title: Hypothalamic SIRT1 prevents age-associated weight gain by improving leptin sensitivity in mice.
abstract: OBJECTIVE
  Obesity is associated with ageing and increased energy intake, while restriction of energy intake improves health and longevity in multiple organisms; the NAD(+)-dependent deacetylase sirtuin 1 (SIRT1) is implicated in this process. Pro-opiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons in the arcuate nucleus (ARC) of the hypothalamus are critical for energy balance regulation, and the level of SIRT1 protein decreases with age in the ARC. In the current study we tested whether conditional Sirt1 overexpression in mouse POMC or AgRP neurons prevents age-associated weight gain and diet-induced obesity.
  
  
  METHODS
  We targeted Sirt1 cDNA sequence into the Rosa26 locus and generated conditional Sirt1 knock-in mice. These mice were crossed with mice harbouring either Pomc-Cre or Agrp-Cre and the metabolic variables, food intake, energy expenditure and sympathetic activity in adipose tissue of the resultant mice were analysed. We also used a hypothalamic cell line to investigate the molecular mechanism by which Sirt1 overexpression modulates leptin signalling.
  
  
  RESULTS
  Conditional Sirt1 overexpression in mouse POMC or AgRP neurons prevented age-associated weight gain; overexpression in POMC neurons stimulated energy expenditure via increased sympathetic activity in adipose tissue, whereas overexpression in AgRP neurons suppressed food intake. SIRT1 improved leptin sensitivity in hypothalamic neurons in vitro and in vivo by downregulating protein-tyrosine phosphatase 1B, T cell protein-tyrosine phosphatase and suppressor of cytokine signalling 3. However, these phenotypes were absent in mice consuming a high-fat, high-sucrose diet due to decreases in ARC SIRT1 protein and hypothalamic NAD(+) levels.
  
  
  CONCLUSIONS
  ARC SIRT1 is a negative regulator of energy balance, and decline in ARC SIRT1 function contributes to disruption of energy homeostasis by ageing and diet-induced obesity.
authors.affiliation: Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi-shi, Gunma, 371-8512, Japan, tsutomus@gunma-u.ac.jp.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Sasaki
authors.forename: Osamu
authors.initials: O
authors.lastname: Kikuchi
authors.forename: Mayumi
authors.initials: M
authors.lastname: Shimpuku
authors.forename: Vina Yanti
authors.initials: VY
authors.lastname: Susanti
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yokota-Hashimoto
authors.forename: Ryo
authors.initials: R
authors.lastname: Taguchi
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Shibusawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
authors.forename: Lijun
authors.initials: L
authors.lastname: Tang
authors.forename: Kosuke
authors.initials: K
authors.lastname: Amano
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kitazumi
authors.forename: Mitsutaka
authors.initials: M
authors.lastname: Kuroko
authors.forename: Yuki
authors.initials: Y
authors.lastname: Fujita
authors.forename: Jun
authors.initials: J
authors.lastname: Maruyama
authors.forename: Yong-Soo
authors.initials: YS
authors.lastname: Lee
authors.forename: Masaki
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Minokoshi
authors.forename: Akihiro
authors.initials: A
authors.lastname: Harada
authors.forename: Masanobu
authors.initials: M
authors.lastname: Yamada
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Kitamura
mesh_terms: D000818:Animals; D002153:Calorimetry, Indirect; D005838:Genotype; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D007150:Immunohistochemistry; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D015430:Weight Gain / Q000235:genetics / Q000502:physiology*
chemical_list: D020738:Leptin; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1