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

Abstract

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.

Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14

“…Most prior studies have found that increased SIRT1 is involved in healthful aging (Herranz et al., 2010; Sasaki et al., 2014; Satoh et al., 2013), whereas the results for SIRT3 are more controversial (Bellizzi et al., 2005; De Rango et al., 2008; Lescai et al., 2009; McDonnell, Peterson, Bomze & Hirschey, 2015; Rose et al., 2003). However, decreases in SIRT1 have been associated with cancer protection, which also is involved in healthful aging (Chen et al., 2014; Ohanna et al., 2014).…”

Overexpression of insulin receptor partially improves obese and diabetic phenotypes in <i>db/db</i> mice

“…INSR-Tg mice (in a B6 background) and db/+ mice (in a BKS background) were mated to generate parent mice (db/+ or INSR; db/+ in a B6 x BKS background), and these parents were mated to generate experimental groups (wild type, INSR heterozygote (het), db/db, and INSR(het); db/db). Body weight, food intake, and perigonadal white adipose tissue weight of male and female mice were measured as described previously [10]. Mice were euthanized under anesthesia.…”

Overexpression of Nmnat3 efficiently increases NAD and NGD levels and ameliorates age‐associated insulin resistance

“…In addition to NAD synthesis activity, Nmnat3 possesses reported chaperone‐like activities that may be beneficial independently of NAD production (Zhai et al., 2008). Finally, in this study, we only demonstrated the benefits of Nmnat3 overexpression in skeletal muscle, and several studies have shown roles of NAD and sirtuins in the regulation of insulin sensitivity in other tissues, including adipose tissues and brain (Chalkiadaki & Guarente, 2012; Sasaki et al., 2014; Satoh et al., 2013; Stromsdorfer et al., 2016; Yoon et al., 2015). We also observed significant increases in NAD levels in WAT, BAT, and brain.…”

“…The O 2  and CO 2  measurements were performed every 18 min for each mouse over a 3‐day period, and the data from the final day were analyzed. Locomotor activity was measured with the ACTIMO‐100 (Shinfactory, Fukuoka, Japan) (Sasaki et al., 2014, 2015). …”