Central Neural Mediation of Cytokine Induced Anorexia

Peripherally administered IL-1 p induces c-fos immunoreactivity in the PVN and ARC of the hypothalamus [34]. The ARC is considered to be the major hypothalamic detection site for blood-derived signals. Yet, severing the ARC from PVN or its connections with the PVN only slightly attenuated peripheral IL-1p-induced anorexia [35], indicating that the ARC is involved but not necessary for peripheral IL-1p-induced anorexia. Several lines of evidence [20] implicate activation of hindbrain to forebrain aminergic neurons in the feeding suppression and hypermetabolic effects of circulating IL-1p. IL-1p-induced anorexia may in part be mediated through prostaglandin E2-dependent activation of serotoninergic neurons originating in the raphe nuclei and projecting to the hypothalamus [36]. In line with this idea, systemic administration of a serotonin (5-HT2c) receptor antagonist and microinjection of the 5-HT1A autoreceptor agonist 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) directly into the raphe nucleus both markedly attenuated the feeding-suppressive effect of peripherally injected IL-1-p [3]. Interestingly, anorexia induced by experimental colitis in rats is mediated, in part, by the stimulatory effect of IL-1 on medial hypothalamic 5-HT [37]. It is still largely unknown whether TNF-a inhibits feeding through the same mechanisms as IL-1p. It has been shown, however, that both cytokines can replace each other in mediating infection-induced anorexia [38]. These and other results suggest that cytokines act in concert to inhibit eating [5]. In addition to 5-HT, melanocortins are involved in the anorexia and weight loss associated with inflammatory and neoplastic disease processes. Studies using melanocortin antagonists (SHU9119 or agouti-related peptide) or genetic approaches (melanocortin-4 receptor KO mice) suggest that melanocortin action is required for anorexia and weight loss induced by injected lipopolysaccha-ride (LPS, an inflammatory gram-negative bacterial cell wall product) or by implantation of prostate or lung cancer cells. Although the precise mechanisms for the effects of peripheral inflammation or neoplasia on the melanocortin system remain unknown, it is reasonable to assume that proinflammatory cytokines (IL-1 p, IL-6, TNF-a) play a role [39,40].

Interestingly, 5-HT and the melanocortin system appear to jointly contribute to the anorexia in chronic inflammation and infection. Most recent data indicate that activation of 5-HTergic neurons ultimately influences the hypothalamic melanocortin pathways of energy balance regulation and that activation of the melanocortin system is necessary to produce the complete anorec-tic effect of 5-HTergic activation [41]. In line with this hypothesis, anorectic 5-HTergic drugs activated pro-opiomelanocortin (POMC) neurons in the ARC, and this effect appeared to be mediated by the 5-HT2C receptor expressed on POMC neurons [41]. The exact mechanisms of this interaction between 5-HT and the melanocortin pathway still need to be determined.

Also, IL-1p appears to be essential for the production of ciliary neurotrophic factor (CNTF) in response to brain injury or trauma [42]. CNTF was first characterised as a trophic factor for motor neurons in the ciliary ganglion and spinal cord and subsequently found to markedly reduce food intake and body weight [43]. This makes CNTF a possible mediator of IL-1p effects on food intake and energy expenditure. Some data suggest that CNTF ultimately affects energy balance by markedly reducing the expression and action of NPY [44]. A reduction of hypothalamic NPY has also been implicated in the feeding-suppressive effect of IL-1p [45]. Summarising, several lines of evidence suggest that the pathways of cytokine-induced suppression of feeding and stimulation of energy expenditure ultimately converge on the well-characterised hypothalamic neuropeptide systems that control energy balance.

Breaking Bulimia

Breaking Bulimia

We have all been there: turning to the refrigerator if feeling lonely or bored or indulging in seconds or thirds if strained. But if you suffer from bulimia, the from time to time urge to overeat is more like an obsession.

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