Multiple Cytokines and Acute Inflammation Raise Mouse Leptin Levels: Potential Role in Inflammatory Anorexia

Several inflammatory cytokines, most notably tumor necrosis factor (TNF) and IL-1, induce anorexia and loss of lean body mass, common manifestations of acute and chronic inflammatory conditions. In C57BL/6 female mice, the administration of TNF, IL-1, and, to a lesser extent, leukemia inhibitory factor (LIF), produced a prompt and dose-dependent increase in serum leptin levels and leptin mRNA expression in fat. IL-10, IL-4, ciliary neurotrophic factor, and IL-2, cytokines not known to induce anorexia or decrease food intake, had no effect on leptin gene expression or serum leptin levels. After administration of Escherichia coli lipopolysaccharide (LPS), leptin gene expression and leptin levels were increased. These findings suggest that leptin levels may be one mechanism by which anorexia is induced during acute inflammatory conditions.

[1]  K. Bendtzen Interleukin 1, interleukin 6 and tumor necrosis factor in infection, inflammation and immunity. , 1988, Immunology letters.

[2]  M. Maffei,et al.  Positional cloning of the mouse obese gene and its human homologue , 1994, Nature.

[3]  G. Mundy,et al.  Chinese hamster ovarian cells transfected with the murine interleukin-6 gene cause hypercalcemia as well as cachexia, leukocytosis and thrombocytosis in tumor-bearing nude mice. , 1991, Endocrinology.

[4]  J. Blay,et al.  Administration of an anti-interleukin-6 monoclonal antibody to patients with acquired immunodeficiency syndrome and lymphoma: effect on lymphoma growth and on B clinical symptoms. , 1994, Blood.

[5]  S. Rudikoff,et al.  Induction of Interferon‐β2/Interleukin‐6 (IL‐6) by Cytokine Administration and Detection of Circulating Interleukin‐6 in the Tumor‐bearing State , 1989, Annals of the New York Academy of Sciences.

[6]  J. Auwerx,et al.  Transient increase in obese gene expression after food intake or insulin administration , 1995, Nature.

[7]  J. M. Argiles,et al.  Metabolic Effects of Tumour Necrosis Factor-α (Cachectin) and Interleukin-1 , 1989 .

[8]  V. Devita,et al.  Biologic Therapy of Cancer , 1992 .

[9]  M. Maffei,et al.  Positional cloning of the mouse obese gene and its human homologue , 1995, Nature.

[10]  C. Nathan,et al.  Modulation of Macrophage Function by Transforming Growth Factor β, Interleukin‐4, and Interleukin‐10 a , 1993, Annals of the New York Academy of Sciences.

[11]  J. Flier,et al.  The adipocyte: Storage depot or node on the energy information superhighway? , 1995, Cell.

[12]  B. Lowell,et al.  Expression of ob mRNA and its encoded protein in rodents. Impact of nutrition and obesity. , 1995, The Journal of clinical investigation.

[13]  L. Moldawer,et al.  Role of endogenous tumor necrosis factor alpha and interleukin 1 for experimental tumor growth and the development of cancer cachexia. , 1991, Cancer research.

[14]  J. Friedman,et al.  Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters. , 1996, The Journal of clinical investigation.

[15]  M. Pelleymounter,et al.  Effects of the obese gene product on body weight regulation in ob/ob mice. , 1995, Science.

[16]  F. Chehab,et al.  Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin , 1996, Nature Genetics.

[17]  F. Halberg,et al.  Circadian rhythms in mice fed a single daily meal at different stages of lighting regimen. , 1975, The Journal of nutrition.

[18]  R. Devos,et al.  Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. , 1995, Science.

[19]  D. Metcalf The leukemia inhibitory factor (LIF). , 1991, International journal of cell cloning.

[20]  J. Norton,et al.  Tolerance to tumor necrosis factor in rats and the relationship to endotoxin tolerance and toxicity , 1988, The Journal of experimental medicine.

[21]  Steven L. Cohen,et al.  Weight-reducing effects of the plasma protein encoded by the obese gene. , 1995, Science.

[22]  K. Tracey,et al.  Cachectin/tumor necrosis factor induces cachexia, anemia, and inflammation , 1988, The Journal of experimental medicine.

[23]  A. Mikhail,et al.  Novel B219/OB receptor isoforms: Possible role of leptin in hematopoiesis and reproduction , 1996, Nature Medicine.

[24]  L. Moldawer,et al.  Anticachectin/tumor necrosis factor‐α antibodies attenuate development of cachexia in tumor models , 1989, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[25]  Rene Devos,et al.  Identification and expression cloning of a leptin receptor, OB-R , 1995, Cell.

[26]  J. Norton,et al.  Cytokines and their role in the pathophysiology of cancer cachexia. , 1992, JPEN. Journal of parenteral and enteral nutrition.

[27]  R. L. Cain,et al.  Interleukin 1-induced pathophysiology: induction of cytokines, development of histopathologic changes, and immunopharmacologic intervention. , 1989, Clinical immunology and immunopathology.

[28]  L. Moldawer,et al.  Interleukin 1, tumour necrosis factor-alpha (cachectin) and the pathogenesis of cancer cachexia. , 1987, Clinical physiology.

[29]  S. Akira,et al.  Interleukin-6 and its receptor: a paradigm for cytokines. , 1992, Science.

[30]  O. Ekindjian,et al.  Ornithine α-Ketoglutarate and Glutamine Supplementation During Refeeding of Food-Deprived Rats , 1992 .

[31]  B. Lowell,et al.  Leptin levels reflect body lipid content in mice: Evidence for diet-induced resistance to leptin action , 1995, Nature Medicine.

[32]  A. Oliff,et al.  Tumors secreting human TNF/cachectin induce cachexia in mice , 1987, Cell.

[33]  G. Strassmann,et al.  Evidence for the involvement of interleukin 6 in experimental cancer cachexia. , 1992, The Journal of clinical investigation.

[34]  K. Abe,et al.  Cancer cachexia syndrome developed in nude mice bearing melanoma cells producing leukemia-inhibitory factor. , 1991, Cancer research.

[35]  R. Surwit,et al.  Role of leptin in fat regulation , 1996, Nature.

[36]  S. H. Socher,et al.  Recombinant human tumor necrosis factor induces acute reductions in food intake and body weight in mice , 1988, The Journal of experimental medicine.

[37]  D. Gearing,et al.  Fatal syndrome in mice engrafted with cells producing high levels of the leukemia inhibitory factor. , 1989, Proceedings of the National Academy of Sciences of the United States of America.