title: Early postnatal amylin treatment enhances hypothalamic leptin signaling and neural development in the selectively bred diet-induced obese rat.
abstract: Selectively bred diet-induced obese (DIO) rats become obese on a high-fat diet and are leptin resistant before becoming obese. Compared with diet-resistant (DR) neonates, DIO neonates have impaired leptin-dependent arcuate (ARC) neuropeptide Y/agouti-related peptide (NPY/AgRP) and α-melanocyte-stimulating hormone (α-MSH; from proopiomelanocortin (POMC) neurons) axon outgrowth to the paraventricular nucleus (PVN). Using phosphorylation of STAT3 (pSTAT3) as a surrogate, we show that reduced DIO ARC leptin signaling develops by postnatal day 7 (P7) and is reduced within POMC but not NPY/AgRP neurons. Since amylin increases leptin signaling in adult rats, we treated DIO neonates with amylin during postnatal hypothalamic development and assessed leptin signaling, leptin-dependent ARC-PVN pathway development, and metabolic changes. DIO neonates treated with amylin from P0-6 and from P0-16 increased ARC leptin signaling and both AgRP and α-MSH ARC-PVN pathway development, but increased only POMC neuron number. Despite ARC-PVN pathway correction, P0-16 amylin-induced reductions in body weight did not persist beyond treatment cessation. Since amylin enhances adult DIO ARC signaling via an IL-6-dependent mechanism, we assessed ARC-PVN pathway competency in IL-6 knockout mice and found that the AgRP, but not the α-MSH, ARC-PVN pathway was reduced. These results suggest that both leptin and amylin are important neurotrophic factors for the postnatal development of the ARC-PVN pathway. Amylin might act as a direct neurotrophic factor in DIO rats to enhance both the number of POMC neurons and their α-MSH ARC-PVN pathway development. This suggests important and selective roles for amylin during ARC hypothalamic development.
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: The Saban Research Institute, Developmental Neuroscience Program, Children's Hospital Los Angeles, University of Southern California, Los Angeles, California.|INSERM, Jean-Pierre Aubert Research Center, Lille, France.
authors.forename: Sebastien G
authors.initials: SG
authors.lastname: Bouret
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; and.
authors.forename: Christina N
authors.initials: CN
authors.lastname: Boyle
authors.affiliation: Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland; and.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Lutz
authors.affiliation: 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 / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001835:Body Weight / Q000187:drug effects; D059305:Diet, High-Fat; D004041:Dietary Fats; D005260:Female; D007031:Hypothalamus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D058228:Islet Amyloid Polypeptide / Q000008:administration & dosage* / Q000494:pharmacology; D020738:Leptin / Q000378:metabolism*; D008297:Male; D055495:Neurogenesis / Q000187:drug effects; D009765:Obesity / Q000188:drug therapy* / Q000503:physiopathology*; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D011181:Postnatal Care; D051381:Rats; D016896:Treatment Outcome
chemical_list: D004041:Dietary Fats; D058228:Islet Amyloid Polypeptide; D020738:Leptin
keywords: AgRP; NPY; POMC; amylin; hypothalamus; leptin