| First Author | Surwit RS | Year | 1994 |
| Journal | Mouse Genome | Volume | 92 |
| Pages | 523-8 | Mgi Jnum | J:40713 |
| Mgi Id | MGI:708109 | Citation | Surwit RS, et al. (1994) Diet-induced obesity and diabetes in C57BL/6J and C57BL/KsJ mice. Mouse Genome 92:523-8 |
| abstractText | Full text of Mouse Genome contribution: DIET-INDUCED OBESITY AND DIABETES IN C57BL/6J AND C57BL/KsJ MICE. Richard S. Sutwit1, Michael F. Seldin, Cynthia M. Kuhn, Christina Secor and Mark N. Feinglos. Department of Psychiatry, Medicine and Pharmacology, and the Sarah Stedman Nutrition Center, Duke University Medical Center. 1Box 3842, Duke University Medical Center, Durham, NC 27710. Phone (919) 684-4317, FAX (919) 684-8629. Abstract Ob and db mutations produce severe diabetes when placed on the C57BL/KsJ (B/KsJ) background, but produce only mild diabetes when placed on the C57BL/6J (B/6J) background. However, BL/6 mice will develop marked insulin resistance and fasting hyperglycemia when weaned onto a high fat, high sucrose diet. In the present study we explored the comparative effects of this diet on B/6J and B/KsJ mice. Ten B/6J, ten B/KsJ and ten A/J mice were fed normal Purina Rodent Chow and water ad libitum while another ten animals from each strain were given access to a high-fat, high sucrose, low fiber diet. After five months on the diet, blood samples were collected following an eight hour fast. All animals on the experimental diet gained a significant amount of weight; however B/6J mice gained the most weight while B/KsJ and A/J mice gained weight equally. The experimental diet produced severe fasting hyperglycemia and hyper-insulinemia in B/6J mice while A/J and B/KsJ mice on the experimental diet showed only moderate elevations in glucose and insulin. Thus, the interactions of the ob/ob and db/db mutations and diet-induced effects with B/6J and B/KsJ genetic backgrounds appear to be different. Introduction Ob and db homozygote mutations produce severe diabetes when placed on the C57BL/KsJ (B/KsJ) background (1). However, these mutations produce only mild diabetes when placed on the C57BL/6J (B/6J) background (1). For this reason, it has been hypothesized previously that B/6J mice may be a diabetes resistant strain (2). Kaku, Province and Permutt (3) have postulated that B/KsJ mice carry a gene(s) that triggers a diabetes syndrome when animals become obese and that the other strains are resistant to this phenomenon. These investigators recently reported (3) that multiple modifier genes are responsible for determining a limited capacity to synthesize insulin, causing diabetes, when the db mutation is placed on the B/KsJ background. In contrast, we have demonstrated that B/6J mice will develop an analogue of type 2 diabetes when weaned onto a high fat, high sucrose diet. This syndrome consists of obesity, severe insulin resistance and fasting hyperglycemia (4). We have shown that the development of diet-induced diabetes in the B/6J mouse is determined by only a few genes and that insulin resistance and hyperglycemia are controlled by different genetic factors (5, 6). We now report that severe obesity and diabetes do not develop in B/KsJ mice treated with a diet similar to that which causes obesity and diabetes in B/6J mice. Methods of Procedure Twenty male B/KsJ mice, 20 male B/6J mice and 20 male A/J mice were obtained from the Jackson Laboratories at 4 weeks of age. Half the animals from each strain were fed normal Purina Rodent Chow and water ad libitum; the remainder were given access to a high-fat, high sucrose, low fiber diet (4). Animals were weighed monthly. After five months on the diet, blood samples were collected following an eight hour fast via retroorbital sinus puncture, and analyzed for glucose (Beckman Autoanalyzer) and Insulin (Cambridge Kit). Results were analyzed by ANOVA and expressed as means +/SEM. Results All animals on the experimental diet gained a significant amount of weight. However, B/6J mice gained more weight than the other two strains, P<.001. After five months on the diet, weights for B/6J mice were control = 27.5±.42g experimental = 49.5±1.3g,(P<.001) B/KsJ and A/J mice gained weight equally (control = 27.9±.55g, experimental = 38.5±2.2g P<.001; control = 26.0±.76g experimental = 35.8±2.2g P<.001, respectively). As previously reported (4), five months of the experimental diet produced significantly greater fasting hyperglycemia and hyperinsulinemia in B/6J mice than in the other strains. Blood glucose in control and experimental B/6J mice was 8.2 + 0.27 mM/1 and 12.5 +/- 0.40 mM/l respectively, P<.001, while blood glucose for B/KsJ and A/J control and experimental animals was 7.3 +/- 0.39 mM/l and 9.4 +/- 0.58 mM/1 (P<.005), and 6.9 +/- 0.35 mM/l and 8.3 +/- 0.38 mM/l (P<.02) respectively. Of the three strains, B/6J mice showed the largest increase in insulin following the introduction of the experimental diet (P<.001). Insulin values for B/6J animals on the control and experimental diets were 110.0 +/- 11.3 pM/1 and 893.6 +/- 40.5 pM/l respectively. Insulin values for control and experimental B/KsJ animals were 121.4 +/- 29.3 pM/l and 217.1 +/- 68 pM/l (P>.05), while comparable values for A/J animals were 88.6 +/- 12.9 pM/l and 187.9 +/- 21.2 pM/1 (p<.001) respectively. Discussion It is known that both the db and ob mutations will produce obesity as well as diabetes in both B/KsJ and B/6J background and the diabetic syndrome is more severe on the B/KsJ background than on the B/6J background (1). As both of these mutations are associated with obesity, it is logical to assume that diabetes results from the effects of the obesity (3). Surprisingly, our results indicate that the comparative susceptibility of these inbred strains to the effects of high fat, high sucrose diets is the reverse of that seen when obesity and diabetes are associated with the db or ob mutation. B/6J mice develop more severe diet-induced obesity than B/KsJ and B/6J mice develop diabetes while B/KsJ mice are resistant to the diabetogenic effects of diet. Recent data show that the effects of diet appear to be due to fat and not to sucrose (7). The differential susceptibility to diabetes is probably not simply a function of the different effects of the experimental diet on weight in these strains. Marked hyperglycemia develops in B/6J mice after one month on the diet, before significant weight gain is obvious (4). Thus, the effects of these obesity-related mutations upon the development of diabetes are probably not simply a function of the associated obesity, but must involve some more basic interaction of the mutations with the background genotype. Since, like human type 2 diabetes, the B/6J mouse can remain euglycemic unless it is fed a diabetogenic diet, it is arguably a better model of most human diabetes than is the B/KsJ mouse. Furthermore, the fact that the B/6J mouse tends to gain more weight on a high fat diet than other strains may have relevance to the understanding of human obesity. We have recently demonstrated that, as in several human populations, there is a significant linkage of hyperglycemia to the glycogen synthase locus in B/6J mice (6). Identification of the background genes that predispose B/6J mice to develop obesity and diabetes on high fat diets may lead to new insight into the mechanism of these diseases. Acknowledgements This research was supported by a grant from the American Diabetes Association, Funds from the John D. and Catherine T. MacArthur Foundation Research Network on the Consequences and Determinants of Health Promoting and Health Damaging Behavior, by NIH Grant DK42923 and Research Scientist Award K05-MH-00303 from the National Institute of Mental Health to Richard S. Surwit. References 1. Hummel DP, Coleman DL, Lane PW: Biochem Genetics 7:l-13, 1972. 2. Leiter EH, Coleman DL, Eisenstein AB, et al: Diabetologia 19:58-65, 1980. 3. Kaku K, Province P, and Permutt MA: Diabetologia 32:636-43, 1988. 4. Surwit RS, Kuhn CM, Cochrane C, et al: Diabetes 37:1163-1167, 1988. 5. Surwit RS, Seldin MF, Kuhn CM, et al: Diabetes 40:82-87, 1991. 6. Seldin M.F., Mott D., Bhat D., et al: J Clin Invest in press. 7. Surwit R, Feinglos M, Petro A, et al: Diabetes, in press (abstract). |
