Lipopolysacharide Rapidly and Completely Suppresses AgRP Neuron-Mediated Food Intake in Male Mice

Abstract

Although Agouti-related peptide (AgRP) neurons play a key role in the regulation of food intake, their contribution to the anorexia caused by proinflammatory insults has yet to be identified. Using a combination of neuroanatomical and pharmacogenetics experiments, this study sought to investigate the importance of AgRP neurons and downstream targets in the anorexia caused by the peripheral administration of a moderate dose of lipopolysaccharide (LPS) (100 μg/kg, ip). First, in the C57/Bl6 mouse, we demonstrated that LPS induced c-fos in select AgRP-innervated brain sites involved in feeding but not in any arcuate proopiomelanocortin neurons. Double immunohistochemistry further showed that LPS selectively induced c-Fos in a large subset of melanocortin 4 receptor-expressing neurons in the lateral parabrachial nucleus. Secondly, we used pharmacogenetics to stimulate the activity of AgRP neurons during the course of LPS-induced anorexia. In AgRP-Cre mice expressing the designer receptor hM3Dq-Gq only in AgRP neurons, the administration of the designer drug clozapine-N-oxide (CNO) induced robust food intake. Strikingly, CNO-mediated food intake was rapidly and completely blunted by the coadministration of LPS. Neuroanatomical experiments further indicated that LPS did not interfere with the ability of CNO to stimulate c-Fos in AgRP neurons. In summary, our findings combined together support the view that the stimulation of select AgRP-innervated brain sites and target neurons, rather than the inhibition of AgRP neurons themselves, is likely to contribute to the rapid suppression of food intake observed during acute bacterial endotoxemia.

Lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNFα) blunt the response of Neuropeptide Y/Agouti-related peptide (NPY/AgRP) glucose inhibited (GI) neurons to decreased glucose

“…Liu et al showed that LPS may be acting on the downstream targets of the AgRP neurons as opposed to directly affecting this neuronal population (Liu et al, 2016). Sartin et al showed that cfos actually increased in AgRP neurons 6 hours after LPS injection while Sergeyev et al showed that NPY expression was unaffected 4 hours post-LPS injection (Sartin JL, 2008; Sergeyev et al, 2001).…”

PI3K signaling: A molecular pathway associated with acute hypophagic response during inflammatory challenges

“…Nevertheless, studies found no detectable changes in LPS-induced c-Fos expression in POMC neurons [Gautron et al, 2005; Liu et al, 2016]. Previous reports by our group and others have described no changes in POMC mRNA expression in the ARC of rats treated with LPS [Gautron et al, 2005; Borges et al, 2007].…”

“…Activation of AgRP neurons rapidly stimulates vigorous feeding whereas its inhibition or ablation suppresses food consumption [Krashes et al, 2011, Liu et al, 2016]. Considering that central AgRP injection blunted the hypophagic effect of LPS [Sartin et al, 2008] it has been postulated that inflammatory hypophagia might be caused by lack of AgRP action.…”

“…Considering that central AgRP injection blunted the hypophagic effect of LPS [Sartin et al, 2008] it has been postulated that inflammatory hypophagia might be caused by lack of AgRP action. Using pharmacogenetics and the DREADD (designer receptors exclusively activated by designer drug) technique Liu and colleagues [2016] attempted to delineate the exact neural circuits linking LPS-induced hypophagia to the AgRP neuronal pathway. They assessed if activation of AgRP neurons attenuates LPS-induced hypophagia.…”

“…Data from pharmacogenetically activated AgRP neurons in LPS-treated mice indicate that the absence of AgRP action is unlikely to play a role in inflammation-induced hypophagia, given that LPS similarly reduced food intake in both AgRP-DREADD negative or positive mice. Therefore, AgRP-DREADD neuronal activation is not sufficient to prevent LPS hypophagia in mice [Liu et al, 2016]. …”