AJP Endocrinology and Metabolism

Mahmoud A. Mohammad , Darryl L. Hadsell , and Morey W. Haymond

doi: 10.1152/ajpendo.00175.2012pmid: 22649065

Lactose synthesis is believed to be rate limiting for milk production. However, understanding the molecular events controlling lactose synthesis in humans is still rudimentary. We have utilized our established model of the RNA isolated from breast milk fat globule from seven healthy, exclusively breastfeeding women from 6 h to 42 days following delivery to determine the temporal coordination of changes in gene expression in the carbohydrate metabolic processes emphasizing the lactose synthesis pathway in human mammary epithelial cell. We showed that milk lactose concentrations increased from 75 to 200 mM from 6 to 96 h. Milk progesterone concentrations fell by 65% at 24 h and were undetectable by day 3 . Milk prolactin peaked at 36 h and then declined progressively afterward. In concordance with lactose synthesis, gene expression of galactose kinase 2, UDP-glucose pyrophosphorylase 2 (UGP2), and phosphoglucomutase 1 increased 18-, 10-, and threefold, respectively, between 6 and 72 h. Between 6 and 96 h, gene expression of UDP-galactose transporter 2 (SLC35A2) increased threefold, whereas glucose transporter 1 was unchanged. Gene expression of lactose synthase no. 3 increased 1.7-fold by 96 h, whereas α-lactalbumin did not change over the entire study duration. Gene expression of prolactin receptor (PRLR) and its downstream signal transducer and activator of transcription complex 5 (STAT5) were increased 10- and 2.5-fold, respectively, by 72 h. In summary, lactose synthesis paralleled the induction of gene expression of proteins involved in UDP-galactose synthesis and transport, suggesting that they are potentially rate limiting in lactose synthesis and thus milk production. Progesterone withdrawal may be the signal that triggers PRLR signaling via STAT5, which may in turn induce UGP2 and SLC35A2 expression. fat globule lactose synthesis glucose metabolism microarray « Previous | Next Article » Table of Contents This Article Published online before print May 29, 2012 , doi: 10.​1152/​ajpendo.​00175.​2012 AJP - Endo August 1, 2012 vol. 303 no. 3 E365-E376 » Abstract Free Full Text Free to you Full Text (PDF) Free to you All Versions of this Article: ajpendo.00175.2012v1 303/3/E365 most recent Classifications Article Services Email this article to a friend Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Citing articles via Web of Science Google Scholar Articles by Mohammad, M. A. Articles by Haymond, M. W. PubMed PubMed citation Articles by Mohammad, M. A. Articles by Haymond, M. W. Related Content Load related web page information Current Content August 1, 2012 Alert me to new issues of AJP - Endo About the Journal Calls for Papers Information for Authors Submit a Manuscript Ethical Policies AuthorChoice PubMed Central Policy Reprints and Permissions Advertising Press Copyright © 2012 the American Physiological Society Print ISSN: 0193-1849 Online ISSN: 1522-1555

Jonathan C. Jun , Mi-Kyung Shin , Qiaoling Yao , Shannon Bevans-Fonti , James Poole , Luciano F. Drager , and Vsevolod Y. Polotsky

doi: 10.1152/ajpendo.00641.2011pmid: 22621867

Obstructive sleep apnea (OSA) induces intermittent hypoxia (IH) during sleep and is associated with elevated triglycerides (TG). We previously demonstrated that mice exposed to chronic IH develop elevated TG. We now hypothesize that a single exposure to acute hypoxia also increases TG due to the stimulation of free fatty acid (FFA) mobilization from white adipose tissue (WAT), resulting in increased hepatic TG synthesis and secretion. Male C57BL6/J mice were exposed to FiO 2 = 0.21, 0.17, 0.14, 0.10, or 0.07 for 6 h followed by assessment of plasma and liver TG, glucose, FFA, ketones, glycerol, and catecholamines. Hypoxia dose-dependently increased plasma TG, with levels peaking at FiO 2 = 0.07. Hepatic TG levels also increased with hypoxia, peaking at FiO 2 = 0.10. Plasma catecholamines also increased inversely with FiO 2 . Plasma ketones, glycerol, and FFA levels were more variable, with different degrees of hypoxia inducing WAT lipolysis and ketosis. FiO 2 = 0.10 exposure stimulated WAT lipolysis but decreased the rate of hepatic TG secretion. This degree of hypoxia rapidly and reversibly delayed TG clearance while decreasing ( 3 H)triolein-labeled Intralipid uptake in brown adipose tissue and WAT. Hypoxia decreased adipose tissue lipoprotein lipase (LPL) activity in brown adipose tissue and WAT. In addition, hypoxia decreased the transcription of LPL, peroxisome proliferator-activated receptor-γ, and fatty acid transporter CD36. We conclude that acute hypoxia increases plasma TG due to decreased tissue uptake, not increased hepatic TG secretion. lipolysis lipases adipose thermoregulation metabolism Copyright © 2012 the American Physiological Society « Previous | Next Article » Table of Contents This Article Published online before print May 22, 2012 , doi: 10.​1152/​ajpendo.​00641.​2011 AJP - Endo August 1, 2012 vol. 303 no. 3 E377-E388 » Abstract Free Full Text Free to you Full Text (PDF) Free to you All Versions of this Article: ajpendo.00641.2011v1 303/3/E377 most recent Classifications Article Services Email this article to a friend Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Citing articles via Web of Science Google Scholar Articles by Jun, J. C. Articles by Polotsky, V. Y. PubMed PubMed citation Articles by Jun, J. C. Articles by Polotsky, V. Y. Related Content Load related web page information Current Content August 1, 2012 Alert me to new issues of AJP - Endo About the Journal Calls for Papers Information for Authors Submit a Manuscript Ethical Policies AuthorChoice PubMed Central Policy Reprints and Permissions Advertising Press Copyright © 2012 the American Physiological Society Print ISSN: 0193-1849 Online ISSN: 1522-1555

Kinning Poon , Jessica R. Barson , Shawn E. Fagan , and Sarah F. Leibowitz

doi: 10.1152/ajpendo.00238.2012pmid: 22693204

Maternal consumption of a fat-rich diet during pregnancy, which causes later overeating and weight gain in offspring, has been shown to stimulate neurogenesis and increase hypothalamic expression of orexigenic neuropeptides in these postnatal offspring. The studies here, using an in vitro model that mimics in vivo characteristics after prenatal high-fat diet (HFD) exposure, investigate whether these same peptide changes occur in embryos and if they are specific to neurons. Isolated hypothalamic neurons were compared with whole hypothalamus from embryonic day 19 (E19) embryos that were prenatally exposed to HFD and were both found to show similar increases in mRNA expression of enkephalin (ENK) and neuropeptide Y (NPY) compared with that of chow-exposed embryos, with no change in melanin-concentrating hormone, orexin, or galanin. Further examination using immunofluorescence cytochemistry revealed an increase in the number of cells expressing ENK and NPY. By plotting the fluorescence intensity of each cell as a probability density function, three different populations of neurons with low, medium, or high levels of ENK or NPY were found in both HFD and chow groups. The prenatal HFD shifted the density of neurons from the population containing low peptide levels to the population containing high peptide levels. This study indicates that neuronal culture is a useful in vitro system for studying diet effects on neuronal development and shows that prenatal HFD exposure alters the population of hypothalamic neurons containing ENK and NPY in the embryo. These changes may contribute to the increase in HFD intake and body weight observed in offspring. prenatal high-fat diet hypothalamus cell culture enkephalin neuropeptide Y Copyright © 2012 the American Physiological Society « Previous Table of Contents This Article Published online before print June 12, 2012 , doi: 10.​1152/​ajpendo.​00238.​2012 AJP - Endo August 1, 2012 vol. 303 no. 3 E432-E441 » Abstract Free Full Text Free to you Full Text (PDF) Free to you All Versions of this Article: ajpendo.00238.2012v1 303/3/E432 most recent Classifications Article Services Email this article to a friend Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Citing articles via Web of Science Google Scholar Articles by Poon, K. Articles by Leibowitz, S. F. PubMed PubMed citation Articles by Poon, K. Articles by Leibowitz, S. F. Related Content Load related web page information Current Content August 1, 2012 Alert me to new issues of AJP - Endo About the Journal Calls for Papers Information for Authors Submit a Manuscript Ethical Policies AuthorChoice PubMed Central Policy Reprints and Permissions Advertising Press Copyright © 2012 the American Physiological Society Print ISSN: 0193-1849 Online ISSN: 1522-1555

Amanda T. White and Simon Schenk

doi: 10.1152/ajpendo.00054.2012pmid: 22436696

The pyridine nucleotides, NAD + and NADH, are coenzymes that provide oxidoreductive power for the generation of ATP by mitochondria. In skeletal muscle, exercise perturbs the levels of NAD + , NADH, and consequently, the NAD + /NADH ratio, and initial research in this area focused on the contribution of redox control to ATP production. More recently, numerous signaling pathways that are sensitive to perturbations in NAD + (H) have come to the fore, as has an appreciation for the potential importance of compartmentation of NAD + (H) metabolism and its subsequent effects on various signaling pathways. These pathways, which include the sirtuin (SIRT) proteins SIRT1 and SIRT3, the poly(ADP-ribose) polymerase (PARP) proteins PARP1 and PARP2, and COOH-terminal binding protein (CtBP), are of particular interest because they potentially link changes in cellular redox state to both immediate, metabolic-related changes and transcriptional adaptations to exercise. In this review, we discuss what is known, and not known, about the contribution of NAD + (H) metabolism and these aforementioned proteins to mitochondrial adaptations to acute and chronic endurance exercise. nicotinamide adenine dinucleotide sirtuin-1 sirtuin-3 poly(ADP-ribose) polymerase COOH-terminal binding protein Copyright © 2012 the American Physiological Society « Previous | Next Article » Table of Contents This Article Published online before print March 20, 2012 , doi: 10.​1152/​ajpendo.​00054.​2012 AJP - Endo August 1, 2012 vol. 303 no. 3 E308-E321 » Abstract Free Full Text Free Full Text (PDF) Free All Versions of this Article: ajpendo.00054.2012v1 ajpendo.00054.2012v2 303/3/E308 most recent Classifications Series: Intracellular Signal for Skeletal Muscle Adaptation Review Services Email this article to a friend Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Citing articles via Web of Science Google Scholar Articles by White, A. T. Articles by Schenk, S. PubMed PubMed citation Articles by White, A. T. Articles by Schenk, S. Related Content Load related web page information Current Content August 1, 2012 Alert me to new issues of AJP - Endo About the Journal Calls for Papers Information for Authors Submit a Manuscript Ethical Policies AuthorChoice PubMed Central Policy Reprints and Permissions Advertising Press Copyright © 2012 the American Physiological Society Print ISSN: 0193-1849 Online ISSN: 1522-1555

Glenn K. McConell , Stephen Rattigan , Robert S. Lee-Young , Glenn D. Wadley , and Troy L. Merry

doi: 10.1152/ajpendo.00667.2011pmid: 22550064

Nitric oxide (NO) is an important vasodilator and regulator in the cardiovascular system, and this link was the subject of a Nobel prize in 1998. However, NO also plays many other regulatory roles, including thrombosis, immune function, neural activity, and gastrointestinal function. Low concentrations of NO are thought to have important signaling effects. In contrast, high concentrations of NO can interact with reactive oxygen species, causing damage to cells and cellular components. A less-recognized site of NO production is within skeletal muscle, where small increases are thought to have beneficial effects such as regulating glucose uptake and possibly blood flow, but higher levels of production are thought to lead to deleterious effects such as an association with insulin resistance. This review will discuss the role of NO in skeletal muscle during and following exercise, including in mitochondrial biogenesis, muscle efficiency, and blood flow with a particular focus on its potential role in regulating skeletal muscle glucose uptake during exercise. nitric oxide glucose uptake blood flow oxygen consumption efficiency 5′-adenosine monophosphate-activated protein kinase contraction reactive oxygen species mitochondrial biogenesis metabolism Copyright © 2012 the American Physiological Society « Previous | Next Article » Table of Contents This Article Published online before print May 1, 2012 , doi: 10.​1152/​ajpendo.​00667.​2011 AJP - Endo August 1, 2012 vol. 303 no. 3 E301-E307 » Abstract Free Full Text Free Full Text (PDF) Free All Versions of this Article: ajpendo.00667.2011v1 303/3/E301 most recent Classifications Series: Intracellular Signal for Skeletal Muscle Adaptation Review Services Email this article to a friend Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Citing articles via Web of Science Google Scholar Articles by McConell, G. K. Articles by Merry, T. L. PubMed PubMed citation Articles by McConell, G. K. Articles by Merry, T. L. Related Content Load related web page information Current Content August 1, 2012 Alert me to new issues of AJP - Endo About the Journal Calls for Papers Information for Authors Submit a Manuscript Ethical Policies AuthorChoice PubMed Central Policy Reprints and Permissions Advertising Press Copyright © 2012 the American Physiological Society Print ISSN: 0193-1849 Online ISSN: 1522-1555

Laura D. Brown , Paul J. Rozance , Stephanie R. Thorn , Jacob E. Friedman , and William W. Hay, Jr.

doi: 10.1152/ajpendo.00059.2012pmid: 22649066

Placental insufficiency decreases fetal amino acid uptake from the placenta, plasma insulin concentrations, and protein accretion, thus compromising normal fetal growth trajectory. We tested whether acute supplementation of amino acids or insulin into the fetus with intrauterine growth restriction (IUGR) would increase net fetal protein accretion rates. Late-gestation IUGR and control (CON) fetal sheep received acute, 3-h infusions of amino acids (with euinsulinemia), insulin (with euglycemia and euaminoacidemia), or saline. Fetal leucine metabolism was measured under steady-state conditions followed by a fetal muscle biopsy to quantify insulin signaling. In CON, increasing amino acid delivery rates to the fetus by 100% increased leucine oxidation rates by 100%. In IUGR, amino acid infusion completely suppressed fetal protein breakdown rates but increased leucine oxidation rate by only 25%, resulting in increased protein accretion rates by 150%. Acute insulin infusion, however, had very little effect on amino acid delivery rates, fetal leucine disposal rates, or fetal protein accretion rates in CON or IUGR fetuses despite robust signaling of the fetal skeletal muscle insulin-signaling cascade. These results indicate that, when amino acids are given directly into the fetal circulation independently of changes in insulin concentrations, IUGR fetal sheep have suppressed protein breakdown rates, thus increasing net fetal protein accretion. intrauterine growth restriction insulin signaling fetal muscle protein synthesis insulin leucine Copyright © 2012 the American Physiological Society « Previous | Next Article » Table of Contents This Article Published online before print May 29, 2012 , doi: 10.​1152/​ajpendo.​00059.​2012 AJP - Endo August 1, 2012 vol. 303 no. 3 E352-E364 » Abstract Free Full Text Free to you Full Text (PDF) Free to you All Versions of this Article: ajpendo.00059.2012v1 303/3/E352 most recent Classifications Article Services Email this article to a friend Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Citing articles via Web of Science Google Scholar Articles by Brown, L. D. Articles by Hay, W. W. PubMed PubMed citation Articles by Brown, L. D. Articles by Hay, W. W. Related Content Load related web page information Current Content August 1, 2012 Alert me to new issues of AJP - Endo About the Journal Calls for Papers Information for Authors Submit a Manuscript Ethical Policies AuthorChoice PubMed Central Policy Reprints and Permissions Advertising Press Copyright © 2012 the American Physiological Society Print ISSN: 0193-1849 Online ISSN: 1522-1555

Xiaojun Ma , Yuezhen Lin , Ligen Lin , Guijun Qin , Fred A. Pereira , Morey W. Haymond , Nancy F. Butte , and Yuxiang Sun

doi: 10.1152/ajpendo.00576.2011pmid: 22669248

The orexigenic hormone ghrelin is important in diabetes because it has an inhibitory effect on insulin secretion. Ghrelin ablation in leptin-deficient ob/ob ( Ghrelin −/− : ob / ob ) mice increases insulin secretion and improves hyperglycemia. The physiologically relevant ghrelin receptor is the growth hormone secretagogue receptor (GHS-R), and GHS-R antagonists are thought to be an effective strategy for treating diabetes. However, since some of ghrelin's effects are independent of GHS-R, we have utilized genetic approaches to determine whether ghrelin's effect on insulin secretion is mediated through GHS-R and whether GHS-R antagonism indeed inhibits insulin secretion. We investigated the effects of GHS-R on glucose homeostasis in Ghsr -ablated ob / ob mice ( Ghsr −/− : ob / ob ). Ghsr ablation did not rescue the hyperphagia, obesity, or insulin resistance of ob / ob mice. Surprisingly, Ghsr ablation worsened the hyperglycemia, decreased insulin, and impaired glucose tolerance. Consistently, Ghsr ablation in ob / ob mice upregulated negative β-cell regulators (such as UCP-2, SREBP-1c, ChREBP, and MIF-1) and downregulated positive β-cell regulators (such as HIF-1α, FGF-21, and PDX-1) in whole pancreas; this suggests that Ghsr ablation impairs pancreatic β-cell function in leptin deficiency. Of note, Ghsr ablation in ob / ob mice did not affect the islet size; the average islet size of Ghsr −/− : ob / ob mice is similar to that of ob / ob mice. In summary, because Ghsr ablation in leptin deficiency impairs insulin secretion and worsens hyperglycemia, this suggests that GHS-R antagonists may actually aggravate diabetes under certain conditions. The paradoxical effects of ghrelin ablation and Ghsr ablation in ob/ob mice highlight the complexity of the ghrelin-signaling pathway. growth hormone secretagogue receptor insulin secretion type 2 diabetes « Previous | Next Article » Table of Contents This Article Published online before print June 5, 2012 , doi: 10.​1152/​ajpendo.​00576.​2011 AJP - Endo August 1, 2012 vol. 303 no. 3 E422-E431 » Abstract Free Full Text Free to you Full Text (PDF) Free to you All Versions of this Article: ajpendo.00576.2011v1 303/3/E422 most recent Classifications Article Services Email this article to a friend Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Citing articles via Web of Science Google Scholar Articles by Ma, X. Articles by Sun, Y. PubMed PubMed citation Articles by Ma, X. Articles by Sun, Y. Related Content Load related web page information Current Content August 1, 2012 Alert me to new issues of AJP - Endo About the Journal Calls for Papers Information for Authors Submit a Manuscript Ethical Policies AuthorChoice PubMed Central Policy Reprints and Permissions Advertising Press Copyright © 2012 the American Physiological Society Print ISSN: 0193-1849 Online ISSN: 1522-1555

Jacqueline M. Stephens

doi: 10.1152/ajpendo.00169.2012pmid: 22855523

RIFL (refeeding induced in fat and liver) is highly expressed in brown and white fat as well as in liver. In white adipose tissue and liver, RIFL expression is induced by refeeding and is also elevated in ob/ob mice. The function of RIFL is unknown, and there is some evidence to suggest it may be secreted. RIFL expression is induced during adipogenesis in rodent and human model systems, and cellular knockdown and mouse knockout studies demonstrate that RIFL expression correlates with lipid levels. Overall, these studies indicate that RIFL is a new important player in lipid metabolism. Copyright © 2012 the American Physiological Society « Previous | Next Article » Table of Contents This Article doi: 10.​1152/​ajpendo.​00169.​2012 AJP - Endo August 1, 2012 vol. 303 no. 3 E332-E333 » Abstract Free Full Text Free to you Full Text (PDF) Free to you Classifications Editorial Focus Services Email this article to a friend Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Citing articles via Web of Science Google Scholar Articles by Stephens, J. M. PubMed PubMed citation Articles by Stephens, J. M. Related Content Load related web page information Current Content August 1, 2012 Alert me to new issues of AJP - Endo About the Journal Calls for Papers Information for Authors Submit a Manuscript Ethical Policies AuthorChoice PubMed Central Policy Reprints and Permissions Advertising Press Copyright © 2012 the American Physiological Society Print ISSN: 0193-1849 Online ISSN: 1522-1555

Daniel M. Keenan , Rita Basu , Yan Liu , Ananda Basu , Gerlies Bock , and Johannes D. Veldhuis

doi: 10.1152/ajpendo.00494.2011pmid: 22669243

The present analysis tests the hypothesis that quantifiable disruption of the glucose-stimulated insulin-secretion dose-response pathway mediates impaired fasting glycemia (IFG) and type 2 diabetes mellitus (DM). To this end, adults with normal and impaired fasting glycemia (NFG, n = 30), IFG ( n = 32), and DM ( n = 14) were given a mixed meal containing 75 g glucose. C-peptide and glucose were measured over 4 h, 13 times in NFG and IFG and 16 times in DM (age range 50–57 yr, body mass index 28–32 kg/m 2 ). Wavelet-based deconvolution analysis was used to estimate time-varying C-peptide secretion rates. Logistic dose-response functions were constructed analytically of the sensitivity, potency, and efficacy (in the pharmacological sense of slope, one-half maximal stimulation, and maximal effect) of glucose's stimulation of prehepatic insulin (C-peptide) secretion. A hysteresis changepoint time, demarcating unequal glucose potencies for onset and recovery pathways, was estimated simultaneously. According to this methodology, NFG subjects exhibited distinct onset and recovery potencies of glucose in stimulating C-peptide secretion (6.5 and 8.5 mM), thereby defining in vivo hysteresis (potency shift −2.0 mM). IFG patients manifested reduced glucose onset potency (8.6 mM), and diminished C-peptide hysteretic shift (−0.80 mM). DM patients had markedly decreased glucose potency (18.8 mM), reversal of C-peptide's hysteretic shift (+4.5 mM), and 30% lower C-peptide sensitivity to glucose stimulation. From these data, we conclude that a dynamic dose-response model of glucose-dependent control of C-peptide secretion can identify disruption of in vivo hysteresis in patients with IFG and DM. Pathway-defined analytic models of this kind may aid in the search for prediabetes biomarkers. insulin deconvolution secretion Copyright © 2012 the American Physiological Society « Previous | Next Article » Table of Contents This Article Published online before print June 5, 2012 , doi: 10.​1152/​ajpendo.​00494.​2011 AJP - Endo August 1, 2012 vol. 303 no. 3 E397-E409 » Abstract Free Full Text Free to you Full Text (PDF) Free to you All Versions of this Article: ajpendo.00494.2011v1 303/3/E397 most recent Classifications Article Services Email this article to a friend Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Citing articles via Web of Science Google Scholar Articles by Keenan, D. M. Articles by Veldhuis, J. D. PubMed PubMed citation Articles by Keenan, D. M. Articles by Veldhuis, J. D. Related Content Load related web page information Current Content August 1, 2012 Alert me to new issues of AJP - Endo About the Journal Calls for Papers Information for Authors Submit a Manuscript Ethical Policies AuthorChoice PubMed Central Policy Reprints and Permissions Advertising Press Copyright © 2012 the American Physiological Society Print ISSN: 0193-1849 Online ISSN: 1522-1555

Andrea Bonetto , Tufan Aydogdu , Xiaoling Jin , Zongxiu Zhang , Rui Zhan , Leopold Puzis , Leonidas G. Koniaris , and Teresa A. Zimmers

doi: 10.1152/ajpendo.00039.2012pmid: 22669242

Cachexia, the metabolic dysregulation leading to sustained loss of muscle and adipose tissue, is a devastating complication of cancer and other chronic diseases. Interleukin-6 and related cytokines are associated with muscle wasting in clinical and experimental cachexia, although the mechanisms by which they might induce muscle wasting are unknown. One pathway activated strongly by IL-6 family ligands is the JAK/STAT3 pathway, the function of which has not been evaluated in regulation of skeletal muscle mass. Recently, we showed that skeletal muscle STAT3 phosphorylation, nuclear localization, and target gene expression are activated in C26 cancer cachexia, a model with high IL-6 family ligands. Here, we report that STAT3 activation is a common feature of muscle wasting, activated in muscle by IL-6 in vivo and in vitro and by different types of cancer and sterile sepsis. Moreover, STAT3 activation proved both necessary and sufficient for muscle wasting. In C 2 C 12 myotubes and in mouse muscle, mutant constitutively activated STAT3-induced muscle fiber atrophy and exacerbated wasting in cachexia. Conversely, inhibiting STAT3 pharmacologically with JAK or STAT3 inhibitors or genetically with dominant negative STAT3 and short hairpin STAT3 reduced muscle atrophy downstream of IL-6 or cancer. These results indicate that STAT3 is a primary mediator of muscle wasting in cancer cachexia and other conditions of high IL-6 family signaling. Thus STAT3 could represent a novel therapeutic target for the preservation of skeletal muscle in cachexia. Janus-activated kinase interleukin-6 T cell protein tyrosine phosphatase/protein tyrosine phosphatase, nonreceptor type 2 suppressors of cytokine signaling 3 electroporation atrophy burn sepsis lipopolysaccharide incb018424 signal transducer and activator of transcription 3 inhibitory peptide Copyright © 2012 the American Physiological Society « Previous | Next Article » Table of Contents This Article Published online before print June 5, 2012 , doi: 10.​1152/​ajpendo.​00039.​2012 AJP - Endo August 1, 2012 vol. 303 no. 3 E410-E421 » Abstract Free Full Text Free to you Full Text (PDF) Free to you All Versions of this Article: ajpendo.00039.2012v1 303/3/E410 most recent Classifications Article Services Email this article to a friend Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Citing articles via Web of Science Google Scholar Articles by Bonetto, A. Articles by Zimmers, T. A. PubMed PubMed citation Articles by Bonetto, A. Articles by Zimmers, T. A. Related Content Load related web page information Current Content August 1, 2012 Alert me to new issues of AJP - Endo About the Journal Calls for Papers Information for Authors Submit a Manuscript Ethical Policies AuthorChoice PubMed Central Policy Reprints and Permissions Advertising Press Copyright © 2012 the American Physiological Society Print ISSN: 0193-1849 Online ISSN: 1522-1555