Leptin Accelerates Autoimmune Diabetes in Female NOD Mice

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

Disclosures

Diabetes. 2002;51(5) 

In This Article

Abstract and Introduction

We have recently shown that leptin, the product of the obese gene, can directly influence T-cell function. In the work presented here, we explored the role of leptin in the development of spontaneous autoimmunity in the nonobese diabetic (NOD) mouse, an animal model for the study of human insulin-dependent diabetes mellitus (type 1 diabetes). We found that expression of serum leptin increased soon before the onset of hyperglycemia and diabetes in susceptible females. A pathogenetic role of leptin was assessed by administering recombinant leptin to young female and male NOD mice. Intraperitoneal injections of leptin accelerated autoimmune destruction of insulin-producing beta-cells and significantly increased interferon-gamma production in peripheral T-cells. These findings indicate that leptin can favor proinflammatory cell responses and directly influence development of autoimmune disease mediated by Th1 responses.

Type 1 diabetes is an organ-specific autoimmune disease that results from inflammatory destruction of insulin-producing pancreatic beta-cells. The pathways and the molecules involved in the initiation and amplification of the autoimmune injury to beta-cells remain largely unknown [1,2].

The nonobese diabetic (NOD) mouse is a well-characterized animal model for the study of the immunopathogenetic events that lead to type 1 diabetes [3]. In the NOD mouse, spontaneous development of autoimmune diabetes is associated with lymphomonocytic infiltration of pancreatic islets and local release of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and interleukin (IL)-1beta[4]. These cytokines, secreted by antigen (Ag)-presenting cells and T-cells, can favor initiation and progression of autoimmune responses by influencing Ag processing and presentation [5], by modulating adhesion molecule expression on Ag-presenting cells [6], and by inducing proliferation and differentiation of autoreactive T-cells [7]. Furthermore, these cytokines can be finely regulated by other cytokines and chemokines in a complex network of reciprocal interactions [8].

Leptin, the product of the obese gene, is a 16-kDa protein that structurally belongs to the family of the long-chain helical cytokines (that also includes IL-2, IL-15, and IL-12) [9]. Initial evidence suggested that the main function of leptin was to regulate body weight, energy balance, and endocrine functions [9,10]. However, it was shown recently that leptin can also influence immune responses [11,12]. In particular, leptin can enhance delayed-type hypersensitivity, modulate cognate T-cell interactions, favor proliferation of naïve T-cells and IL-2 secretion, and sustain proinflammatory responses [11,12]. The proinflammatory properties of leptin prompted us to ask whether this cytokine could influence organ-specific autoimmune diseases associated with strong Th1 responses, such as type 1 diabetes. In particular, we examined the role of leptin during the development of spontaneous type 1 diabetes in the NOD mouse model.

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