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

Abstract

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.

Leptin Selectively Augments Thymopoiesis in Leptin Deficiency and Lipopolysaccharide-Induced Thymic Atrophy

“…Corticosteroids induce apoptosis of immature thymocytes and play a critical role in acute thymic involution (28). LPS activates the HPA axis to elevate systemic corticosteroids (26,29). Leptin in turn has been shown to have a negative feedback effect on the HPA axis by inhibiting the corticotropinreleasing hormone protein (25).…”

Role of leptin and melanocortin signaling in uremia-associated cachexia

“…N in these animals did not result in any change in weight gain ( Figure 1B), body composition ( Figure 2, A and B), resting metabolic rate ( Figure 3A), or efficiency of food consumption ( Figure 3B). Recent studies suggested that db/db mice resisted LPS-induced anorexia by reducing TNF-α secretion (27). Thus, leptin may have an important role in the regulation of appetite, body composition, and metabolic rate in uremia.…”

Leptin Downregulates LPS-Induced Lung Injury: Role of Corticosterone and Insulin

“…Leptin-deficient mice (ob/ob) seem to be unaffected [14] or protected [15] from the deleterious effects of endotoxin. On the other hand, Gultekin et al [16] demonstrated that exogenous leptin may be protective role in cerulein-induced acute pancreatitis associated to ALI, and Dong et al [17] showed that leptin-deficient ob/ob mice were more susceptible to LPS-related lethality than lean mice.…”