The Diabetes-Prone NZO/HlLt Strain. I. Immunophenotypic Comparison to the Related NZB/BlNJ and NZW/LacJ Strains

Abstract

SUMMARY:New Zealand Obese (NZO)/HlLt male mice exhibit a polygenic obesity and approximately 50% develop type 2 diabetes. This strain is known to produce a variety of autoantibodies, including autoantibodies to the insulin receptor. Because of their relatedness to the autoimmune-predisposed New Zealand Black (NZB) and New Zealand White (NZW) inbred strains, we compared NZO to its two related strains for shared hematologic and immunologic characteristics. Comparison of the three strains by serotyping and genotyping methods indicated that NZO shared with NZW the rare (recombinant) H2 z haplotype at the major histocompatibility complex. Similar to the NZB and NZW strains, spleens from NZO mice contained increased numbers of CD19 ϩ CD43 ϩ IgM ϩ B-1 B cells, a phenotype associated with natural autoantibody production. NZO mice developed a progressive microcytic anemia that was distinguished from NZB hemolytic anemia by absence of demonstrable antierythrocyte antibodies in the former. Outcross of NZO females with NZB males accelerated development of obesity and diabetes in F1 males. NZO males made B-lymphocyte-deficient by a disrupted immunoglobulin heavy chain gene did not become diabetic. These results suggest that NZO mice should be useful to investigators interested in studying the genetic contributions to autoimmunity made by the related NZW and NZB strains. Further, these results, combined with the pancreatic histopathology contained in the companion manuscript, suggest that B lymphocytes may be important contributors to diabetes pathogenesis in the NZO mouse. (Lab Invest 2002, 82:833-842).

Differential Levels of Diabetogenic Stress in Two New Mouse Models of Obesity and Type 2 Diabetes

“…NZO originates from the same outbred stock as the autoimmune-prone NZB and NZW strains and presents an amalgam of interesting immunodeviant phenotypes found in both related strains. For example, NZO shares the same rare H2 z haplotype expressed in NZW mice and shares hematological anomalies found in the NZB strain (14). We confirmed that NZO/HlLt mice, like NZO/Wehi mice, produce antiinsulin receptor autoantibodies (28) and, like NZB mice, develop peri-insular leukocytic infiltrates that are unique in containing an unusually high percentage of B-cells, including plasma cells (29).…”

“…NZO mice have not been extensively studied because they are difficult to breed and only recently have been available from commercial suppliers. Because the obesity is polygenic, there is no simple control (although NZW and NZB are closely related nonobese strains and share certain hematological anomalies with NZO) (14). Diabetes frequencies vary among the various NZO substrains.…”

B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile

“…Given the importance of B-cell IL-10 in preventing numerous inflammatory diseases (3,4) and the links between IL-8 and T2D (5,6), these data suggest that altered B-cell cytokine production plays an important role in initiating or promoting IR/T2D. Published analyses further support a role for B cells in IR and include studies of B cell-null New Zealand Obese (NZO) mice, which, in contrast to B cell-sufficient NZOs, fail to develop IR in response to obesity (7). These findings have been recently reproduced in studies showing obese B cell-null or B cell-depleted mice have less inflammation and IR than obese WT mice (8).…”

Development of Improved Animal Models for the Study of Diabetes

“…Other studies emphasized that obesity in NZO individuals is the results of hyperphagia and low energy expenditure due to insufficient physical activity [102]. [103]. Particularly, these mice do not express polyphagia, morbid obesity, poor fertility and variable frequency of hyperglycemia as their parental NZO males do.…”