Leptin-Deficient Mice Backcrossed to the BALB/cJ Genetic Background Have Reduced Adiposity, Enhanced Fertility, Normal Body Temperature, and Severe Diabetes

Abstract

A deficiency of leptin synthesis in mice results in a complex phenotype characterized by morbid obesity, diabetes, sterility, and defective thermogenesis. To determine whether the genetic background could alter the pleiotropic effects of leptin deficiency, we backcrossed the ob mutation for 10 generations from the C57BL/6J to the BALB/cJ genetic background. Compared with C57BL/6J ob/ob mice, BALB/cJ ob/ob mice showed at 27 wk of age a 35-40% reduction in body weight attributed to a 60% decrease in white adipose tissue mass. Food intake was not significantly different between the two obese strains, suggesting distinct utilization of energy intake. In the fed state, BALB/cJ ob/ob mice had elevated insulin and triglycerides levels, demonstrating a worsening effect on diabetes. At the reproductive level and in contrast to sterile C57BL/6J ob/ob mice, male and female BALB/cJ ob/ob mice were capable of reproducing after a mating period of 16 and 32 wk, respectively. At thermoneutrality, the body temperature of BALB/cJ ob/ob mice was 2.9 C higher than that of C57BL/6J ob/ob mice, whereas exposure of both groups to 4 C demonstrated a prolonged cold tolerance of BALB/cJ ob/ob mice. These studies show that the abnormalities caused by leptin deficiency can be genetically dissected and separated from each other, suggesting discrete pathways controlled by leptin modifier genes.

Involvement of Sex, Strain and Age Factors in High Fat Diet-Induced Obesity in C57BL/6J and BALB/cA Mice

“…Qiu et al [11] showed that abnormalities caused by leptin deficiency in ob/ob mice can be improved by the genetic background of BALB/cJ. This indicates that BALB/cJ mice have modifier genes which can rescue a defective leptin pathway.…”

“…BALB/cByJ mice eat less fat than B6, when they can freely access fat, protein or carbohydrate [14]. BALB/ cJ, which is another BALB/c substrain, has been used to investigate the genetic factors of diabetes and insulin resistance such as the ob/ob gene [11]. Therefore, it is predicted that HFD-induced obesity of the BALB/c strain may be milder than that of B6 mice, but there were few reports about HFD-feeding BALB/c strain mice.…”

Skeletal muscle mitochondrial uncoupling prevents diabetes but not obesity in NZO mice, a model for polygenic diabesity

“…It has also repeatedly been shown that the genetic background can influence the development of obesity and insulin resistance. Leptin deficiency in mice for example leads to multiple metabolic abnormalities including obesity, insulin resistance, reduced fertility and body temperature while the severity of these traits is strongly affected by the genetic background (Ewart-Toland et al 1999;Haluzik et al 2004;Qiu et al 2001). The NZO mouse is a model for polygenic ''diabesity'' that shows obesity-associated insulin resistance, beta-cell failure, and ultimately chronic hyperglycemia leading to the development of type 2 diabetes thus closely resembling the human metabolic syndrome.…”

Efficient method for obtaining Lepob/Lepob-derived animal models using adipose tissue transplantations

“…When compared with other alternative methods of restoring fertility of ob/ob mice, like backcrossing to the BALB/cj background or injections of leptin, [21][22][23] the stability of restored male fertility and the simplicity/efficiency of our method considerably facilitates this task.…”