Leptin Accelerates Autoimmune Diabetes in Female NOD Mice

Giuseppe Matarese, Veronica Sanna, Robert I. Lechler, Nora Sarvetnick, Silvia Fontana, Serafino Zappacosta, Antonio La Cava


Diabetes. 2002;51(5) 

In This Article


In the present study, we have shown that leptin can exert profound influence on the development of spontaneous autoimmune diabetes in the NOD mouse. Indeed, we first observed a serum leptin surge at preclinical stage, before the onset of hyperglycemia, but after T-cell infiltration into the Langherhans islets had started. This was consistent with the possibility that serum leptin could sustain beta-cell damage and favor hyperglycemia; this phenomenon was not observed in males. Furthermore, it has long been known that plasma leptin levels correlate with fat stores and changes in energy balance [15]. However, we did not observe any significant association between plasma leptin surge and changes in animal body weight or food intake (not shown). Therefore, our findings raised the possibility that changes of serum leptin may associate not only with energy balance [16] but possibly also with certain immune functions associated with the autoimmune attack against pancreatic beta-cells. In relation to possible influence of the leptin gene or its receptor on autoimmune diabetes susceptibility, there was no association between Idd19, Idd6, Idd11, and Idd9 and leptin or leptin-receptor genes [17].

Leptin administration favored early inflammatory infiltration of pancreatic islets and rapidly accelerated type 1 diabetes. These effects were associated with polarization toward Th1 responses, suggesting that leptin could exert at least part of its pathogenic influence by favoring proinflammatory pathways. Because there were no differences in IL-4 mRNA expression between leptin- and PBS-treated controls in these same T-cell areas (not shown), our findings suggested that leptin had affected the kinetics of IFN-gamma mRNA expression by tilting the balance between Th1 and Th2 responses toward Th1 responses. However, these effects only occurred early in life, as leptin administration in adult mice resulted in lack of clonal expansion and/or Th1 commitment of diabetogenic T-cells. The different outcomes of leptin administration at different ages in the NOD mouse might be related to lack of operating counterregulatory immune mechanisms to the poised status in younger animals. Nonetheless, the influence of leptin and possibly the closely related nutritional status of the host [9,18] should be profound enough to affect susceptibility to autoimmune diabetes, possibly by increasing the priming of autoreactive T-cells. Taken together, these results suggested that during early life, leptin could bias the autoreactive repertoire of prediabetic NOD mice toward a proinflammatory phenotype resulting in accelerated diabetes. Conversely, lack of pathogenicity of leptin later in life may reflect that clonal expansion and Th1 commitment of diabetogenic T-cells have already occurred. According to these findings, recent reports have also shown that leptin-deficient C57BL/6J-ob/ob mice are resistant to induction of Th1-mediated diseases such as experimental autoimmune encephalomyelitis [19] and hepatitis [20]. Conversely, administration of leptin in NOD male mice did not result in increased susceptibility or mortality for diabetes. Possibly, the amount of leptin required in male NOD mice to trigger diabetes is higher than what was observed for females, because in the males the leptin levels are 5- to 10-fold lower than in females [9]. Additional investigation is in progress to address this point. We also observed a trend in the increase of leptin levels preceding onset of type 1 diabetes in males by 60 weeks of age, although it did not reach statistical significance (not shown). Additional studies with larger number of mice followed over time are needed to address this point. Of note, SJL male mice displayed reduced disease susceptibility when compared with females in the experimental autoimmune encephalomyelitis model of autoimmunity, and leptin administration to males reversed disease resistance to susceptibility, thus suggesting a role for leptin in sex-related susceptibility to autoimmune disease [21].

Recently, Serreze et al. [22] reported that IFN-gamma-deficient mice also become diabetic and that prevention of diabetes by bacillus Calmette-Guérin was dependent on IFN-gamma and due to activation-induced cell death of pathogenic Th1 cells. We suggest that susceptibility to type 1 diabetes in IFN-gamma-deficient mice may be due to the redundancy of the proinflammatory cytokine network [5,8,9] that could sustain and promote type 1 diabetes in the absence of IFN-gamma. Conversely, leptin also reduces the apoptotic rate of T-cells by upregulating bcl-2 expression [12,23], thus suggesting the possibility that leptin could have interfered with apoptosis of Th1 pathogenic cells by promoting their survival with the result of increased disease severity.

Our data are also in agreement with and may support the findings by Bruining [24], who described increased incidence of type 1 diabetes at younger ages in affluent countries, where affluence is associated with increased postnatal growth and abundant nutrition. More specific, children developing diabetes had increased early BMI gain in the first year of life as compared with healthy siblings and early presence of autoantibodies against IA-2 (pancreatic islets tyrosine phosphatase) [24]. Because serum leptin levels directly correlate with fat stores and BMI [10], our findings suggest an explanation of the observations by Bruining with a possible involvement of leptin in human type 1 diabetes. Furthermore, because leptin displays pleiotropic functions [9], it might have influenced components of the immunologic synapse, such as adhesion and/or co-stimulatory molecules [9,11,25], endocrine pathways, and apoptosis [10,26–28], through its intracellular signaling pathways mediated by the Janus-activated kinase/signal transducers activator of transcription and mitogen-activated protein kinase proteins [29].

The majority of proinflammatory cytokines, such as IL-12, IFN-gamma, and TNF-alpha, has been shown to play an important function in the pathogenesis of animal and human autoimmune diseases [30]. In vivo neutralization of these cytokines often improves the clinical score as well as the disease progression [31]. We suggest that modulation of circulating leptin levels may be a possible strategy to consider for prevention and/or treatment of type 1 diabetes. However, future studies targeting leptin with such pharmacological antagonists and/or nutritional intervention coupled to a better understanding of sex-gender bias and NOD mouse biology are needed to address such possibility.

Ab, antibody; Ag, antigen; BG, blood glucose; ELISA, enzyme-linked immunosorbent assay; IFN-gamma, interferon-gamma; IL, interleukin; i.p., intraperitoneal; TNF-alpha, tumor necrosis factor-alpha.