Endogenous cannabinoids induce fever through the activation of CB<sub>1</sub> receptors

Fraga, Daniel; Zanoni, Cristiane I.; Rae, Giles A.; Parada, Carlos Amílcar; Souza, Glória Emília Petto de

doi:10.1111/j.1476-5381.2009.00312.x

Cited by 31 publications

(31 citation statements)

References 47 publications

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“…Interestingly, the eCB anandamide is without effect on body temperature when administered via this route, whereas it does cause hypothermia when given to the periphery, possibly via an action at non-CB receptors (8,54). Paradoxically, low doses of the CB agonists, ⌬ 9 -tetrahydrocannabinol (16, 52) or anandamide (20), have also been shown to increase body temperature in rats. Similarly, the role of CBs in innate immune febrile responses is unclear.…”

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confidence: 99%

Cannabinoid 1 receptors are critical for the innate immune response to TLR4 stimulation

Duncan

Galic

Wang

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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Sickness behaviors are host defense adaptations that arise from integrated autonomic outputs in response to activation of the innate immune system. These behaviors include fever, anorexia, and hyperalgesia intended to promote survival of the host when encountering pathogens. Cannabinoid (CB) receptor activation can induce hypothermia and attenuate LPS-evoked fever. The aim of the present study was to examine the role of CB1 receptors in the LPS-evoked febrile response. CB1 receptor-deficient (CB1 Ϫ/Ϫ ) mice did not display LPSevoked fever; likewise, pharmacological blockade of CB1 receptors in wild-type mice blocked LPS-evoked fever. This unresponsiveness is not limited to thermogenesis, as the animals were not hyperalgesic after LPS administration. A Toll-like receptor (TLR)3 agonist and viral mimetic polyinosinic:polycytidylic acid evoked a robust fever in CB1 Ϫ/Ϫ mice, suggesting TLR3-mediated responses are functional. LPS-evoked c-Fos activation in areas of the brain associated with the febrile response was evident in wild-type mice but not in CB1 Ϫ/Ϫ mice. Liver and spleen TLR4 mRNA were significantly lower in CB1 Ϫ/Ϫ mice compared with wild-type mice, and peritoneal macrophages from CB1 Ϫ/Ϫ mice did not release proinflammatory cytokines in response to LPS. These data indicate that CB1 receptors play a critical role in LPS-induced febrile responses through inhibiting TLR4-mediated cytokine production.endocannabinoid; Toll-like receptor; fever; cytokine FEVER IS AN IMPORTANT COMPONENT of the innate immune response; subjects that are prevented from developing fever have increased morbidity and mortality (24,30). Fever occurs when structural motifs on bacterial cell walls, e.g., LPS for gramnegative bacteria, or double-stranded viral DNA, are recognized by Toll-like receptors (TLRs) on cells of the innate immune system (2, 32). LPS-evoked inflammation is via TLR4 activation, whereas viral moieties are recognized by TLR3. These signaling pathways are activated in monocytes and circulating or resident macrophages (e.g., Kupffer cells of the liver) to cause synthesis and release of a number of pyrogenic factors, including IL-1, IL-6, TNF-␣, and IFN␥. These cytokines signal to the brain to induce cyclooxygenase (COX) 2-dependent prostaglandin synthesis and additional cytokine synthesis in the brain (11). The resulting thermoregulatory response consists of both hypothermic and hyperthermic components, depending upon pyrogen, dose, and ambient temperature (47) and is often accompanied by other components of the host defense response, including hyperalgesia, anorexia, and sickness behaviors (14). Almost concurrently with the generation of a proinflammatory response is the production of several anti-inflammatory cytokines (e.g., IL-1 receptor antagonist, IL-10) and corticosteroids that limit the febrile response (7,46).Innate immune febrile responses can be modified by endogenous cannabinoids (eCB) acting on cannabinoid receptors (CB 1 and CB 2 ) in the central nervous system and periphery. The best recognized eCBs ar...

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confidence: 99%

Cannabinoid 1 receptors are critical for the innate immune response to TLR4 stimulation

Duncan

Galic

Wang

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Increased levels of endocannabinoids in the hypothalamus were found in animal models of obesity such as ob/ob mice, and leptin treatment reduced 2-Arachidonoylglycerol (2-AG) levels in these animals, suggesting that leptin participates in the control of the endocannabinoid system (17). Several reports show that endocannabinoids interact with LPS systemic actions, suggesting a role of CB1 receptors in the pathogenesis of fever and inflammation during endotoxemia (5,19,22,47). However, studies on endocannabinoid involvement in LPS-induced appetite alterations are lacking.…”

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confidence: 99%

Leptin resistance and desensitization of hypophagia during prolonged inflammatory challenge

Borges¹,

Rorato²,

Avraham

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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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 ...

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“…7,9) Anandamide and sphingosine-1-phosphate led to increased BT following central injection. 13,42) To date, no adipokines or lipid mediators have been shown to produce hypothermia. In contrast, there are several reports that FAs can influence membrane fluidity or characteristics of receptors/ion channels in the cell mem- brane.…”

Section: Discussionmentioning

confidence: 99%

Long-term High-Soybean Oil Feeding Alters Regulation of Body Temperature in Rats

Tsushima

Yamada

Miyazawa

et al. 2014

Biological & Pharmaceutical Bulletin

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We investigated whether body temperature (BT) regulatory mechanisms are influenced by dietary fatty acids (FA). Male Wistar rats were fed a high-fat diet containing fish oil (HFD), soybean oil (HSD) or lard (HLD). At the 20-week intervention, the BT of the HSD and HLD groups were lower than that of the normal diet (ND) group in the light and dark periods. The intracerebroventricular injections of interleukin-1β and bombesin in the HSD group induced greater hyperthermia and weaker hypothermia, respectively, than in the ND group. The HSD differentially affected BT under both physiological and pharmacological conditions. In the hypothalamus, the ratio of n-6/n-3 FAs was higher in the HSD group compared with the ND group. DNA microarrays revealed increased expression of thyroid-stimulating hormone β-subunit, and decreased expression of several genes in the hypothalamus of the HSD group compared with the ND group. The HSD feeding increased several adipokine concentrations in the plasma. However, there were no adipokines or gene expressions that changed in only the HSD and HLD groups showing significant hypothermia under the physiological condition. These findings suggested that long-term HSD intake produces abnormal BT regulation. It is less likely that adipokines or proteins/peptides are involved in abnormal BT regulation under the physiological conditions after HSD feeding.Key words body temperature; hypothalamus; high-fat diet; interleukin (IL)-1β; bombesinWe now obtain more energy from fat and glucose than ever before. These changes have induced hyperlipidemia and adipocyte hypertrophy, resulting in the risk of cardiovascular diseases, diabetes mellitus and obesity. From this point of view, there are many reports on lipid and/or glucose metabolisms during high-fat diet feeding in living animals.

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Endogenous cannabinoids induce fever through the activation of CB₁ receptors

Cited by 31 publications

References 47 publications

Cannabinoid 1 receptors are critical for the innate immune response to TLR4 stimulation

Cannabinoid 1 receptors are critical for the innate immune response to TLR4 stimulation

Leptin resistance and desensitization of hypophagia during prolonged inflammatory challenge

Long-term High-Soybean Oil Feeding Alters Regulation of Body Temperature in Rats

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Endogenous cannabinoids induce fever through the activation of CB1 receptors

Cited by 31 publications

References 47 publications

Cannabinoid 1 receptors are critical for the innate immune response to TLR4 stimulation

Cannabinoid 1 receptors are critical for the innate immune response to TLR4 stimulation

Leptin resistance and desensitization of hypophagia during prolonged inflammatory challenge

Long-term High-Soybean Oil Feeding Alters Regulation of Body Temperature in Rats

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Endogenous cannabinoids induce fever through the activation of CB₁ receptors