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436 records returned

Life is short, if sweet.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Insulin is essential for glucose homeostasis, but reducing its activity delays the aging process in model organisms. In this issue of Cell Metabolism, Lee et al. (2009) show how these effects of insulin signaling intersect when glucose is fed to C. elegans. PMID: 19883611 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - November 1, 2009 Category: Cytology Authors: Abate JP, Blackwell TK Tags: Cell Metab Source Type: journals

A tale of two carboxypeptidases.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Proopiomelanocortin (Pomc) neurons play a central role in energy homeostasis. Despite the complexity of Pomc posttranslational processing, regulation of Pomc gene expression often takes center stage. Complementary papers that zero in on distinct carboxypeptidases (Plum et al., 2009; Wallingford et al., 2009) now refocus the spotlight on regulated peptide cleavage. PMID: 19883612 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - November 1, 2009 Category: Cytology Authors: Low MJ Tags: Cell Metab Source Type: journals

Dominant role of the p110beta isoform of PI3K over p110alpha in energy homeostasis regulation by POMC and AgRP neurons.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PI3K signaling is thought to mediate leptin and insulin action in hypothalamic pro-opiomelanocortin (POMC) and agouti-related protein (AgRP) neurons, key regulators of energy homeostasis, through largely unknown mechanisms. We inactivated either p110alpha or p110beta PI3K catalytic subunits in these neurons and demonstrate a dominant role for the latter in energy homeostasis regulation. In POMC neurons, p110beta inactivation prevented insulin- and leptin-stimulated electrophysiological responses. POMCp110beta null mice exhibited central leptin resistance, increased adiposity, and diet-induced obesity. In contrast, the ...
Source: Cell Metabolism - November 1, 2009 Category: Cytology Authors: Al-Qassab H, Smith MA, Irvine EE, Guillermet-Guibert J, Claret M, Choudhury AI, Selman C, Piipari K, Clements M, Lingard S, Chandarana K, Bell JD, Barsh GS, Smith AJ, Batterham RL, Ashford ML, Vanhaesebroeck B, Withers DJ Tags: Cell Metab Source Type: journals

Nesfatin-1-regulated oxytocinergic signaling in the paraventricular nucleus causes anorexia through a leptin-independent melanocortin pathway.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The hypothalamic paraventricular nucleus (PVN) functions as a center to integrate various neuronal activities for regulating feeding behavior. Nesfatin-1, a recently discovered anorectic molecule, is localized in the PVN. However, the anorectic neural pathway of nesfatin-1 remains unknown. Here we show that central injection of nesfatin-1 activates the PVN and brain stem nucleus tractus solitarius (NTS). In the PVN, nesfatin-1 targets both magnocellular and parvocellular oxytocin neurons and nesfatin-1 neurons themselves and stimulates oxytocin release. Immunoelectron micrographs reveal nesfatin-1 specifically in the s...
Source: Cell Metabolism - November 1, 2009 Category: Cytology Authors: Maejima Y, Sedbazar U, Suyama S, Kohno D, Onaka T, Takano E, Yoshida N, Koike M, Uchiyama Y, Fujiwara K, Yashiro T, Horvath TL, Dietrich MO, Tanaka S, Dezaki K, Oh-I S, Hashimoto K, Shimizu H, Nakata M, Mori M, Yada T Tags: Cell Metab Source Type: journals

KSR2 is an essential regulator of AMP kinase, energy expenditure, and insulin sensitivity.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
xF6;p MH, Lewis RE Kinase suppressors of Ras 1 and 2 (KSR1 and KSR2) function as molecular scaffolds to potently regulate the MAP kinases ERK1/2 and affect multiple cell fates. Here we show that KSR2 interacts with and modulates the activity of AMPK. KSR2 regulates AMPK-dependent glucose uptake and fatty acid oxidation in mouse embryonic fibroblasts and glycolysis in a neuronal cell line. Disruption of KSR2 in vivo impairs AMPK-regulated processes affecting fatty acid oxidation and thermogenesis to cause obesity. Despite their increased adiposity, ksr2(-/-) mice are hypophagic and hyperactive but expend less energy tha...
Source: Cell Metabolism - November 1, 2009 Category: Cytology Authors: Costanzo-Garvey DL, Pfluger PT, Dougherty MK, Stock JL, Boehm M, Chaika O, Fernandez MR, Fisher K, Kortum RL, Hong EG, Jun JY, Ko HJ, Schreiner A, Volle DJ, Treece T, Swift AL, Winer M, Chen D, Wu M, Leon LR, Shaw AS, McNeish J, Kim JK, Morrison DK, Tsch& Tags: Cell Metab Source Type: journals

Glucose shortens the life span of C. elegans by downregulating DAF-16/FOXO activity and aquaporin gene expression.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Many studies have addressed the effect of dietary glycemic index on obesity and diabetes, but little is known about its effect on life span itself. We found that adding a small amount of glucose to the medium (2%) shortened the life span of C. elegans by inhibiting the activities of life span-extending transcription factors that are also inhibited by insulin signaling: the FOXO family member DAF-16 and the heat shock factor HSF-1. This effect involved the downregulation of an aquaporin glycerol channel, aqp-1. We show that changes in glycerol metabolism are likely to underlie the life span-shortening effect of glucose ...
Source: Cell Metabolism - November 1, 2009 Category: Cytology Authors: Lee SJ, Murphy CT, Kenyon C Tags: Cell Metab Source Type: journals

FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The nuclear bile acid receptor FXR is critical for regulation of lipid and glucose metabolism. Here, we report that FXR is a target of SIRT1, a deacetylase that mediates nutritional and hormonal modulation of hepatic metabolism. Lysine 217 of FXR is the major acetylation site targeted by p300 and SIRT1. Acetylation of FXR increases its stability but inhibits heterodimerization with RXRalpha, DNA binding, and transactivation activity. Downregulation of hepatic SIRT1 increased FXR acetylation with deleterious metabolic outcomes. Surprisingly, in mouse models of metabolic disease, FXR interaction with SIRT1 and p300 was d...
Source: Cell Metabolism - November 1, 2009 Category: Cytology Authors: Kemper JK, Xiao Z, Ponugoti B, Miao J, Fang S, Kanamaluru D, Tsang S, Wu SY, Chiang CM, Veenstra TD Tags: Cell Metab Source Type: journals

Akt2 is required for hepatic lipid accumulation in models of insulin resistance.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Insulin drives the global anabolic response to nutrient ingestion, regulating both carbohydrate and lipid metabolism. Previous studies have demonstrated that Akt2/protein kinase B is critical to insulin's control of glucose metabolism, but its role in lipid metabolism has remained controversial. Here, we show that Akt2 is required for hepatic lipid accumulation in obese, insulin-resistant states induced by either leptin deficiency or high-fat diet feeding. Lep(ob/ob) mice lacking hepatic Akt2 failed to amass triglycerides in their livers, associated with and most likely due to a decrease in lipogenic gene expression an...
Source: Cell Metabolism - November 1, 2009 Category: Cytology Authors: Leavens KF, Easton RM, Shulman GI, Previs SF, Birnbaum MJ Tags: Cell Metab Source Type: journals

Hematopoietic cell-specific deletion of toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Chronic low-grade inflammation, particularly in adipose tissue, is an important modulator of obesity-induced insulin resistance. The Toll-like receptor 4 (Tlr4) is a key initiator of inflammatory responses in macrophages. We performed bone marrow transplantation (BMT) of Tlr4lps-del or control C57Bl/10J donor cells into irradiated wild-type C57Bl6 recipient mice to generate hematopoietic cell-specific Tlr4 deletion mutant (BMT-Tlr4(-/-)) and control (BMT-WT) mice. After 16 weeks of a high-fat diet (HFD), BMT-WT mice developed obesity, hyperinsulinemia, glucose intolerance, and insulin resistance. In contrast, BMT-Tlr4(...
Source: Cell Metabolism - November 1, 2009 Category: Cytology Authors: Saberi M, Woods NB, de Luca C, Schenk S, Lu JC, Bandyopadhyay G, Verma IM, Olefsky JM Tags: Cell Metab Source Type: journals

C. elegans major fats are stored in vesicles distinct from lysosome-related organelles.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Genetic conservation allows ancient features of fat storage endocrine pathways to be explored in C. elegans. Multiple studies have used Nile red or BODIPY-labeled fatty acids to identify regulators of fat mass. When mixed with their food, E. coli bacteria, Nile red, and BODIPY-labeled fatty acids stain multiple spherical cellular structures in the C. elegans major fat storage organ, the intestine. However, here we demonstrate that, in the conditions previously reported, the lysosome-related organelles stained by Nile red and BODIPY-labeled fatty acids are not the C. elegans major fat storage compartment. We show that t...
Source: Cell Metabolism - November 1, 2009 Category: Cytology Authors: O'Rourke EJ, Soukas AA, Carr CE, Ruvkun G Tags: Cell Metab Source Type: journals

Does hypothalamic inflammation cause obesity?Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Obesity-induced inflammation causes cellular resistance to both insulin and leptin. In this issue, Brüning and colleagues (Kleinridders et al., 2009) add to growing evidence that this response occurs in the hypothalamus, as well as in peripheral tissues, which helps to explain how high-fat feeding induces a gradual increase in defended body weight. PMID: 19808014 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - September 30, 2009 Category: Cytology Authors: Wisse BE, Schwartz MW Tags: Cell Metab Source Type: journals

Leptin's RIGHT turn to the brain stem.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In a paper by Yadav and colleagues, a novel pathway linking the central nervous system effects of leptin on bone mass and energy expenditure to serotonin signaling in brainstem circuits is described. The data from those studies strengthen the tenet that skeletal remodeling is intimately connected to central regulation of metabolism. PMID: 19808015 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - September 30, 2009 Category: Cytology Authors: Rosen CJ Tags: Cell Metab Source Type: journals

A new wrinkle in the fold: hepcidin links inflammation to the unfolded protein response.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The unfolded protein response (UPR) coordinates translational and transcriptional changes triggered by unfolded proteins within the endoplasmic reticulum. Two recent papers (Oliveira et al., 2009; Vecchi et al., 2009) show that the UPR modulates transcription of the hormone hepcidin, which controls plasma iron levels and perhaps innate immunity. PMID: 19808016 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - September 30, 2009 Category: Cytology Authors: De Domenico I, Kaplan J Tags: Cell Metab Source Type: journals

Translate this ... during dietary restriction.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Several studies indicate that reduced TOR signaling underlies life span extension by dietary restriction. Recently, Zid et al. (Zid et al., 2009) linked the benefits of dietary restriction in flies to increased levels of the downstream TOR target 4E-BP1 and corresponding changes in the relative translation rates of classes of mRNAs. PMID: 19808017 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - September 30, 2009 Category: Cytology Authors: Kennedy BK, Mackay VL Tags: Cell Metab Source Type: journals

MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Obesity-associated activation of inflammatory pathways represents a key step in the development of insulin resistance in peripheral organs, partially via activation of TLR4 signaling by fatty acids. Here, we demonstrate that palmitate acting in the central nervous system (CNS) inhibits leptin-induced anorexia and Stat3 activation. To determine the functional significance of TLR signaling in the CNS in the development of leptin resistance and diet-induced obesity in vivo, we have characterized mice deficient for the TLR adaptor molecule MyD88 in the CNS (MyD88(DeltaCNS)). Compared to control mice, MyD88(DeltaCNS) mice a...
Source: Cell Metabolism - September 30, 2009 Category: Cytology Authors: Kleinridders A, Schenten D, Könner AC, Belgardt BF, Mauer J, Okamura T, Wunderlich FT, Medzhitov R, Brüning JC Tags: Cell Metab Source Type: journals

Reactive oxygen species enhance insulin sensitivity.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Chronic reactive oxygen species (ROS) production by mitochondria may contribute to the development of insulin resistance, a primary feature of type 2 diabetes. In recent years it has become apparent that ROS generation in response to physiological stimuli such as insulin may also facilitate signaling by reversibly oxidizing and inhibiting protein tyrosine phosphatases (PTPs). Here we report that mice lacking one of the key enzymes involved in the elimination of physiological ROS, glutathione peroxidase 1 (Gpx1), were protected from high-fat-diet-induced insulin resistance. The increased insulin sensitivity in Gpx1(-/-)...
Source: Cell Metabolism - September 30, 2009 Category: Cytology Authors: Loh K, Deng H, Fukushima A, Cai X, Boivin B, Galic S, Bruce C, Shields BJ, Skiba B, Ooms LM, Stepto N, Wu B, Mitchell CA, Tonks NK, Watt MJ, Febbraio MA, Crack PJ, Andrikopoulos S, Tiganis T Tags: Cell Metab Source Type: journals

MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Repression of mitochondrial respiration represents an evolutionarily ancient cellular adaptation to hypoxia and profoundly influences cell survival and function; however, the underlying molecular mechanisms are incompletely understood. Primarily utilizing pulmonary arterial endothelial cells as a representative hypoxic cell type, we identify the iron-sulfur cluster assembly proteins (ISCU1/2) as direct targets for repression by the hypoxia-induced microRNA-210 (miR-210). ISCU1/2 facilitate the assembly of iron-sulfur clusters, prosthetic groups that are critical for electron transport and mitochondrial oxidation-reduct...
Source: Cell Metabolism - September 30, 2009 Category: Cytology Authors: Chan SY, Zhang YY, Hemann C, Mahoney CE, Zweier JL, Loscalzo J Tags: Cell Metab Source Type: journals

Loss of Lkb1 in adult beta cells increases beta cell mass and enhances glucose tolerance in mice.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The Lkb1 tumor suppressor exerts its biological effects through phosphorylation and consequent activation of the AMP kinase (AMPK) family. Extensive genetic and biochemical evidence supports a role for Lkb1 in cell cycle arrest, establishment of cell polarity, and cellular energy metabolism. However, the role of Lkb1 and the AMPK family in beta cell function in vivo has not been established. We generated conditional knockout mice with a deletion of the Lkb1 gene in the beta cell compartment of pancreatic islets; these mice display improved glucose tolerance and protection against diet-induced hyperglycemia. Lkb1(-/-) b...
Source: Cell Metabolism - September 30, 2009 Category: Cytology Authors: Fu A, Ng AC, Depatie C, Wijesekara N, He Y, Wang GS, Bardeesy N, Scott FW, Touyz RM, Wheeler MB, Screaton RA Tags: Cell Metab Source Type: journals

LKB1 regulates pancreatic beta cell size, polarity, and function.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Pancreatic beta cells, organized in the islets of Langerhans, sense glucose and secrete appropriate amounts of insulin. We have studied the roles of LKB1, a conserved kinase implicated in the control of cell polarity and energy metabolism, in adult beta cells. LKB1-deficient beta cells show a dramatic increase in insulin secretion in vivo. Histologically, LKB1-deficient beta cells have striking alterations in the localization of the nucleus and cilia relative to blood vessels, suggesting a shift from hepatocyte-like to columnar polarity. Additionally, LKB1 deficiency causes a 65% increase in beta cell volume. We show t...
Source: Cell Metabolism - September 30, 2009 Category: Cytology Authors: Granot Z, Swisa A, Magenheim J, Stolovich-Rain M, Fujimoto W, Manduchi E, Miki T, Lennerz JK, Stoeckert CJ, Meyuhas O, Seino S, Permutt MA, Piwnica-Worms H, Bardeesy N, Dor Y Tags: Cell Metab Source Type: journals

Suppression of sulfonylurea- and glucose-induced insulin secretion in vitro and in vivo in mice lacking the chloride transport protein ClC-3.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Priming of insulin secretory granules for release requires intragranular acidification and depends on vesicular Cl(-)-fluxes, but the identity of the chloride transporter/ion channel involved is unknown. We tested the hypothesis that the chloride transport protein ClC-3 fulfills these actions in pancreatic beta cells. In ClC-3(-/-) mice, insulin secretion evoked by membrane depolarization (high extracellular K(+), sulfonylureas), or glucose was >60% reduced compared to WT animals. This effect was mirrored by a approximately 80% reduction in depolarization-evoked beta cell exocytosis (monitored as increases in cell c...
Source: Cell Metabolism - September 30, 2009 Category: Cytology Authors: Li DQ, Jing X, Salehi A, Collins SC, Hoppa MB, Rosengren AH, Zhang E, Lundquist I, Olofsson CS, Mörgelin M, Eliasson L, Rorsman P, Renström E Tags: Cell Metab Source Type: journals

The granular chloride channel ClC-3 is permissive for insulin secretion.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study, immuno-EM of beta cells revealed colocalization of ClC-3 and insulin on secretory granules. Clcn3(-/-) mice as well as isolated islets demonstrate impaired insulin secretion; Clcn3(-/-) beta cells are defective in regulated insulin exocytosis and granular acidification. Increased amounts of proinsulin were found in the majority of secretory granules in the Clcn3(-/-) mice, while in Clcn3(+/+) cells, proinsulin was confined to the immature secretory granules. These results demonstrate that in pancreatic beta cells, chloride channels, specifically ClC-3, are localized on insulin granules and play a role in ins...
Source: Cell Metabolism - September 30, 2009 Category: Cytology Authors: Deriy LV, Gomez EA, Jacobson DA, Wang X, Hopson JA, Liu XY, Zhang G, Bindokas VP, Philipson LH, Nelson DJ Tags: Cell Metab Source Type: journals

Proteome differences between brown and white fat mitochondria reveal specialized metabolic functions.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Mitochondria are functionally specialized in different tissues, and a detailed understanding of this specialization is important to elucidate mitochondrial involvement in normal physiology and disease. In adaptive thermogenesis, brown fat converts mitochondrial energy to heat, whereas tissue-specific functions of mitochondria in white fat are less characterized. Here we apply high-resolution quantitative mass spectrometry to directly and accurately compare the in vivo mouse mitochondrial proteomes of brown and white adipocytes. Their proteomes are substantially different qualitatively and quantitatively and are further...
Source: Cell Metabolism - September 30, 2009 Category: Cytology Authors: Forner F, Kumar C, Luber CA, Fromme T, Klingenspor M, Mann M Tags: Cell Metab Source Type: journals

Getting a "Hold" on NPC2.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Lipoprotein cholesterol is mobilized from lysosomes by actions of the NPC1 and NPC2 proteins. In this issue of Cell Metabolism, Harrison et al. report on identification of an NPC2-interacting protein, the Nogo-B receptor, that regulates NPC2 protein levels. NPC2 stabilization may represent a novel mechanism through which cells respond to endocytosed cholesterol. PMID: 19723490 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - August 31, 2009 Category: Cytology Authors: Ory DS Tags: Cell Metab Source Type: journals

Bile acids have the gall to function as hormones.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this issue of Cell Metabolism, Thomas et al. (2009) show that specific activation of the bile-acid-activated G protein-coupled receptor TGR5 improves pancreatic and hepatic function and impairs the development of obesity following administration of a high-fat diet. PMID: 19723491 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - August 31, 2009 Category: Cytology Authors: Vallim TQ, Edwards PA Tags: Cell Metab Source Type: journals

Metabolism by remote control.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Drosophila melanogaster produce insulin-like peptides in specialized neuroendocrine cells to regulate growth, metabolism, aging, and reproduction. In this issue of Cell Metabolism, Géminard et al. (2009) describe how secretion of insulin-like peptides is remotely controlled by the fat body (an adipose, liver-like tissue) in response to dietary amino acids. PMID: 19723492 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - August 31, 2009 Category: Cytology Authors: Tatar M Tags: Cell Metab Source Type: journals

TGR5-mediated bile acid sensing controls glucose homeostasis.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
TGR5 is a G protein-coupled receptor expressed in brown adipose tissue and muscle, where its activation by bile acids triggers an increase in energy expenditure and attenuates diet-induced obesity. Using a combination of pharmacological and genetic gain- and loss-of-function studies in vivo, we show here that TGR5 signaling induces intestinal glucagon-like peptide-1 (GLP-1) release, leading to improved liver and pancreatic function and enhanced glucose tolerance in obese mice. In addition, we show that the induction of GLP-1 release in enteroendocrine cells by 6alpha-ethyl-23(S)-methyl-cholic acid (EMCA, INT-777), a sp...
Source: Cell Metabolism - August 31, 2009 Category: Cytology Authors: Thomas C, Gioiello A, Noriega L, Strehle A, Oury J, Rizzo G, Macchiarulo A, Yamamoto H, Mataki C, Pruzanski M, Pellicciari R, Auwerx J, Schoonjans K Tags: Cell Metab Source Type: journals

Angiopoietin-like protein 2 promotes chronic adipose tissue inflammation and obesity-related systemic insulin resistance.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
, Oike Y Recent studies of obesity have provided new insights into the mechanisms underlying insulin resistance and metabolic dysregulation. Numerous efforts have been made to identify key regulators of obesity-linked adipose tissue inflammation and insulin resistance. We found that angiopoietin-like protein 2 (Angptl2) was secreted by adipose tissue and that its circulating level was closely related to adiposity, systemic insulin resistance, and inflammation in both mice and humans. Angptl2 activated an inflammatory cascade in endothelial cells via integrin signaling and induced chemotaxis of monocytes/macrophages. Co...
Source: Cell Metabolism - August 31, 2009 Category: Cytology Authors: Tabata M, Kadomatsu T, Fukuhara S, Miyata K, Ito Y, Endo M, Urano T, Zhu HJ, Tsukano H, Tazume H, Kaikita K, Miyashita K, Iwawaki T, Shimabukuro M, Sakaguchi K, Ito T, Nakagata N, Yamada T, Katagiri H, Kasuga M, Ando Y, Ogawa H, Mochizuki N, Itoh H, Suda Tags: Cell Metab Source Type: journals

Non-CpG methylation of the PGC-1alpha promoter through DNMT3B controls mitochondrial density.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Epigenetic modification through DNA methylation is implicated in metabolic disease. Using whole-genome promoter methylation analysis of skeletal muscle from normal glucose-tolerant and type 2 diabetic subjects, we identified cytosine hypermethylation of peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator-1 alpha (PGC-1alpha) in diabetic subjects. Methylation levels were negatively correlated with PGC-1alpha mRNA and mitochondrial DNA (mtDNA). Bisulfite sequencing revealed that the highest proportion of cytosine methylation within PGC-1alpha was found within non-CpG nucleotides. Non-CpG methylation ...
Source: Cell Metabolism - August 31, 2009 Category: Cytology Authors: Barrès R, Osler ME, Yan J, Rune A, Fritz T, Caidahl K, Krook A, Zierath JR Tags: Cell Metab Source Type: journals

Remote control of insulin secretion by fat cells in Drosophila.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Insulin-like peptides (ILPs) couple growth, metabolism, longevity, and fertility with changes in nutritional availability. In Drosophila, several ILPs called Dilps are produced by the brain insulin-producing cells (IPCs), from which they are released into the hemolymph and act systemically. We show here that in response to nutrient deprivation, brain Dilps are no longer secreted and accumulate in the IPCs. We further demonstrate that the larval fat body, a functional homolog of vertebrate liver and white fat, couples the level of circulating Dilps with dietary amino acid levels by remotely controlling Dilp release thro...
Source: Cell Metabolism - August 31, 2009 Category: Cytology Authors: Géminard C, Rulifson EJ, Léopold P Tags: Cell Metab Source Type: journals

Nogo-B receptor stabilizes Niemann-Pick type C2 protein and regulates intracellular cholesterol trafficking.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The Nogo-B receptor (NgBR) is a recently identified receptor for the N terminus of reticulon 4B/Nogo-B. Other than its role in binding Nogo-B, little is known about the biology of NgBR. To elucidate a basic cellular role for NgBR, we performed a yeast two-hybrid screen for interacting proteins, using the C-terminal domain as bait, and identified Niemann-Pick type C2 protein (NPC2) as an NgBR-interacting protein. NPC2 protein levels are increased in the presence of NgBR, and NgBR enhances NPC2 protein stability. NgBR localizes primarily to the endoplasmic reticulum (ER) and regulates the stability of nascent NPC2. RNAi-...
Source: Cell Metabolism - August 31, 2009 Category: Cytology Authors: Harrison KD, Miao RQ, Fernandez-Hernándo C, Suárez Y, Dávalos A, Sessa WC Tags: Cell Metab Source Type: journals

Ablation of neutral cholesterol ester hydrolase 1 accelerates atherosclerosis.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Cholesterol ester (CE)-laden macrophage foam cells are the hallmark of atherosclerosis, and the hydrolysis of intracellular CE is one of the key steps in foam cell formation. Although hormone-sensitive lipase (LIPE) and cholesterol ester hydrolase (CEH), which is identical to carboxylsterase 1 (CES1, hCE1), were proposed to mediate the neutral CE hydrolase (nCEH) activity in macrophages, recent evidences have suggested the involvement of other enzymes. We have recently reported the identification of a candidate, neutral cholesterol ester hydrolase 1(Nceh1). Here we demonstrate that genetic ablation of Nceh1 promotes fo...
Source: Cell Metabolism - August 31, 2009 Category: Cytology Authors: Sekiya M, Osuga J, Nagashima S, Ohshiro T, Igarashi M, Okazaki H, Takahashi M, Tazoe F, Wada T, Ohta K, Takanashi M, Kumagai M, Nishi M, Takase S, Yahagi N, Yagyu H, Ohashi K, Nagai R, Kadowaki T, Furukawa Y, Ishibashi S Tags: Cell Metab Source Type: journals

T lymphocytes amplify the anabolic activity of parathyroid hormone through Wnt10b signaling.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Intermittent administration of parathyroid hormone (iPTH) is used to treat osteoporosis because it improves bone architecture and strength, but the underlying cellular and molecular mechanisms are unclear. Here, we show that iPTH increases the production of Wnt10b by bone marrow CD8+ T cells and induces these lymphocytes to activate canonical Wnt signaling in preosteoblasts. Accordingly, in responses to iPTH, T cell null mice display diminished Wnt signaling in preosteoblasts and blunted osteoblastic commitment, proliferation, differentiation, and life span, which result in decreased trabecular bone anabolism and no in...
Source: Cell Metabolism - August 31, 2009 Category: Cytology Authors: Terauchi M, Li JY, Bedi B, Baek KH, Tawfeek H, Galley S, Gilbert L, Nanes MS, Zayzafoon M, Guldberg R, Lamar DL, Singer MA, Lane TF, Kronenberg HM, Weitzmann MN, Pacifici R Tags: Cell Metab Source Type: journals

Leptin: taking the path less traveled.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The metabolic hormone leptin influences feeding and metabolism through action on a distributed brain network. In this issue, Leinninger et al. (2009) describe a novel lateral hypothalamic neuronal population that is responsive to leptin and interfaces with dopamine circuits. PMID: 19656482 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - July 31, 2009 Category: Cytology Authors: DiLeone RJ Tags: Cell Metab Source Type: journals

Walk the (germ) line.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Germ cells possess the unique ability to transmit genetic information from generation to generation. In a recent paper, Curran et al. (2009) explore the possibility that some features of germ cells, including enhanced genomic stability, can be acquired by the soma as a mechanism to increase longevity. PMID: 19656483 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - July 31, 2009 Category: Cytology Authors: Jones DL Tags: Cell Metab Source Type: journals

Tangled up in red: intertwining of the heme and iron-sulfur cluster biogenesis pathways.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
A large-scale computational and genetic analysis study by Nilsson et al. (2009) has identified five genes that coexpress with heme biosynthetic enzymes and are required for normal heme synthesis. Several are implicated in iron-sulfur cluster biogenesis, and malfunction of these genes may repress heme synthesis by activating the IRE/IRP posttranscriptional regulatory system. PMID: 19656484 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - July 31, 2009 Category: Cytology Authors: Rouault TA, Tong WH Tags: Cell Metab Source Type: journals

From GH to Billy Ghrelin.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The octanoylated peptide hormone ghrelin regulates episodic growth hormone release and energy balance. Work in genetically modified mice (Kirchner et al., 2009) now shows that in vivo activity of ghrelin O-acyltransferase (GOAT), responsible for ghrelin octanoylation, decreases during fasting but increases after ingesting medium-chain fatty acid triglycerides (MCT). PMID: 19656485 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - July 31, 2009 Category: Cytology Authors: Smith RG Tags: Cell Metab Source Type: journals

Regulation of intestinal iron absorption: the mucosa takes control?Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Two studies (Shah et al., 2009; Mastrogiannaki et al., 2009) show that the hypoxia inducible factor HIF-2alpha is a major player in regulating iron absorption by directly controlling the transcription of iron transporters in the intestine in response to changes in mucosal iron or oxygen levels. The HIF-2alpha mechanism has major effects on iron metabolism which can override the well-known hepcidin-ferroportin regulatory axis. PMID: 19656486 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - July 31, 2009 Category: Cytology Authors: Simpson RJ, McKie AT Tags: Cell Metab Source Type: journals

Leptin acts via leptin receptor-expressing lateral hypothalamic neurons to modulate the mesolimbic dopamine system and suppress feeding.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The lateral hypothalamic area (LHA) acts in concert with the ventral tegmental area (VTA) and other components of the mesolimbic dopamine (DA) system to control motivation, including the incentive to feed. The anorexigenic hormone leptin modulates the mesolimbic DA system, although the mechanisms underlying this control have remained incompletely understood. We show that leptin directly regulates a population of leptin receptor (LepRb)-expressing inhibitory neurons in the LHA and that leptin action via these LHA LepRb neurons decreases feeding and body weight. Furthermore, these LHA LepRb neurons innervate the VTA, and...
Source: Cell Metabolism - July 31, 2009 Category: Cytology Authors: Leinninger GM, Jo YH, Leshan RL, Louis GW, Yang H, Barrera JG, Wilson H, Opland DM, Faouzi MA, Gong Y, Jones JC, Rhodes CJ, Chua S, Diano S, Horvath TL, Seeley RJ, Becker JB, Münzberg H, Myers MG Tags: Cell Metab Source Type: journals

Intestinal cholecystokinin controls glucose production through a neuronal network.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Cholecystokinin (CCK) is a peptide hormone that is released from the gut in response to nutrients such as lipids to lower food intake. Here we report that a primary increase of CCK-8, the biologically active form of CCK, in the duodenum lowers glucose production independent of changes in circulating insulin levels. Furthermore, we show that duodenal CCK-8 requires the activation of the gut CCK-A receptor and a gut-brain-liver neuronal axis to lower glucose production. Finally, duodenal CCK-8 fails to lower glucose production in the early onset of high-fat diet-induced insulin resistance. These findings reveal a role fo...
Source: Cell Metabolism - July 31, 2009 Category: Cytology Authors: Cheung GW, Kokorovic A, Lam CK, Chari M, Lam TK Tags: Cell Metab Source Type: journals

PDX1 deficiency causes mitochondrial dysfunction and defective insulin secretion through TFAM suppression.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Mutations in the transcription factor Pdx1 cause maturity-onset diabetes of the young 4 (MODY4). Islet transduction with dominant-negative Pdx1 (RIPDN79PDX1) impairs mitochondrial metabolism and glucose-stimulated insulin secretion (GSIS). Transcript profiling revealed suppression of nuclear-encoded mitochondrial factor A (TFAM). Herein, we show that Pdx1 suppression in adult mice reduces islet TFAM expression coinciding with hyperglycemia. We define TFAM as a direct target of Pdx1 both in rat INS1 cells and human islets. Adenoviral overexpression of TFAM along with RIPDN79PDX1 in isolated rat islets rescued mitochondr...
Source: Cell Metabolism - July 31, 2009 Category: Cytology Authors: Gauthier BR, Wiederkehr A, Baquié M, Dai C, Powers AC, Kerr-Conte J, Pattou F, MacDonald RJ, Ferrer J, Wollheim CB Tags: Cell Metab Source Type: journals

Discovery of genes essential for heme biosynthesis through large-scale gene expression analysis.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Heme biosynthesis consists of a series of eight enzymatic reactions that originate in mitochondria and continue in the cytosol before returning to mitochondria. Although these core enzymes are well studied, additional mitochondrial transporters and regulatory factors are predicted to be required. To discover such unknown components, we utilized a large-scale computational screen to identify mitochondrial proteins whose transcripts consistently coexpress with the core machinery of heme biosynthesis. We identified SLC25A39, SLC22A4, and TMEM14C, which are putative mitochondrial transporters, as well as C1orf69 and ISCA1,...
Source: Cell Metabolism - July 31, 2009 Category: Cytology Authors: Nilsson R, Schultz IJ, Pierce EL, Soltis KA, Naranuntarat A, Ward DM, Baughman JM, Paradkar PN, Kingsley PD, Culotta VC, Kaplan J, Palis J, Paw BH, Mootha VK Tags: Cell Metab Source Type: journals

Random point mutations with major effects on protein-coding genes are the driving force behind premature aging in mtDNA mutator mice.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We report that mitochondrial protein synthesis is unimpaired in mtDNA mutator mice consistent with the observed minor alterations of steady-state levels of mitochondrial transcripts. These findings refute recent claims that circular mtDNA molecules with large deletions are driving the premature aging phenotype. We further show that the stability of several respiratory chain complexes is severely impaired despite normal synthesis of the corresponding mtDNA-encoded subunits. Our findings reveal a mechanism for induction of aging phenotypes by demonstrating a causative role for amino acid substitutions in mtDNA-encoded respir...
Source: Cell Metabolism - July 31, 2009 Category: Cytology Authors: Edgar D, Shabalina I, Camara Y, Wredenberg A, Calvaruso MA, Nijtmans L, Nedergaard J, Cannon B, Larsson NG, Trifunovic A Tags: Cell Metab Source Type: journals

Cannabinoid receptor type 1 protects against age-related osteoporosis by regulating osteoblast and adipocyte differentiation in marrow stromal cells.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Age-related osteoporosis is characterized by reduced bone formation and accumulation of fat in the bone marrow compartment. Here, we report that the type 1 cannabinoid receptor (CB1) regulates this process. Mice with CB1 deficiency (CB1(-/-)) had increased peak bone mass due to reduced bone resorption, but developed age-related osteoporosis with reduced bone formation and accumulation of adipocytes in the bone marrow space. Marrow stromal cells from CB1(-/-) mice had an enhanced capacity for adipocyte differentiation, a reduced capacity for osteoblast differentiation, and increased expression of phosphorylated CREB (pC...
Source: Cell Metabolism - July 31, 2009 Category: Cytology Authors: Idris AI, Sophocleous A, Landao-Bassonga E, Canals M, Milligan G, Baker D, van't Hof RJ, Ralston SH Tags: Cell Metab Source Type: journals

PET imaging of leptin biodistribution and metabolism in rodents and primates.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We have determined the systemic biodistribution of the hormone leptin by PET imaging. PET imaging using (18)F- and (68)Ga-labeled leptin revealed that, in mouse, the hormone was rapidly taken up by megalin (gp330/LRP2), a multiligand endocytic receptor localized in renal tubules. In addition, in rhesus monkeys, 15% of labeled leptin localized to red bone marrow, which was consistent with hormone uptake in rodent tissues. These data confirm a megalin-dependent mechanism for renal uptake in vivo. The significant binding to immune cells and blood cell precursors in bone marrow is also consistent with prior evidence showin...
Source: Cell Metabolism - July 31, 2009 Category: Cytology Authors: Ceccarini G, Flavell RR, Butelman ER, Synan M, Willnow TE, Bar-Dagan M, Goldsmith SJ, Kreek MJ, Kothari P, Vallabhajosula S, Muir TW, Friedman JM Tags: Cell Metab Source Type: journals

Beta testing the antioxidant function of eIF2alpha phosphorylation in diabetes prevention.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this issue of Cell Metabolism, Kaufman and colleagues (Back et al., 2009) elegantly demonstrate that appropriate regulation of eIF2alpha phosphorylation improves glucose tolerance and beta cell viability by preventing the lethal buildup of oxidative damage due to unregulated synthesis, trafficking, and misfolding of proteins. PMID: 19583945 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - June 30, 2009 Category: Cytology Authors: Wek RC, Anthony TG Tags: Cell Metab Source Type: journals

Spreading the wealth: Niemann-Pick type C proteins bind and transport cholesterol.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Endocytosed cholesterol must be transferred from the environment (e.g., low-density lipoproteins) via the lysosomal system to the rest of the cell. In Niemann-Pick type C disease, this process fails. In a recent issue of Cell, Kwon et al. (2009) suggest how this transpires mechanistically by crystallizing a domain of a protein defective in this syndrome. PMID: 19583946 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - June 30, 2009 Category: Cytology Authors: Munkacsi AB, Pentchev PG, Sturley SL Tags: Cell Metab Source Type: journals

A crystallized view of AMPK activation.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
AMP-activated protein kinase (AMPK) is a key metabolic regulator. Recent work (Chen et al., 2009) elucidates the structural interaction between the autoinhibitory sequence and the kinase domain of the AMPK catalytic subunit. Enhanced understanding of the molecular mechanics of AMPK activation might lead to novel therapeutic approaches. PMID: 19583947 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - June 30, 2009 Category: Cytology Authors: Young LH Tags: Cell Metab Source Type: journals

The gutsy side of bone.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Though surgical removal of the stomach has long been linked to low bone mass, the molecular mechanism has been elusive. Amling and coworkers now demonstrate that gastric cell acid production is necessary for calcium absorption. Mice lacking this acidification develop hypocalcemia, with increased parathyroid hormone and osteoclast differentiation, and decreased bone mass. PMID: 19583948 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - June 30, 2009 Category: Cytology Authors: Ferron M, Karsenty G Tags: Cell Metab Source Type: journals

As a matter of fat.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Excess fatty acid accumulation in nonadipose tissues is a hallmark of metabolic disease. When elevated lipid levels exceed the cell's capacity to store or utilize fatty acids, a lipotoxic-response is elicited, characterized by destruction of organelle membranes, activation of stress pathways, and apoptosis. This Minireview focuses on the mechanisms by which lipid overload causes nonadipose cell death and contributes to the pathogenesis of obesity and diabetes. PMID: 19583949 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - June 30, 2009 Category: Cytology Authors: Brookheart RT, Michel CI, Schaffer JE Tags: Cell Metab Source Type: journals

Translation attenuation through eIF2alpha phosphorylation prevents oxidative stress and maintains the differentiated state in beta cells.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Accumulation of unfolded protein within the endoplasmic reticulum (ER) attenuates mRNA translation through PERK-mediated phosphorylation of eukaryotic initiation factor 2 on Ser51 of the alpha subunit (eIF2alpha). To elucidate the role of eIF2alpha phosphorylation, we engineered mice for conditional expression of homozygous Ser51Ala mutant eIF2alpha. The absence of eIF2alpha phosphorylation in beta cells caused a severe diabetic phenotype due to heightened and unregulated proinsulin translation; defective intracellular trafficking of ER cargo proteins; increased oxidative damage; reduced expression of stress response a...
Source: Cell Metabolism - June 30, 2009 Category: Cytology Authors: Back SH, Scheuner D, Han J, Song B, Ribick M, Wang J, Gildersleeve RD, Pennathur S, Kaufman RJ Tags: Cell Metab Source Type: journals