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In obesity and type 2 diabetes, Glut4 glucose transporter expression is decreased selectively in adipocytes. Adipose-specific knockout or overexpression of Glut4 alters systemic insulin sensitivity. Here we show, using DNA array analyses, that nicotinamide N-methyltransferase (Nnmt) is the most strongly reciprocally regulated gene when comparing gene expression in white adipose tissue (WAT) from adipose-specific Glut4-knockout or adipose-specific Glut4-overexpressing mice with their respective controls. NNMT methylates nicotinamide (vitamin B3) using S-adenosylmethionine (SAM) as a methyl donor. Nicotinamide is a precursor of NAD(+), an important cofactor linking cellular redox states with energy metabolism. SAM provides propylamine for polyamine biosynthesis and donates a methyl group for histone methylation. Polyamine flux including synthesis, catabolism and excretion, is controlled by the rate-limiting enzymes ornithine decarboxylase (ODC) and spermidine-spermine N(1)-acetyltransferase (SSAT; encoded by Sat1) and by polyamine oxidase (PAO), and has a major role in energy metabolism. We report that NNMT expression is increased in WAT and liver of obese and diabetic mice. Nnmt knockdown in WAT and liver protects against diet-induced obesity by augmenting cellular energy expenditure. NNMT inhibition increases adipose SAM and NAD(+) levels and upregulates ODC and SSAT activity as well as expression, owing to the effects of NNMT on histone H3 lysine 4 methylation in adipose tissue. Direct evidence for increased polyamine flux resulting from NNMT inhibition includes elevated urinary excretion and adipocyte secretion of diacetylspermine, a product of polyamine metabolism. NNMT inhibition in adipocytes increases oxygen consumption in an ODC-, SSAT- and PAO-dependent manner. Thus, NNMT is a novel regulator of histone methylation, polyamine flux and NAD(+)-dependent SIRT1 signalling, and is a unique and attractive target for treating obesity and type 2 diabetes.

Normal epithelial cells require matrix attachment for survival, and the ability of tumour cells to survive outside their natural extra-cellular matrix (ECM) niches is dependent on acquisition of anchorage independence [...]

AMP-activated protein kinase (AMPK) is a metabolic fuel gauge conserved along the evolutionary scale in eukaryotes that senses changes in the intracellular AMP/ATP ratio (1). Recent evidence indicated an important role for AMPK in the therapeutic benefits of metformin (2,3), thiazolidinediones (4) and exercise (5), which form the cornerstones of the clinical management of type 2 diabetes and associated metabolic disorders. In general, activation of AMPK acts to maintain cellular energy stores, switching on catabolic pathways that produce ATP, mostly by enhancing oxidative metabolism and mitochondrial biogenesis, while switching off anabolic pathways that consume ATP (1). This regulation can take place acutely, through the regulation of fast post-translational events, but also by transcriptionally reprogramming the cell to meet energetic needs. Here we demonstrate that AMPK controls the expression of genes involved in energy metabolism in mouse skeletal muscle by acting in coordination with another metabolic sensor, the [NAD.sup.+]-dependent type III deacetylase SIRT1. AMPK enhances SIRT1 activity by increasing cellular [NAD.sup.+] levels, resulting in the deacetylation and modulation of the activity of downstream SIRT1 targets that include the peroxisome proliferator-activated receptor-γ coactivator 1αand the forkhead box O1 (FOXO1) and 03 (FOXO3a) transcription factors. The AMPK-induced SIRT1-mediated deacetylation of these targets explains many of the convergent biological effects of AMPK and SIRT1 on energy metabolism., AMPK is a critical regulator of mitochondrial biogenesis in response to energy deprivation (6). Although the mechanisms by which AMPK modulates mitochondrial gene expression are not entirely elucidated, they seem [...]

Author(s): John T. Cunningham [1, 2]; Joseph T. Rodgers [1]; Daniel H. Arlow [3]; Francisca Vazquez [1]; Vamsi K. Mootha (corresponding author) [3]; Pere Puigserver (corresponding author) [1, 2] Transcriptional [...]

Author(s): Joseph T. Rodgers [1]; Carlos Lerin [1]; Wilhelm Haas [3]; Steven P. Gygi [3]; Bruce M. Spiegelman [2, 3]; Pere Puigserver (corresponding author) [1] Homeostatic mechanisms in mammals respond [...]

Author(s): Pere Puigserver [1, 2]; James Rhee [1]; Jerry Donovan [1]; Christopher J. Walkey [1]; J. Cliff Yoon [1]; Francesco Oriente [3]; Yukari Kitamura [3]; Jennifer Altomonte [4]; Hengjiang Dong [...]

Author(s): Jiandie Lin [1]; Hai Wu [2]; Paul T. Tarr [1]; Chen-Yu Zhang [3]; Zhidan Wu [1]; Olivier Boss [3]; Laura F. Michael [1]; Pere Puigserver [1]; Eiji Isotani [4]; [...]

Author(s): Stephan Herzig [1]; Fanxin Long [1, 2]; Ulupi S. Jhala [1]; Susan Hedrick [1]; Rebecca Quinn [3]; Anton Bauer [4]; Dorothea Rudolph [4]; Gunther Schutz [4]; Cliff Yoon [5]; [...]

Author(s): J. Cliff Yoon [1]; Pere Puigserver [1]; Guoxun Chen [2]; Jerry Donovan [1]; Zhidan Wu [1]; James Rhee [1]; Guillaume Adelmant [1]; John Stafford [3]; C. Ronald Kahn [4]; [...]

Author(s): Chi Luo [1]; Ji-Hong Lim [1]; Yoonjin Lee [1, 2]; Scott R. Granter [3]; Ajith Thomas [1]; Francisca Vazquez [1, 4, 5]; Hans R. Widlund [6]; Pere Puigserver (corresponding [...]

Author(s): Stephan Herzig; Fanxin Long; Ulupi S. Jhala; Susan Hedrick; Rebecca Quinn; Anton Bauer; Dorothea Rudolph; Gunther Schutz; Cliff Yoon; Pere Puigserver; Bruce Spiegelman; Marc Montminy Nature, 413, 179-183 (2001). [...]

Insulin constitutes a principal evolutionarily conserved hormonal axis for maintaining glucose homeostasis; dysregulation of this axis causes diabetes. PGC-1α (peroxisome-proliferator-activated receptor-γ coactivator-1α) links insulin signalling to the expression of glucose and lipid metabolic genes. The histone acetyltransferase GCN5 (general control non-repressed protein 5) acetylates PGC-1α and suppresses its transcriptional activity, whereas sirtuin 1 deacetylates and activates PGC-1α. Although insulin is a mitogenic signal in proliferative cells, whether components of the cell cycle machinery contribute to its metabolic action is poorly understood. Here we report that in mice insulin activates cyclin D1-cyclin-dependent kinase 4 (Cdk4), which, in turn, increases GCN5 acetyltransferase activity and suppresses hepatic glucose production independently of cell cycle progression. Through a cell-based high-throughput chemical screen, we identify a Cdk4 inhibitor that potently decreases PGC-1α acetylation. Insulin/GSK-3β (glycogen synthase kinase 3-beta) signalling induces cyclin D1 protein stability by sequestering cyclin D1 in the nucleus. In parallel, dietary amino acids increase hepatic cyclin D1 messenger RNA transcripts. Activated cyclin D1-Cdk4 kinase phosphorylates and activates GCN5, which then acetylates and inhibits PGC-1α activity on gluconeogenic genes. Loss of hepatic cyclin D1 results in increased gluconeogenesis and hyperglycaemia. In diabetic models, cyclin D1-Cdk4 is chronically elevated and refractory to fasting/feeding transitions; nevertheless further activation of this kinase normalizes glycaemia. Our findings show that insulin uses components of the cell cycle machinery in post-mitotic cells to control glucose homeostasis independently of cell division. [ABSTRACT FROM AUTHOR]

AMP-activated protein kinase (AMPK) is a metabolic fuel gauge conserved along the evolutionary scale in eukaryotes that senses changes in the intracellular AMP/ATP ratio. Recent evidence indicated an important role for AMPK in the therapeutic benefits of metformin, thiazolidinediones and exercise, which form the cornerstones of the clinical management of type 2 diabetes and associated metabolic disorders. In general, activation of AMPK acts to maintain cellular energy stores, switching on catabolic pathways that produce ATP, mostly by enhancing oxidative metabolism and mitochondrial biogenesis, while switching off anabolic pathways that consume ATP. This regulation can take place acutely, through the regulation of fast post-translational events, but also by transcriptionally reprogramming the cell to meet energetic needs. Here we demonstrate that AMPK controls the expression of genes involved in energy metabolism in mouse skeletal muscle by acting in coordination with another metabolic sensor, the NAD+-dependent type III deacetylase SIRT1. AMPK enhances SIRT1 activity by increasing cellular NAD+ levels, resulting in the deacetylation and modulation of the activity of downstream SIRT1 targets that include the peroxisome proliferator-activated receptor-γ coactivator 1α and the forkhead box O1 (FOXO1) and O3 (FOXO3a) transcription factors. The AMPK-induced SIRT1-mediated deacetylation of these targets explains many of the convergent biological effects of AMPK and SIRT1 on energy metabolism. [ABSTRACT FROM AUTHOR]

Homeostatic mechanisms in mammals respond to hormones and nutrients to maintain blood glucose levels within a narrow range. Caloric restriction causes many changes in glucose metabolism and extends lifespan; however, how this metabolism is connected to the ageing process is largely unknown. We show here that the Sir2 homologue, SIRT1-which modulates ageing in several species-controls the gluconeogenic/glycolytic pathways in liver in response to fasting signals through the transcriptional coactivator PGC-1a. A nutrient signalling response that is mediated by pyruvate induces SIRT1 protein in liver during fasting. We find that once SIRT1 is induced, it interacts with and deacetylates PGC-1aat specific lysine residues in an NAD+-dependent manner. SIRT1 induces gluconeogenic genes and hepatic glucose output through PGC-1a, but does not regulate the effects of PGC-1aon mitochondrial genes. In addition, SIRT1 modulates the effects of PGC-1arepression of glycolytic genes in response to fasting and pyruvate. Thus, we have identified a molecular mechanism whereby SIRT1 functions in glucose homeostasis as a modulator of PGC-1a. These findings have strong implications for the basic pathways of energy homeostasis, diabetes and lifespan. [ABSTRACT FROM AUTHOR]