RGD Reference Report - Differential effects of leptin receptor mutation on male and female BBDR Gimap5-/Gimap5- spontaneously diabetic rats.

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Differential effects of leptin receptor mutation on male and female BBDR Gimap5-/Gimap5- spontaneously diabetic rats.
Authors:	Moralejo, DH Hansen, CT Treuting, P Hessner, MJ Fuller, JM Van Yserloo, B Jensen, R Osborne, W Kwitek, AE Lernmark, A
Citation:	Moralejo DH, etal., Physiol Genomics. 2010 Mar 3;41(1):9-20. Epub 2009 Dec 8.
RGD ID:	6893459
Pubmed:	PMID:19996157 (View Abstract at PubMed)
PMCID:	PMC2841494 (View Article at PubMed Central)
DOI:	DOI:10.1152/physiolgenomics.00186.2009 (Journal Full-text)
Rodents homozygous for autosomal leptin receptor gene mutations not only become obese, insulin resistant, and hyperleptinemic but also develop a dysregulated immune system. Using marker-assisted breeding to introgress the Koletsky rat leptin receptor mutant (lepr-/lepr-), we developed a novel congenic BBDR.(lepr-/lepr-) rat line to study the development of obesity and type 2 diabetes (T2D) in the BioBreeding (BB) diabetes-resistant (DR) rat. While heterozygous lepr (-/+) or homozygous (+/+) BBDR rats remained lean and metabolically normal, at 3 wk of age all BBDR.(lepr-/lepr-) rats were obese without hyperglycemia. Between 45 and 70 days of age, male but not female obese rats developed T2D. We had previously developed congenic BBDR.(Gimap5-/Gimap5-) rats, which carry an autosomal frameshift mutation in the Gimap5 gene linked to lymphopenia and spontaneous development of type 1 diabetes (T1D) without sex differences. Because the autoimmune-mediated destruction of pancreatic islet beta-cells may be affected not only by obesity but also by the absence of leptin receptor signaling, we next generated BBDR.(lepr-/lepr-,Gimap5-/Gimap5-) double congenic rats carrying the mutation for Gimap5 and T1D as well as the Lepr mutation for obesity and T2D. The hyperleptinemia rescued end-stage islets in BBDR.(lepr-/lepr-,Gimap5-/Gimap5-) congenic rats and induced an increase in islet size in both sexes, while T1D development was delayed and reduced only in females. These results demonstrate that obesity and T2D induced by introgression of the Koletsky leptin receptor mutation in the BBDR rat result in islet expansion associated with protection from T1D in female but not male BBDR.(lepr-/lepr-,Gimap5-/Gimap5-) congenic rats. BBDR.(lepr-/lepr-,Gimap5-/Gimap5-) congenic rats should prove valuable to study interactions between lack of leptin receptor signaling, obesity, and sex-specific T2D and T1D.

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Disease Annotations

hyperglycemia (IAGP)

lymphopenia (IAGP)

obesity (IAGP)

type 1 diabetes mellitus (IAGP)

type 2 diabetes mellitus (IAGP)

Phenotype Annotations

Mammalian Phenotype

abnormal pancreatic islet morphology (IAGP)

decreased lymphocyte cell number (IAGP)

increased body weight (IAGP)

increased circulating cholesterol level (IAGP)

increased circulating glucose level (IAGP)

increased circulating insulin level (IAGP)

increased circulating leptin level (IAGP)

increased gonadal fat pad weight (IAGP)

increased mesenteric fat pad weight (IAGP)

increased retroperitoneal fat pad weight (IAGP)

increased susceptibility to autoimmune diabetes (IAGP)

increased susceptibility to non-insulin-dependent diabetes (IAGP)

obese (IAGP)

pancreas inflammation (IAGP)

pancreatic islet hyperplasia (IAGP)

Objects Annotated

Strains

BBDR.BBDP-(D4Mit6-D4Mit7)/1Rhw (NA)

BBDR.LA-(D5Rat98-D5Rat233), BBDP-(D4Mit6-D4Mit7)/Rhw (NA)

BBDR.LA-(D5Rat98-D5Rat233)/Rhw (NA)

BBDR/RhwMcwi (NA)

Objects referenced in this article

Strain	LA/N-cp	null	Rattus norvegicus

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Differential effects of leptin receptor mutation on male and female BBDR Gimap5-/Gimap5- spontaneously diabetic rats.

Mammalian Phenotype