Leptin Is an Endogenous Protective Protein against the Toxicity Exerted by Tumor Necrosis Factor

Takahashi, Nozomi

doi:10.1084/jem.189.1.207

Cited by 104 publications

(114 citation statements)

References 28 publications

(36 reference statements)

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“…This observation is supported by other studies showing that pretreatment of ob/ob mice with leptin does not exacerbate the anorexic effects of LPS, but rather protects against LPS-induced toxicity (13). Likewise, pretreatment of starved wildtype mice with leptin protects them against the lethal effects of TNF-␣ (36). The resistance to LPS may also be due to increased free leptin in BL/3J mice who might have lost the functionality of the Ob-Re due to a premature stop codon that produces a truncated receptor (20).…”

Section: Discussionsupporting

confidence: 76%

“…The involvement of leptin in the immune response to LPS has been demonstrated by hypersensitivity of ob/ob mice to endotoxin administration. Leptin-deficient (ob/ob) mice are hypersensitive to the lethal effects of LPS and TNF-␣, but C57BL/6J db/db mice are resistant to LPS-induced anorexia and lethality (10,12,36). Leptin administration to ob/ob mice blunts the increased sensitivity to LPS and TNF-␣ (36).…”

mentioning

confidence: 99%

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Hyperleptinemia and reduced TNF-α secretion cause resistance of db/db mice to endotoxin

Madiehe

Mitchell

Harris

2003

American Journal of Physiology-Regulatory, Integrative and Comp

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Madiehe, Abram M., Tiffany D. Mitchell, and Ruth B. S. Harris. Hyperleptinemia and reduced TNF-␣ secretion cause resistance of db/db mice to endotoxin. Am J Physiol Regul Integr Comp Physiol 284: R763-R770, 2003; 10.1152/ ajpregu.00610.2002-Leptin deficiency in ob/ob mice increases susceptibility to endotoxic shock, whereas leptin pretreatment protects them against LPS-induced lethality. Lack of the long-form leptin receptor (Ob-Rb) in db/db mice causes resistance. We tested the effects of LPS in C57BL/6J db 3J / db 3J (BL/3J) mice, which express only the circulating leptin receptors, compared with C57BL/6J db/db (BL/6J) mice, which express all short-form and circulating isoforms of the leptin receptor. Intraperitoneal injections of LPS significantly decreased rectal temperature and increased leptin, corticosterone, and free TNF-␣ in fed and fasted BL/3J and BL/6J mice. TNF-␣ was increased three-and fourfold in BL/3J and BL/6J, respectively. LPS (100 g) caused 50% mortality of fasted BL/6J mice but caused no mortality in fasted BL/3J mice. Pretreatment of fasted BL/3J mice with 30 g leptin prevented the drop in rectal temperature, blunted the increase in corticosterone, but had no effect on TNF-␣ induced by 100 g LPS. Taken together, these data provide evidence that fasted BL/3J mice are more resistant than BL/6J mice to LPS toxicity, presumably due to the absence of leptin receptors in BL/3J mice. This resistance may be due to high levels of free leptin cross-reacting with other cytokine receptors.tumor necrosis factor-␣; leptin receptor; lipopolysaccharides LOSS OF BODY WEIGHT and lack of appetite are serious complications associated with acute and chronic infections due to increased levels of inflammatory mediators and cytokines needed for killing pathogens (24,25). A severe inflammatory response can, therefore, cause deleterious changes in nutrition that adversely affect growth, reproduction, and the immune system (3). LPS, a gram-negative bacterial endotoxin, has been extensively used for experimental induction of an inflammatory response; its administration results in anorexia, fever, and increased cytokine production in rodents (27,33). The anorexia and host responses to LPS infection are mediated by IL-1␤ and TNF-␣ (7). The involvement of leptin in the immune response to LPS has been demonstrated by hypersensitivity of ob/ob mice to endotoxin administration. Leptin-deficient (ob/ob) mice are hypersensitive to the lethal effects of LPS and TNF-␣, but C57BL/6J db/db mice are resistant to LPS-induced anorexia and lethality (10,12,36). Leptin administration to ob/ob mice blunts the increased sensitivity to LPS and TNF-␣ (36).Flier (16) hypothesized that leptin signals a shift between adequate and inadequate stores of energy, whereby a fall in leptin may lead to a series of physiological and metabolic adaptations that improve survival during times of energy insufficiency. One potential adaptation could be in the interaction between leptin and the immune system.

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Section: Discussionsupporting

confidence: 76%

mentioning

confidence: 99%

Hyperleptinemia and reduced TNF-α secretion cause resistance of db/db mice to endotoxin

Madiehe

Mitchell

Harris

2003

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Specifically TNF␣ has been shown to up-regulate PLAA and CASP6 (51,52), both of which increased after IR in the wild type but not in the mutant. Decreased TNF␣ activity in p53 K317R thymocytes is also consistent with the observed lack of change in WARS, TCF7, and ETFDH protein levels after IR; all of these proteins are indirectly regulated by TNF␣ (53)(54)(55)(56)(57)(58). Finally TNF␣ has been shown to induce the expression of TGF␤1 (59), which has been shown to increase the expression of FABP5 and SSRP1 (60,61), two additional proteins that exhibit the same pattern.…”

Section: Discussionsupporting

confidence: 62%

Quantitative Proteomics Analysis of the Effects of Ionizing Radiation in Wild Type and p53K317R Knock-in Mouse Thymocytes

Jenkins

Mazur

Rossi

et al. 2008

Molecular & Cellular Proteomics

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The tumor suppressor protein p53 is a sequence-specific transcription factor that has crucial roles in apoptosis, cell cycle arrest, cellular senescence, and DNA repair. Following exposure to a variety of stresses, p53 becomes posttranslationally modified with concomitant increases in activity and stability. To better understand the role of acetylation of Lys-317 in mouse p53, the effect of ionizing radiation (IR) on the thymocytes of p53 K317R knock-in mice was studied at the global level. Using cleavable ICAT quantitative mass spectrometry, the effect of IR on protein levels in either the wild type or p53 K317R thymocytes was determined. We found 102 proteins to be significantly affected by IR in the wild type thymocytes, including several whose expression has been shown to be directly regulated by p53. When the effects of IR in the wild type and p53 K317R samples were compared, 46 proteins were found to be differently affected (p < 0.05). The p53 K317R mutation has widespread effects on specific protein levels following IR, including the levels of proteins involved in apoptosis, transcription, and translation. Pathway analysis of the differently regulated proteins suggests an increase in p53 activity in the p53 K317R thymocytes as well as a decrease in tumor necrosis factor ␣ signaling. These results suggest that acetylation of Lys-317 modulates the functions of p53 and influences the cross-talk between

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“…Nesse contexto, a leptina parece participar de respostas relacionadas com a função imune como: respostas inflamatórias (89) ; desenvolvimento e proliferação de células mielódes (90) ; células sanguíneas (91,92) , produção de linfocinas pelos linfócitos T (35) ; recuperação da depressão da imunocompetência induzida pelo jejum (36) ; e um papel de proteção contra respostas inflamatórias sistêmicas do TNF-α (93) . Além disso, tem sido demonstrado que a leptina pode estimular atividade de macró-fagos e células formadoras de colônias de neurotrófilos, aumentando dessa forma a resposta imune (91) .…”

Section: Implicações Práticasunclassified

Obesidade e adipocinas inflamatórias: implicações práticas para a prescrição de exercício

Prado¹,

Lofrano

Oyama

et al. 2009

Rev Bras Med Esporte

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A obesidade é uma doença complexa de etiologia multifacetada, com sua própria fisiopatologia, comorbidades e capacidades desabilitantes. Aceitar a obesidade como uma doença é fundamental para o seu tratamento. Atualmente, o tecido adiposo é um dos principais focos das pesquisas em obesidade, devido a uma revolução no entendimento da função biológica desse tecido desde a última década. Já está muito claro que o tecido adiposo branco secreta múltiplos peptídeos bioativos, denominados adipocinas (proteínas sintetizadas e secretadas pelo tecido adiposo). Dessa forma, o objetivo deste trabalho de revisão foi investigar a relação entre obesidade e adipocinas inflamatórias, buscando discutir o papel do exercício físico no tratamento dessa patologia. Os resultados demonstram que uma das mais importantes descobertas das pesquisas recentes em obesidade é o conceito de que ela é caracterizada por uma inflamação crônica. Dentre todas as adipocinas, sem dúvida, a IL-6, o TNF-a, a leptina (pró-inflamatórias) e a adiponectina (anti-inflamatória) vêm recebendo atenção especial da literatura especializada. O aumento da concentração dessas adipocinas promove grande impacto em diversas funções corporais que estão fortemente correlacionadas com doenças cardiovasculares. Uma vez que a obesidade é considerada uma doença inflamatória e o exercício físico modula de forma direta tais processos, é essencial que tenhamos como um dos objetivos principais de nossos programas de exercícios físicos a melhora da resposta inflamatória de obesos.Palavras-chave: tecido adiposo, sistema imunológico, metabolismo lipídico, inflamação. AbstRActObesity is a complex disease with a multifaceted etiology with its own physiopathology, co-morbidities and disabiliting capacities. It is crucial that obesity is acknowledged as a disease in order to treat it. Nowadays, the adipose tissue is the main focus of obesity research due to the improvement in the last decade on biological function of this tissue. It is now clear that white adipose tissue release a large amount of bioactive peptides called adipokines (which are proteins synthesized and released by adipose tissue). Thus, the aim of this review was to investigate the relationship between obesity and inflammatory adipokines, trying to discuss the role of physical exercise in the treatment of this pathology. The results have shown that one of the most important recent discoveries is the concept that obesity is characterized by a chronic inflammation state. Among all adipokines, IL-6, TNF-a, leptin (pro-inflammatory) and adiponectin (anti-inflammatory), have received special attention from the specialized literature. High concentration of these adipokines promotes impact in several body functions, which is strongly linked with cardiovascular diseases. Since obesity is considered an inflammatory disease, and exercise directly modulates this process, it is essential that one of the main aims of exercise therapies is the improvement of the inflammatory response of obese individuals.Keywords: adipose tissue; imm...

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Leptin Is an Endogenous Protective Protein against the Toxicity Exerted by Tumor Necrosis Factor

Cited by 104 publications

References 28 publications

Hyperleptinemia and reduced TNF-α secretion cause resistance of db/db mice to endotoxin

Hyperleptinemia and reduced TNF-α secretion cause resistance of db/db mice to endotoxin

Quantitative Proteomics Analysis of the Effects of Ionizing Radiation in Wild Type and p53K317R Knock-in Mouse Thymocytes

Obesidade e adipocinas inflamatórias: implicações práticas para a prescrição de exercício

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