Aims/hypothesisObesity 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.MethodsWe 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.ResultsConditional 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/interpretationARC 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-013-3140-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

THERE are 347 million diabetic patients worldwide and 95 % of them are type 2 diabetes mellitus (T2DM), hallmarks of which are impaired secretion and action of insulin [1,2]. Several treatment options for T2DM are in clinical use, including injecting insulin, promoting insulin secretion by insulin secretagogues (such as sulfonylureas and glinides), and improving insulin sensitivity by insulin sensitizers (such as biguanides and thiazolidinediones). However, increasing the amount of insulin receptor in insulin-target tissues has not been explored.Insulin exerts its physiological effects through insulin receptors by binding to the alpha subunit of insulin receptor and stimulating the intrinsic kinase activity of the beta subunit [3][4][5]. However, chronic exposure of cells to insulin leads to down-regulation of insulin signaling through a net loss of insulin receptor from the plasma membrane [6], which is one of the mechanisms involved in insulin resistance. Therefore, increasing the amount of insulin receptor could alleviate insulin resistance. Leptin is an adipokine crucial for the regulation of energy homeostasis [7]. A homozygous loss-of-function mutation in the leptin receptor (the db mutation) causes hyperphagia and obesity, leading to diabetes in mice [8,9]. Since obesity is a major risk factor for impaired insulin sensitivity and T2DM, db/db mice are used as a genetic model of T2DM.

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