Hypothalamic SIRT1 prevents age-associated weight gain by improving leptin sensitivity in mice

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 YamadaTadahiro Kitamura

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

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: 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/ 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.

Original languageEnglish
Pages (from-to)819-831
Number of pages13
JournalDiabetologia
Volume57
Issue number4
DOIs
StatePublished - 2014/04

Keywords

  • AgRP
  • Brown adipose tissue
  • Diet-induced obesity
  • Energy expenditure
  • Food intake
  • Hypothalamus
  • Leptin sensitivity
  • POMC
  • Sympathetic activity

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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