Lipopolysacharide Rapidly and Completely Suppresses AgRP Neuron-Mediated Food Intake in Male Mice.
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.
Division of Hypothalamic Research and Department of Internal Medicine (Y.L., Y.H., T.L., L.G.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390; Department of Orthopedics (Y.L., H.W.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 430030; and Department of Pharmacology (H.C.), Center for Hypertension Research, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Carver College of Medicine, Iowa City, Iowa 52242.
Yang
Y
Liu
Division of Hypothalamic Research and Department of Internal Medicine (Y.L., Y.H., T.L., L.G.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390; Department of Orthopedics (Y.L., H.W.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 430030; and Department of Pharmacology (H.C.), Center for Hypertension Research, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Carver College of Medicine, Iowa City, Iowa 52242.
Ying
Y
Huang
Division of Hypothalamic Research and Department of Internal Medicine (Y.L., Y.H., T.L., L.G.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390; Department of Orthopedics (Y.L., H.W.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 430030; and Department of Pharmacology (H.C.), Center for Hypertension Research, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Carver College of Medicine, Iowa City, Iowa 52242.
Tiemin
T
Liu
Division of Hypothalamic Research and Department of Internal Medicine (Y.L., Y.H., T.L., L.G.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390; Department of Orthopedics (Y.L., H.W.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 430030; and Department of Pharmacology (H.C.), Center for Hypertension Research, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Carver College of Medicine, Iowa City, Iowa 52242.
Hua
H
Wu
Division of Hypothalamic Research and Department of Internal Medicine (Y.L., Y.H., T.L., L.G.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390; Department of Orthopedics (Y.L., H.W.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 430030; and Department of Pharmacology (H.C.), Center for Hypertension Research, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Carver College of Medicine, Iowa City, Iowa 52242.
Huxing
H
Cui
Division of Hypothalamic Research and Department of Internal Medicine (Y.L., Y.H., T.L., L.G.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390; Department of Orthopedics (Y.L., H.W.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 430030; and Department of Pharmacology (H.C.), Center for Hypertension Research, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Carver College of Medicine, Iowa City, Iowa 52242.
Laurent
L
Gautron
D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004435:Eating / Q000187:drug effects*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics / Q000378:metabolism
D054369:Agouti-Related Protein; D008070:Lipopolysaccharides; D016760:Proto-Oncogene Proteins c-fos; D044105:Receptor, Melanocortin, Type 4; D011333:Pro-Opiomelanocortin