon 105 resulting from a C to T point mutation. The 16 kDa leptin protein, expressed predominantly in adipose tissue of normal mice, is missing from homozygous mutant mice (J:29081). [MGI Ref ID J:20512] [MGI Ref ID J:29081] [MGI Ref ID J:45748]

Genotyping

Genotyping Information

Genotyping Protocols

Lepob, PYRO, vers. 2
Lepob, REST, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Coleman DL; Hummel KP. 1973. The influence of genetic background on the expression of the obese (Ob) gene in the mouse. Diabetologia 9(4):287-93. [PubMed: 4588246]  [MGI Ref ID J:5400]

Ewart-Toland A; Mounzih K; Qiu J; Chehab FF. 1999. Effect of the genetic background on the reproduction of leptin-deficient obese mice. Endocrinology 140(2):732-8. [PubMed: 9927300]  [MGI Ref ID J:52903]

Fantuzzi G; Faggioni R. 2000. Leptin in the regulation of immunity, inflammation, and hematopoiesis. J Leukoc Biol 68(4):437-46. [PubMed: 11037963]  [MGI Ref ID J:109886]

Malik NM; Carter ND; Murray JF; Scaramuzzi RJ; Wilson CA; Stock MJ. 2001. Leptin requirement for conception, implantation, and gestation in the mouse. Endocrinology 142(12):5198-202. [PubMed: 11713215]  [MGI Ref ID J:94783]

Mancuso P; Gottschalk A; Phare SM; Peters-Golden M; Lukacs NW; Huffnagle GB. 2002. Leptin-deficient mice exhibit impaired host defense in gram-negative pneumonia. J Immunol 168(8):4018-24. [PubMed: 11937559]  [MGI Ref ID J:75906]

Oler AT; Attie AD. 2008. A rapid, microplate SNP genotype assay for the leptinob allele. J Lipid Res 49(5):1126-9. [PubMed: 18272929]  [MGI Ref ID J:133040]

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