title: Amylin-induced central IL-6 production enhances ventromedial hypothalamic leptin signaling.
abstract: Amylin acts acutely via the area postrema to reduce food intake and body weight, but it also interacts with leptin over longer periods of time, possibly via the ventromedial hypothalamus (VMH), to increase leptin signaling and phosphorylation of STAT3. We postulated that amylin enhances VMH leptin signaling by inducing interleukin (IL)-6, which then interacts with its gp130 receptor to activate STAT3 signaling and gene transcription downstream of the leptin receptor. We found that components of the amylin receptor (RAMPs1-3, CTR1a,b) are expressed in cultured VMH astrocytes, neurons, and microglia, as well as in micropunches of arcuate and ventromedial hypothalamic nuclei (VMN). Amylin exposure for 5 days increased IL-6 mRNA expression in VMH explants and microglia by two- to threefold, respectively, as well as protein abundance in culture supernatants by five- and twofold, respectively. Amylin had no similar effects on cultured astrocytes or neurons. In rats, 5 days of amylin treatment decreased body weight gain and/or food intake and increased IL-6 mRNA expression in the VMN. Similar 5-day amylin treatment increased VMN leptin-induced phosphorylation of STAT3 expression in wild-type mice and rats infused with lateral ventricular IgG but not in IL-6 knockout mice or rats infused with ventricular IL-6 antibody. Lateral ventricular infusion of IL-6 antibody also prevented the amylin-induced decrease of body weight gain. These results show that amylin-induced VMH microglial IL-6 production is the likely mechanism by which amylin treatment interacts with VMH leptin signaling to increase its effect on weight loss.
authors.affiliation: Department of Neurology and Neurosciences, Rutgers New Jersey Medical School, Newark, NJ christelle.lefoll@gmail.com.
authors.forename: Christelle
authors.initials: C
authors.lastname: Le Foll
authors.affiliation: Department of Neurology and Neurosciences, Rutgers New Jersey Medical School, Newark, NJ Rutgers Graduate School of Biomedical Sciences at New Jersey Medical School and Rutgers School of Dental Medicine, Newark, NJ.
authors.forename: Miranda D
authors.initials: MD
authors.lastname: Johnson
authors.affiliation: VA Medical Center, East Orange, NJ.
authors.forename: Ambrose A
authors.initials: AA
authors.lastname: Dunn-Meynell
authors.affiliation: Zurich Center for Integrative Human Physiology, Zurich, Switzerland Institute of Veterinary Physiology, Zurich, Switzerland.
authors.forename: Christina N
authors.initials: CN
authors.lastname: Boyle
authors.affiliation: Zurich Center for Integrative Human Physiology, Zurich, Switzerland Institute of Veterinary Physiology, Zurich, Switzerland Institute of Laboratory Animal Sciences, Zurich, Switzerland.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Lutz
authors.affiliation: Department of Neurology and Neurosciences, Rutgers New Jersey Medical School, Newark, NJ VA Medical Center, East Orange, NJ.
authors.forename: Barry E
authors.initials: BE
authors.lastname: Levin
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D058228:Islet Amyloid Polypeptide / Q000494:pharmacology*; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D012333:RNA, Messenger; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014697:Ventromedial Hypothalamic Nucleus / Q000166:cytology / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D058228:Islet Amyloid Polypeptide; D020738:Leptin; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat