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Leptin is an endogenous protective protein against the toxicity exerted by tumor necrosis factor.

Takahashi N, Waelput W, Guisez Y - J. Exp. Med. (1999)

Bottom Line: The in vivo effects of TNF are largely mediated by a complex network of TNF-induced cytokines and hormones acting together or antagonistically.Ob/ob and db/db mice, as well as normal mice treated with antagonist, exhibited increased sensitivity to the lethal effect of TNF.We conclude that leptin is involved in the protective mechanisms that allow an organism to cope with the potentially autoaggressive effects of its immune system.

View Article: PubMed Central - PubMed

Affiliation: Molecular Pathophysiology and Experimental Therapy Unit, Department of Molecular Biology, Flanders Interuniversity Institute for Technology, University of Ghent, B-9000 Ghent, Belgium. nozomi.takahashi@dumb.rug.ac.be

ABSTRACT
Tumor necrosis factor (TNF) is a central mediator of a number of important pathologies such as the systemic inflammatory response syndrome. Administration of high TNF doses induces acute anorexia, metabolic derangement, inflammation, and eventually shock and death. The in vivo effects of TNF are largely mediated by a complex network of TNF-induced cytokines and hormones acting together or antagonistically. Since TNF also induces leptin, a hormone secreted by adipocytes that modulates food intake and metabolism, we questioned the role of leptin in TNF-induced pathology. To address this question, we tested mouse strains that were defective either in leptin gene (ob/ob) or in functional leptin receptor gene (db/db), and made use of a receptor antagonist of leptin. Ob/ob and db/db mice, as well as normal mice treated with antagonist, exhibited increased sensitivity to the lethal effect of TNF. Exogenous leptin afforded protection to TNF in ob/ob mice, but failed to enhance the protective effect of endogenous leptin in normal mice. We conclude that leptin is involved in the protective mechanisms that allow an organism to cope with the potentially autoaggressive effects of its immune system.

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Effect of leptin and leptin antagonist on mTNF-induced lethality. C57BL/6 mice were pretreated with leptin (100 μg/mouse) or  R128Q (100 μg/mouse) in combination with 2A5 antibody (100 μg/ mouse) as described in Materials and Methods. Mice were challenged  with a low dose (A, 375 μg/kg) or a high dose (B, 750 μg/kg) of mTNF.  The percentage of survival was plotted as a function of time (hours after  challenge). Each group consisted of 13 mice. The result is a cumulative  sum of two independent experiments. (A) ○, 2A5; □, leptin + 2A5; ▵,  R128Q + 2A5; ***P = 0.0008 (2A5 versus R128Q + 2A5); (B) •, 2A5;  ▪, leptin + 2A5; ▴, R128Q + 2A5. **P = 0.0063 (2A5 versus R128Q +  2A5).
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Figure 3: Effect of leptin and leptin antagonist on mTNF-induced lethality. C57BL/6 mice were pretreated with leptin (100 μg/mouse) or R128Q (100 μg/mouse) in combination with 2A5 antibody (100 μg/ mouse) as described in Materials and Methods. Mice were challenged with a low dose (A, 375 μg/kg) or a high dose (B, 750 μg/kg) of mTNF. The percentage of survival was plotted as a function of time (hours after challenge). Each group consisted of 13 mice. The result is a cumulative sum of two independent experiments. (A) ○, 2A5; □, leptin + 2A5; ▵, R128Q + 2A5; ***P = 0.0008 (2A5 versus R128Q + 2A5); (B) •, 2A5; ▪, leptin + 2A5; ▴, R128Q + 2A5. **P = 0.0063 (2A5 versus R128Q + 2A5).

Mentions: If sensitization to the toxic effect of TNF in the genetically defective leptin system is fully attributable to leptin (and not to the consequence of secondary effects, such as obesity, elevated levels of insulin, or corticoids), the same sensitization should be obtained in normal lean mice, where the function of leptin is blocked. Therefore, we examined the effect of leptin and leptin antagonist R128Q on the lethal toxicity of mTNF in normal mice. We tested two doses of mTNF that would result in ∼50 and 0% lethality, respectively, in normal mice. Mice were pretreated with leptin or R128Q antagonist, both in the presence of 100 μg 2A5 antibody per mouse. Treatment with R128Q clearly sensitized mice to TNF toxicity, since 60% died even in response to a low dose of mTNF (Fig. 3 A; P = 0.0008, a significant difference compared with the control group receiving 2A5 alone). Moreover, treatment with R128Q and a higher dose of TNF increased the death toll from 50 to 100%, and the survival time was significantly reduced (Fig. 3 B; P = 0.0063, compared with the control group receiving 2A5 alone). On the other hand, exogenous leptin did not provide any further protection, suggesting that the endogenous leptin level is sufficient for a protective effect. The difference observed between mice pretreated with leptin antagonist and those with antibody alone is due to the functional level of leptin. These experiments allow us to conclude that endogenous leptin protects against TNF-induced lethality.


Leptin is an endogenous protective protein against the toxicity exerted by tumor necrosis factor.

Takahashi N, Waelput W, Guisez Y - J. Exp. Med. (1999)

Effect of leptin and leptin antagonist on mTNF-induced lethality. C57BL/6 mice were pretreated with leptin (100 μg/mouse) or  R128Q (100 μg/mouse) in combination with 2A5 antibody (100 μg/ mouse) as described in Materials and Methods. Mice were challenged  with a low dose (A, 375 μg/kg) or a high dose (B, 750 μg/kg) of mTNF.  The percentage of survival was plotted as a function of time (hours after  challenge). Each group consisted of 13 mice. The result is a cumulative  sum of two independent experiments. (A) ○, 2A5; □, leptin + 2A5; ▵,  R128Q + 2A5; ***P = 0.0008 (2A5 versus R128Q + 2A5); (B) •, 2A5;  ▪, leptin + 2A5; ▴, R128Q + 2A5. **P = 0.0063 (2A5 versus R128Q +  2A5).
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Related In: Results  -  Collection

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Figure 3: Effect of leptin and leptin antagonist on mTNF-induced lethality. C57BL/6 mice were pretreated with leptin (100 μg/mouse) or R128Q (100 μg/mouse) in combination with 2A5 antibody (100 μg/ mouse) as described in Materials and Methods. Mice were challenged with a low dose (A, 375 μg/kg) or a high dose (B, 750 μg/kg) of mTNF. The percentage of survival was plotted as a function of time (hours after challenge). Each group consisted of 13 mice. The result is a cumulative sum of two independent experiments. (A) ○, 2A5; □, leptin + 2A5; ▵, R128Q + 2A5; ***P = 0.0008 (2A5 versus R128Q + 2A5); (B) •, 2A5; ▪, leptin + 2A5; ▴, R128Q + 2A5. **P = 0.0063 (2A5 versus R128Q + 2A5).
Mentions: If sensitization to the toxic effect of TNF in the genetically defective leptin system is fully attributable to leptin (and not to the consequence of secondary effects, such as obesity, elevated levels of insulin, or corticoids), the same sensitization should be obtained in normal lean mice, where the function of leptin is blocked. Therefore, we examined the effect of leptin and leptin antagonist R128Q on the lethal toxicity of mTNF in normal mice. We tested two doses of mTNF that would result in ∼50 and 0% lethality, respectively, in normal mice. Mice were pretreated with leptin or R128Q antagonist, both in the presence of 100 μg 2A5 antibody per mouse. Treatment with R128Q clearly sensitized mice to TNF toxicity, since 60% died even in response to a low dose of mTNF (Fig. 3 A; P = 0.0008, a significant difference compared with the control group receiving 2A5 alone). Moreover, treatment with R128Q and a higher dose of TNF increased the death toll from 50 to 100%, and the survival time was significantly reduced (Fig. 3 B; P = 0.0063, compared with the control group receiving 2A5 alone). On the other hand, exogenous leptin did not provide any further protection, suggesting that the endogenous leptin level is sufficient for a protective effect. The difference observed between mice pretreated with leptin antagonist and those with antibody alone is due to the functional level of leptin. These experiments allow us to conclude that endogenous leptin protects against TNF-induced lethality.

Bottom Line: The in vivo effects of TNF are largely mediated by a complex network of TNF-induced cytokines and hormones acting together or antagonistically.Ob/ob and db/db mice, as well as normal mice treated with antagonist, exhibited increased sensitivity to the lethal effect of TNF.We conclude that leptin is involved in the protective mechanisms that allow an organism to cope with the potentially autoaggressive effects of its immune system.

View Article: PubMed Central - PubMed

Affiliation: Molecular Pathophysiology and Experimental Therapy Unit, Department of Molecular Biology, Flanders Interuniversity Institute for Technology, University of Ghent, B-9000 Ghent, Belgium. nozomi.takahashi@dumb.rug.ac.be

ABSTRACT
Tumor necrosis factor (TNF) is a central mediator of a number of important pathologies such as the systemic inflammatory response syndrome. Administration of high TNF doses induces acute anorexia, metabolic derangement, inflammation, and eventually shock and death. The in vivo effects of TNF are largely mediated by a complex network of TNF-induced cytokines and hormones acting together or antagonistically. Since TNF also induces leptin, a hormone secreted by adipocytes that modulates food intake and metabolism, we questioned the role of leptin in TNF-induced pathology. To address this question, we tested mouse strains that were defective either in leptin gene (ob/ob) or in functional leptin receptor gene (db/db), and made use of a receptor antagonist of leptin. Ob/ob and db/db mice, as well as normal mice treated with antagonist, exhibited increased sensitivity to the lethal effect of TNF. Exogenous leptin afforded protection to TNF in ob/ob mice, but failed to enhance the protective effect of endogenous leptin in normal mice. We conclude that leptin is involved in the protective mechanisms that allow an organism to cope with the potentially autoaggressive effects of its immune system.

Show MeSH
Related in: MedlinePlus