Leptin resistance and desensitization of hypophagia during prolonged inflammatory challenge

Abstract

LL. Leptin resistance and desensitization of hypophagia during prolonged inflammatory challenge. Am J Physiol Endocrinol Metab 300: E858-E869, 2011. First published February 22, 2011 doi:10.1152/ajpendo.00558.2010.-Acute exposure to bacterial lipopolysaccharide (LPS) is a potent inducer of immune response as well as hypophagia. Nevertheless, desensitization of responses to LPS occurs during long-term exposure to endotoxin. We induced endotoxin tolerance, injecting repeated (6LPS) LPS doses compared with single (1LPS) treatment. 1LPS, but not 6LPS group, showed decreased food intake and body weight, which was associated with an increased plasma leptin and higher mRNA expression of OB-Rb, MC4R, and SOCS3 in the hypothalamus. Hypophagia induced by 1LPS was associated with lower levels of 2-arachidonoylglycerol (2-AG), increased number of p-STAT3 neurons, and decreased AMPactivated protein kinase (AMPK) activity. Desensitization of hypophagia in the 6LPS group was related to high 2-AG, with no changes in p-STAT3 or increased p-AMPK. Leptin decreased food intake, body weight, 2-AG levels, and AMPK activity and enhanced p-STAT3 in control rats. However, leptin had no effects on 2-AG, p-STAT3, or p-AMPK in the 1LPS and 6LPS groups. Rats treated with HFD to induce leptin resistance showed neither hypophagia nor changes in p-STAT3 after 1LPS, suggesting that leptin and LPS recruit a common signaling pathway in the hypothalamus to modulate food intake reduction. Desensitization of hypophagia in response to repeated exposure to endotoxin is related to an inability of leptin to inhibit AMPK phosphorylation and 2-AG production and activate STAT3. SOCS3 is unlikely to underlie this resistance to leptin signaling in the endotoxin tolerance. The present model of prolonged inflammatory challenge may contribute to further investigations on mechanisms of leptin resistance. lipopolysaccharide tolerance; leptin signaling; adenosine 5=-monophosphate-activated protein kinase; phosphorylated signal transducer and activator of transcription 3; 2-arachidonoyl glycerol DEPRESSED APPETITE AND WEIGHT LOSS have been found to be acutely induced by bacterial endotoxins, such as lipopolysaccharide (LPS) from gram-negative bacteria (25,48,49). However, earlier reports confirmed that long-term administration of LPS is followed by a tolerance of its effects with desensitization of LPS-stimulated responses (9, 56). As cited by Cavaillon et al. (13), the endotoxin tolerance phenomenon was first observed by Beeson in 1946 after repeated injections of typhoid vaccine and absence of fever induction. Freudenberg and Galanos (23) provided additional data on the protective effect of endotoxin tolerance against a lethal challenge of LPS.However, the comprehension of the effect of chronic exposure to LPS on energy intake and homeostasis remains unclear.It has been demonstrated that leptin, the cytokine adiposity signal, mediates to some extent the anorexigenic responses during endotoxemia induced by LPS (49). Leptin binds to the long full-length receptor ...

Pharmacological inhibition of endocannabinoid degradation modulates the expression of inflammatory mediators in the hypothalamus following an immunological stressor

“…This may be somewhat surprising in light of in vitro evidence indicating that LPS increases AEA and 2-AG levels, an effect mediated by inhibition of FAAH and MAGL activity and/or enhancement of AEA biosynthesis (Varga et al, 1998;Di Marzo et al, 1999;Maccarrone et al, 2001;Liu et al, 2003). In vivo, LPS has been demonstrated to increase AEA synthesis (Fernandez-Solari et al, 2006) and reduce 2-AG levels (Borges et al, 2011) in the rat hypothalamus. Although the dose of LPS (100µg/kg) and time post injection (2hrs) used in both the present and former (Borges et al, 2011) times greater than that given in the present study.…”

“…In vivo, LPS has been demonstrated to increase AEA synthesis (Fernandez-Solari et al, 2006) and reduce 2-AG levels (Borges et al, 2011) in the rat hypothalamus. Although the dose of LPS (100µg/kg) and time post injection (2hrs) used in both the present and former (Borges et al, 2011) times greater than that given in the present study. To our knowledge, the effects of LPS on levels of OEA or PEA have not been reported, however, should LPS inhibit FAAH activity, it would have been expected that all three fatty acid amides would be enhanced.…”

“…SOCS3 also mediates some of the anti-inflammatory effects of IL-10 (Berlato et al, 2002;Qin et al, 2007), however as URB597 attenuated rather than enhanced LPS-induced IL-10, it seems unlikely that the enhanced SOCS3 expression in the present study was induced following IL-10 signalling. It should also be noted that LPS induces increases in other cytokine-like molecules such as leptin which are also capable of inducing STAT-3 phosphorlyation and SOCS3 expression in the hypothalamus (Hubschle et al, 2001), an effect proposed to underlie, at least in part, LPSinduced hypophagia (Borges et al, 2011). Further studies are required to assess the contribution of the individual fatty acid amides to the activation of SOCS3 and the downstream consequences of this activation.…”

Protein tyrosine phosphatase-1B contributes to LPS-induced leptin resistance in male rats

“…We previously demonstrated that the hypophagia and body weight reduction under acute inflammation, such as those observed after a single LPS administration, are also associated with the activation of STAT3 signaling in the ARC and paraventricular (PVN) nuclei, and this signaling does not increase further after leptin stimulation (6). In contrast to single LPS responses, repeated low-dose LPS exposure (100 g·kg Ϫ1 ·day Ϫ1 for 6 days) induced a desensitization of the hypophagia and body weight loss.…”

“…In contrast to single LPS responses, repeated low-dose LPS exposure (100 g·kg Ϫ1 ·day Ϫ1 for 6 days) induced a desensitization of the hypophagia and body weight loss. Noticeably, the repeated LPS treatment failed to change the hypothalamic pSTAT3 and SOCS3 expression induced by exogenous leptin, suggesting that the reduced capability to respond to leptin contributes to the preserved food intake and body weight gain in the endotoxin-tolerant animals (6). It has been known that SOCS3 expression inhibits the tyrosine phosphorylation of the LepRb, thus providing an important feedback mechanism for leptin signaling (17,38).…”