Abstract | AIMS/HYPOTHESIS:
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: CONCLUSIONS/INTERPRETATION:
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.
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Authors | Tsutomu Sasaki, Osamu Kikuchi, Mayumi Shimpuku, Vina Yanti Susanti, Hiromi Yokota-Hashimoto, Ryo Taguchi, Nobuyuki Shibusawa, Takashi Sato, Lijun Tang, Kosuke Amano, Tomoya Kitazumi, Mitsutaka Kuroko, Yuki Fujita, Jun Maruyama, Yong-Soo Lee, Masaki Kobayashi, Takashi Nakagawa, Yasuhiko Minokoshi, Akihiro Harada, Masanobu Yamada, Tadahiro Kitamura |
Journal | Diabetologia
(Diabetologia)
Vol. 57
Issue 4
Pg. 819-31
(Apr 2014)
ISSN: 1432-0428 [Electronic] Germany |
PMID | 24374551
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Leptin
- Sirt1 protein, mouse
- Sirtuin 1
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Topics |
- Animals
- Calorimetry, Indirect
- Genotype
- Hypothalamus
(drug effects, metabolism)
- Immunohistochemistry
- Leptin
(pharmacology)
- Male
- Mice
- Mice, Inbred C57BL
- Polymerase Chain Reaction
- Sirtuin 1
(genetics, metabolism)
- Weight Gain
(genetics, physiology)
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