title: Endogenous VMH amylin signaling is required for full leptin signaling and protection from diet-induced obesity.
abstract: Amylin enhances arcuate (ARC) and ventromedial (VMN) hypothalamic nuclei leptin signaling and synergistically reduces food intake and body weight in selectively bred diet-induced obese (DIO) rats. Since DIO (125)I-amylin dorsomedial nucleus-dorsomedial VMN binding was reduced, we postulated that this contributed to DIO ventromedial hypothalamus (VMH) leptin resistance, and that impairing VMH (ARC + VMN) calcitonin receptor (CTR)-mediated signaling by injecting adeno-associated virus (AAV) expressing a short hairpin portion of the CTR mRNA would predispose diet-resistant (DR) rats to obesity on high-fat (45%) diet (HFD). Depleting VMH CTR by 80-90% in 4-wk-old male DR rats reduced their ARC and VMN (125)I-labeled leptin binding by 57 and 51%, respectively, and VMN leptin-induced phospho-signal transducer and activator of transcription 3-positive neurons by 59% vs. AAV control rats. After 6 wk on chow, VMH CTR-depleted DR rats ate and gained the equivalent amount of food and weight but had 18% heavier fat pads (relative to carcass weight), 144% higher leptin levels, and were insulin resistant compared with control AAV DR rats. After 6 wk more on HFD, VMH CTR-depleted DR rats ate the same amount but gained 28% more weight, had 60% more carcass fat, 254% higher leptin levels, and 132% higher insulin areas under the curve during an oral glucose tolerance test than control DR rats. Therefore, impairing endogenous VMH CTR-mediated signaling reduced leptin signaling and caused DR rats to become more obese and insulin resistant, both on chow and HFD. These results suggest that endogenous VMH amylin signaling is required for full leptin signaling and protection from HFD-induced obesity.
authors.affiliation: Neurology Service, Veterans Administration Medical Center, East Orange, New Jersey;
authors.forename: Ambrose A
authors.initials: AA
authors.lastname: Dunn-Meynell
authors.affiliation: Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland;
authors.forename: Christelle
authors.initials: C
authors.lastname: Le Foll
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Miranda D
authors.initials: MD
authors.lastname: Johnson
authors.affiliation: Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland;
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Lutz
authors.affiliation: Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; and.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Hayes
authors.affiliation: Neurology Service, Veterans Administration Medical Center, East Orange, New Jersey; Department of Neurology, Rutgers, New Jersey Medical School, Newark, New Jersey levin@njms.rutgers.edu.
authors.forename: Barry E
authors.initials: BE
authors.lastname: Levin
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism; D059305:Diet, High-Fat; D004435:Eating; D018149:Glucose Intolerance / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics; D007457:Iodine Radioisotopes; D058228:Islet Amyloid Polypeptide / Q000235:genetics / Q000378:metabolism*; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009765:Obesity / Q000235:genetics / Q000503:physiopathology*; D034741:RNA, Small Interfering / Q000235:genetics; D011877:Radionuclide Imaging; D051381:Rats; D018003:Receptors, Calcitonin / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics; D014697:Ventromedial Hypothalamic Nucleus / Q000000981:diagnostic imaging / Q000378:metabolism*; D015430:Weight Gain
chemical_list: D007457:Iodine Radioisotopes; D058228:Islet Amyloid Polypeptide; D020738:Leptin; D034741:RNA, Small Interfering; D018003:Receptors, Calcitonin; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat
keywords: arcuate nucleus; calcitonin receptor; insulin resistance; pSTAT3; ventromedial nucleus