The Leptin Defense against Wasting Is Abolished in the IL-2–Deficient Mouse Model of Inflammatory Bowel Disease

Gaetke, Lisa M.; Oz, Helieh S.; Villiers, Willem J.S. de; Varilek, Gary W.; Frederich, Robert

doi:10.1093/jn/132.5.893

Cited by 18 publications

(19 citation statements)

References 21 publications

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“…Hi transfer model and IL-2-deficient mice, show signs of wasting disease, e.g., reduced body weight, body fat, or lean mass (14,18), which are in line with the data presented here. Reduced body weight, food intake, and protein loss in the liver, spleen, and muscles have also been reported in other models of wasting disease, e.g., upon intravenous Esherichia coli administration to rats (4) or in mice exposed to 2,3,7,8-tetrachlorodibenzo-pdioxin (22a).…”

Section: Cd45rbsupporting

confidence: 91%

Mice with experimental colitis show an altered metabolism with decreased metabolic rate

Melgar¹,

Bjursell²,

Gerdin³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Melgarn S, Bjursell M, Gerdin AK, Svensson L, Michaëlsson E, and Bohlooly-Y M. Mice with experimental colitis show an altered metabolism with decreased metabolic rate. Am J Physiol Gastrointest Liver Physiol 292: G165-G172, 2007. First published July 13, 2006; doi:10.1152/ajpgi.00152.2006.-Patients with inflammatory bowel disease (IBD) suffer from body weight loss, malnutrition, and several other metabolic alterations affecting their quality of life. The aim of this study was to investigate the metabolic changes that may occur during acute and chronic colonic inflammation induced by dextran sulfate sodium (DSS) in mice. Clinical symptoms and inflammatory markers revealed the presence of an ongoing inflammatory response in the DSS-treated mice. Mice with acute inflammation had decreased body weight, respiratory exchange ratios (RER), food intake, and body fat content. Mice with chronic inflammation had decreased nutrient uptake, body fat content, locomotor activity, metabolic rates, and bone mineral density. Despite this, the body weight, food and water intake, lean mass, and RER of these mice returned to values similar to those in healthy controls. Thus, murine experimental colitis is associated with significant metabolic alterations similar to IBD patients. Our data show that the metabolic responses during acute and chronic inflammation are different, although the metabolic rate is reduced in both phases. These observations suggest compensatory metabolic alterations in chronic colitis resulting in a healthy appearance despite gross colon pathology. dual-energy X-ray absorptiometry; dextran sulfate sodium; colon inflammation; respiratory exchange ratio INFLAMMATORY BOWEL DISEASE (IBD) in humans consists of two main chronic diseases: ulcerative colitis (UC) and Crohn's disease (CD). Patients with CD can be affected anywhere along the gastrointestinal tract, with the majority being affected in the ileum or in the ileocolonic area. The inflammatory response can extend through all layers of the intestinal wall (28). In contrast, patients with UC are affected in the large intestine, where the inflammation starts in the rectum and spreads upward. The inflammatory response is usually confined to the mucosal layer (28). UC and CD are chronic diseases, and IBD patients have an affected quality of life, suffering from wasting and malnutrition, hypoalbuminemia, anemia, and various vitamin and mineral deficiencies (12). As a consequence, the body composition of an adult IBD patient is altered, e.g., with a reduction in bone mineral density (BMD), which implies that there is a high prevalence of osteopenia and osteoporosis in these patients (20). Nutritional impairment occurs in up to 60% of UC patients and in up to 75% of CD patients (6). It has been suggested that factors contributing to weight loss in CD patients are suppression of food intake secondary to anorexia and pain associated with eating (26, 29). Furthermore, an increased metabolic rate and a reduction in body fat mass may contribute to the decreased body weigh...

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Section: Cd45rbsupporting

confidence: 91%

Mice with experimental colitis show an altered metabolism with decreased metabolic rate

Melgar¹,

Bjursell²,

Gerdin³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…NOD mice have higher basal serum leptin levels than normal age-, sex-, and fat-matched controls (25). IL-2 Ϫ/Ϫ mice are prone to spontaneous development of inflammatory bowel disease and other autoimmune disorders (26). Whereas in normal mice, serum leptin decreases with fat-mass loss, in IL-2 Ϫ/Ϫ mice there is a paradoxical rise in serum leptin compared with control mice, even after starvation, which reduces serum leptin (26).…”

Section: Discussionmentioning

confidence: 99%

“…It appears therefore that, early in the disease, the effects on T Regs in MS may be different from the effect observed after therapy has been initiated. Regarding the correlation with leptin, it is worth mentioning that strains of mice prone to the spontaneous development of autoimmune diseases, such as nonobese-diabetic (NOD) and IL-2-deficient (IL-2 Ϫ/Ϫ ) mice, show reduced frequency of T Regs in the periphery (9) associated with abnormal leptin responses due to increased serum leptin concentrations (disproportionate to fat mass) (25,26). NOD mice have higher basal serum leptin levels than normal age-, sex-, and fat-matched controls (25).…”

Section: Discussionmentioning

confidence: 99%

“…IL-2 Ϫ/Ϫ mice are prone to spontaneous development of inflammatory bowel disease and other autoimmune disorders (26). Whereas in normal mice, serum leptin decreases with fat-mass loss, in IL-2 Ϫ/Ϫ mice there is a paradoxical rise in serum leptin compared with control mice, even after starvation, which reduces serum leptin (26). These data support the hypothesis that a disproportionate response in leptin secretion can correlate with a reduction in the periphery of the T Regs compartment in these two models.…”

Section: Discussionmentioning

confidence: 99%

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Leptin increase in multiple sclerosis associates with reduced number of CD4 ⁺ CD25 ⁺ regulatory T cells

Matarese

Carrieri

Cava

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

272

214

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autoimmunity ͉ tolerance ͉ metabolism ͉ hormones I t has recently been shown that leptin, a cytokine-like hormone mainly secreted by adipocytes, can play a significant role in the pathogenesis of several autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE), antigen-induced arthritis, and experimentally induced colitis (1-6). EAE is an animal model for the human demyelinating disease multiple sclerosis (MS) (7,8). EAE can be induced in susceptible strains of mice through immunization with myelin antigens or by adoptive transfer of myelinspecific T helper 1 (Th-1) cells (7,8). Genetically leptin-deficient (ob͞ob) mice are resistant to the induction and progression of EAE, and WT EAE-susceptible mice show an increase in serum leptin preceding the clinical onset of the disease that correlates with inflammatory anorexia and disease susceptibility (2, 3). In addition, pathogenic Th-1 cells and macrophages in active EAE brain lesions secrete consistent amounts of leptin (3). These data account for an involvement of leptin in CNS autoimmunity, at least in the EAE model. Despite this finding, in humans, the role of leptin in the pathogenesis of MS is not yet fully elucidated. In this study, we analyzed the secretion of leptin in the cerebrospinal fluid (CSF) and serum of naïve-to-treatment relapsing-remitting MS (RRMS) patients and leptin's interaction with the CD4 ϩ CD25 ϩ regulatory T cells (T Regs ). T Regs are known to dampen autoreactive responses mediated by CD4 ϩ CD25 Ϫ T cells and may influence the onset and progression of autoimmunity (9). In mice, depletion of T Regs is associated with autoimmunity, and defects of T Regs have been described in nonobese diabetic mice and in humans with type 1 diabetes (9, 10). Also, reduced frequency of T Regs and͞or defective suppressor function have been observed in humans with systemic lupus erythematosus, juvenile idiopathic arthritis, autoimmune polyglandular syndrome type II, and RRMS (11-15). T Regs are anergic in vitro but can expand in vivo (9). Although the mechanisms operated by T Regs in suppression are not fully delineated, the forkhead transcription factor FoxP-3 seems to be required for suppression to occur (9).Here, we report increased leptin levels in CSF and serum of naïve-to-therapy RRMS patients and an inverse correlation with T Regs frequency. These findings may be relevant in better understanding the disease pathogenesis and may have therapeutic implications. Materials and MethodsSubjects. All MS patients and controls were recruited at the Università di Napoli ''Federico II.'' For serum and CSF leptin measurement, we included in the study 126 individuals (Table 1) with MS defined according to the criteria of McDonald et al. (16) and 117 age-, gender-, and body mass index (BMI)-matched controls with other noninf lammatory neurologic disorders (NIND). All MS patients had RRMS and an expanded disability status scale score of Յ3.5 and were naïve to treatment. The inclusion criteria for RRMS patients were (i) onset of relapse within 4 w...

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“…More specifically, leptin administration significantly increases inflammatory infiltrates in pancreatic islets, increases IFN-␥ production by T cells, anticipates the onset of type 1 diabetes, increases mortality, and increases inflammatory infiltrates in pancreatic islets (65). Mouse strains spontaneously developing autoimmune diseases, such as the NOD/LtJ and the IL-2-deficient mice, have increased basal serum leptin before the development of disease onset (45,65,67) and reduced numbers of circulating regulatory T cells (68). In humans, the prevalence of autoimmune diseases (i.e., multiple sclerosis, rheumatoid arthritis, thyroiditis, and systemic lupus erythematosus) is increased in females (69), as are serum leptin levels.…”

Section: Leptin Inflammation and Enhanced Anti-self-immune Responsesmentioning

confidence: 99%

Leptin in Immunology

Matarese

Moschos

Mantzoros

2005

The Journal of Immunology

513

426

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Leptin is an adipokine which conveys information on energy availability. In humans, leptin influences energy homeostasis and regulates neuroendocrine function primarily in states of energy deficiency. As a cytokine, leptin also affects thymic homeostasis and, similar to other proinflammatory cytokines, leptin promotes Th1 cell differentiation and cytokine production. We review herein recent advances on the role of leptin in the pathophysiology of immune responses.

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The Leptin Defense against Wasting Is Abolished in the IL-2–Deficient Mouse Model of Inflammatory Bowel Disease

Cited by 18 publications

References 21 publications

Mice with experimental colitis show an altered metabolism with decreased metabolic rate

Mice with experimental colitis show an altered metabolism with decreased metabolic rate

Leptin increase in multiple sclerosis associates with reduced number of CD4 ⁺ CD25 ⁺ regulatory T cells

Leptin in Immunology

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The Leptin Defense against Wasting Is Abolished in the IL-2–Deficient Mouse Model of Inflammatory Bowel Disease

Cited by 18 publications

References 21 publications

Mice with experimental colitis show an altered metabolism with decreased metabolic rate

Mice with experimental colitis show an altered metabolism with decreased metabolic rate

Leptin increase in multiple sclerosis associates with reduced number of CD4 + CD25 + regulatory T cells

Leptin in Immunology

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Leptin increase in multiple sclerosis associates with reduced number of CD4 ⁺ CD25 ⁺ regulatory T cells