BTBR.Cg-Lep^ob/WiscJ

Stock number: 004824
Product name: BTBR obese
Research areas: Cardiovascular Research, Diabetes and Obesity Research, Endocrine Deficiency Research, Immunology, Inflammation and Autoimmunity Research, Internal/Organ Research, Metabolism Research, Mouse/Human Gene Homologs, Reproductive Biology Research

Description

These ob/ob mice on a BTBR background are diabetic, severely hyperglycemic and obese, with increased triglycerides.

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Detailed description

Mice homozygous for the obese spontaneous mutation, (Lep^ob 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 number and 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. Hyperinsulinemia does not develop until after the increase body weight and is probably the result of it. Homozygotes have an abnormally low threshold for stimulation of pancreatic islet insulin secretion even in very young pre-obese animals.

As is the case with mice carrying the diabetes mutation (Lepr^db), manifestation of the diabetic syndrome is strikingly dependent on genetic background. Lep^ob homozygotes on the BTBR background develop diabetes at six weeks of age (males), and eight weeks of age (females). Hyperglycemia is severe and progressive with a fasting plasma glucose of 400 mg/dl at 10 weeks (Stoehr et al., 2000). In contrast to homozygotes on the C57BL/6 background, BTBR homozygotes develop extreme obesity (Stoehr et al., 2004) and progressive hypertriglyceridemia (Lan et al., 2003). Hepatic lipogenesis is not increased and homozygotes do not develop hepatic steatosis (Lan et al., 2003). Males remain hyperinsulinemic although insulin levels and islet mass are much reduced (Stoehr personal communication).

Two modifier loci (Mobe1, Mobe2, formerly, Moo1 and Moo2) regulate total fat mass. BTBR alleles of these loci semi-dominantly increase body mass (Stoehr et al., 2004).

The diabetic BTBRob/ob mouse model mimics key features of early diabetic nephropathy in humans, but with chronic injury limited to glomeruli (Björnson Granqvist, 2019). Mice challenged with a high-protein diet (HPD; 30%) show enhanced metabolic derangements, evidenced by further increased levels of glucose, HbA_1C, cholesterol, and alanine aminotransferase.

Hair loss is a strain background characteristic in this strain (regardless of mutation genotype).

Development

The obese mutation, ob, arose spontaneously at The Jackson Laboratory, Bar Harbor, Maine in 1949. The ob allele from B6.V-Lep^ob/J was introgressed into BTBR T⁺ tf/J (Stock No. 002282) using a marker-assisted backcrossing program for six generations at the University of Wisconsin, Madison (Stoehr, 2000). The donating investigator reports that no C57BL/6J alleles were detected with the exception of a 20 cM region on chromosome 6 flanking the leptin locus. Heterozygotes were intercrossed to produce mice homozygous for ob. This strain was donated to The Jackson Laboratory in 2003 and the backcross will be continued to N10.

In 2019, the live colony had been backcrossed to the BTBR inbred strain (Stock No. 002282) for a total of 13 generations and then intercrossed together for at least 18 generations.

Allele

Symbol: Lep^ob
Name: obese
MGI accession ID: MGI:1856424
Generation method: Spontaneous
Attributes: Null/Knockout
Synonyms: ob; ob/ob
Marker symbol: Lep
Marker name: leptin
Marker synonyms: LEPD; OB; obese; OBS
Chromosome: 6
Strain of origin: STOCK Mlph^ln a Tgfa^wa1 Cdh23^v Ednrb^s
Molecular note: Sequencing of RT-PCR products revealed a nonsense mutation in arginine codon 105 (p.R105*) 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).