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.

Kitamura T. FoxO1 as a double-edged sword in the pancreas: analysis of pancreas-and ␤-cell-specific FoxO1 knockout mice. Am J Physiol Endocrinol Metab 302: E603-E613, 2012. First published January 3, 2012; doi:10.1152/ajpendo.00469.2011.-Diabetes is characterized by an absolute or relative deficiency of pancreatic ␤-cells. New strategies to accelerate ␤-cell neogenesis or maintain existing ␤-cells are desired for future therapies against diabetes. We previously reported that forkhead box O1 (FoxO1) inhibits ␤-cell growth through a Pdx1-mediated mechanism. However, we also reported that FoxO1 protects against ␤-cell failure via the induction of NeuroD and MafA. Here, we investigate the physiological roles of FoxO1 in the pancreas by generating the mice with deletion of FoxO1 in the domains of the Pdx1 promoter (P-FoxO1-KO) or the insulin 2 promoter (␤-FoxO1-KO) and analyzing the metabolic parameters and pancreatic morphology under two different conditions of increased metabolic demand: high-fat high-sucrose diet (HFHSD) and db/db background. P-FoxO1-KO, but not ␤-FoxO1-KO, showed improved glucose tolerance with HFHSD. Immunohistochemical analysis revealed that P-FoxO1-KO had increased ␤-cell mass due to increased islet number rather than islet size, indicating accelerated ␤-cell neogenesis. Furthermore, insulin-positive pancreatic duct cells were increased in P-FoxO1-KO but not ␤-FoxO1-KO. In contrast, db/db mice crossed with P-FoxO1-KO or ␤-FoxO1-KO showed more severe glucose intolerance than control db/db mice due to decreased glucose-responsive insulin secretion. Electron microscope analysis revealed fewer insulin granules in FoxO1 knockout db/db mice. We conclude that FoxO1 functions as a double-edged sword in the pancreas; FoxO1 essentially inhibits ␤-cell neogenesis from pancreatic duct cells but is required for the maintenance of insulin secretion under metabolic stress.forkhead box O1; pancreatic ␤-cell; diabetes; insulin secretion PANCREATIC ␤-CELLS secrete insulin to maintain plasma glucose levels in an appropriate physiological range. The development of new strategies to accelerate ␤-cell neogenesis or maintain preexisting ␤-cells is desired for future therapies against diabetes.

Recent studies have revealed that insulin signaling in pancreatic β-cells and the hypothalamus is critical for maintaining nutrient and energy homeostasis, the failure of which are hallmarks of metabolic syndrome. We previously reported that forkhead transcription factor forkhead box-containing protein of the O subfamily (FoxO)1, a downstream effector of insulin signaling, plays important roles in β-cells and the hypothalamus when we investigated the roles of FoxO1 independently in the pancreas and hypothalamus. However, because metabolic syndrome is caused by the combined disorders in hypothalamus and pancreas, to elucidate the combined implications of FoxO1 in these organs, we generated constitutively active FoxO1 knockin (KI) mice with specific activation in both the hypothalamus and pancreas. The KI mice developed obesity, insulin resistance, glucose intolerance, and hypertriglyceridemia due to increased food intake, decreased energy expenditure, and impaired insulin secretion, which characterize metabolic syndrome. The KI mice also had increased hypothalamic Agouti-related protein and neuropeptide Y levels and decreased uncoupling protein 1 and peroxisome proliferator-activated receptor γ coactivator 1α levels in adipose tissue and skeletal muscle. Impaired insulin secretion was associated with decreased expression of pancreatic and duodenum homeobox 1 (Pdx1), muscyloaponeurotic fibrosarcoma oncogene homolog A (MafA), and neurogenic differentiation 1 (NeuroD) in islets, although β-cell mass was paradoxically increased in KI mice. Based on these results, we propose that uncontrolled FoxO1 activation in the hypothalamus and pancreas accounts for the development of obesity and glucose intolerance, hallmarks of metabolic syndrome.

OBJECTIVES Postoperative acute kidney injury (AKI) is known as a risk factor for death after surgery for Stanford type A acute aortic dissection under hypothermic circulatory arrest. It may also adversely affect long-term survival. We searched for modifiable risk factors for postoperative AKI, focusing on lower body ischaemic time. METHODS We reviewed 191 patients undergoing surgical repair for Stanford type A acute aortic dissection. The distal anastomosis depended on excluding the primary tear location, resulting in ascending/hemiarch (n = 119), partial arch (n = 18) and total arch replacement (n = 54). We defined an increase in the serum creatinine level to ≧2 times the baseline level as AKI. The incidence of AKI was investigated with multivariate analysis of its risk factors. RESULTS Postoperative AKI was observed in 49 patients (26%), 31% of whom required renal replacement therapy. The overall hospital mortality rate was 8.5%. Postoperative AKI, preoperative shock and organ malperfusion were predictors of hospital death. Multivariate stepwise logistic regression analysis identified age, body mass index, preoperative chronic kidney disease and lower body ischaemic time as risk factors for postoperative AKI. CONCLUSIONS Although surgical repair for Stanford type A acute aortic dissection showed favourable results, the incidence of postoperative AKI is still high, closely associated with hospital death. Lower body ischaemic time should be recognized specifically as a modifiable surgical risk factor for postoperative AKI.

Abstract. In this paper, we show that for every constant 0 < ǫ < 1/2 and for every constant d ≥ 2, the minimum size of a depth d Boolean circuit that ǫ-approximates Majority function on n variables is exp(Θ(n 1/(2d−2) )). The lower bound for every d ≥ 2 and the upper bound for d = 2 have been previously shown by O'Donnell and Wimmer [ICALP'07], and the contribution of this paper is to give a matching upper bound for d ≥ 3.