Publications by authors named "Claudia Lindtner"

16 Publications

  • Page 1 of 1

Considerable mortality and morbidity in neonates born below 500 gram.

Acta Paediatr 2021 08 19;110(8):2359-2365. Epub 2021 May 19.

Comprehensive Center for Pediatrics, Department of Pediatrics and Adolescent Medicine, Division of Neonatology, Intensive Care and Neuropediatrics, Medical University of Vienna, Vienna, Austria.

Data evaluating mortality and morbidity in infants born ≤500 g are scarce and show wide variability. To support counselling and decision-making, we analysed neurodevelopmental outcome in all neonates ≤500 g birth weight. Retrospective analysis including preterm infants with a birth weight ≤500 g and a gestational age >22 weeks born at a single tertiary perinatal centre between 2010 and 2017. Of 59 live births, 88% received standard care. Birth weight ranged from 318 to 500 g and gestational age from 23 to 29 weeks. 56% of neonates were born ≤3rd percentile and 42% of treated infants survived. Neurodevelopmental outcome was available in 91% of patients and was evaluated using Bayley Scales of Infant Development at two years. 50% showed a favourable mental development (normal or mild impairment), 75% a favourable motor development and 45% a favourable outcome in both outcome subcategories. When additionally considering visual and hearing disability and, or, cerebral palsy level ≥2 according to the Gross Motor Function Classification System 35% had a good neurodevelopmental outcome. Survival rate was 37% for all live births and 42% for infants with standard care. More than one-third of survivors showed no significant neurodevelopmental impairment at two years.
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http://dx.doi.org/10.1111/apa.15885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360180PMC
August 2021

VEGF Treatment Ameliorates Depression-Like Behavior in Adult Offspring After Maternal Immune Activation.

Cells 2020 04 22;9(4). Epub 2020 Apr 22.

Department of Neurophysiology and Neuropharmacology, Medical University of Vienna, 1090 Vienna, Austria.

Maternal immune activation (MIA) during pregnancy impacts offspring neurodevelopmental trajectories and induces lifelong consequences, including emotional and cognitive alterations. Using the polyinosinic:polycytidilic acid (PIC) MIA model we have previously demonstrated enhanced depression-like behavior in adult MIA offspring, which was associated with reduced expression of the vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) in the hippocampus. Since VEGF mediates the effects of various antidepressant agents, we here set out to explore whether VEGF administration could rescue the depression-like behavioral deficits in MIA offspring. To test our hypothesis, control and MIA offspring were intracerebroventricularly (i.c.v.) infused with either VEGF or vehicle solution and depression-related behavior was assessed in the sucrose preference test (SPT) and the tail suspension test (TST). As a surrogate of VEGF activity, the phosphorylation of the extracellular signal-regulated kinase (ERK) in hippocampus was quantified. We found that VEGF treatment reduced depression-related behavioral despair in the TST in MIA offspring but had no effect on anhedonia-like behavior in the SPT. While VEGF administration induced the phosphorylation of ERK in the hippocampus of control offspring, this effect was blunted in the MIA offspring. We conclude that VEGF administration, at the dosage tested, beneficially affects some aspects of the depression-like phenotype in the adult MIA offspring, inviting further studies using different dosage regimes to further explore the therapeutic potential of VEGF treatment in MIA-related changes in brain function and behavior.
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http://dx.doi.org/10.3390/cells9041048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226255PMC
April 2020

Impact and Time Course of Clostridium difficile Colonization in Very Low Birth Weight Infants.

Neonatology 2018 12;114(2):149-154. Epub 2018 Jun 12.

Division of Neonatology, Intensive Care, and Neuropediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.

Background: Clostridium difficile is a gram-positive, anaerobic spore-forming, toxin-producing bacillus, which is one of the most common causes for health care-associated infections. High colonization rates in clinically asymptomatic neonates and infants have been described, although most studies go back to the early 1980 and 1990s, and were carried out in term and late preterm infants.

Objectives: The aim of our study was to determine both the impact and time course of C. difficile colonization in a cohort of very low birth weight infants (VLBWI) in an era of PCR-based technologies for diagnosis.

Methods: Stool samples of VLBWI were analyzed for the presence of C. difficile strains in regular intervals during the hospital stay by PCR ribotyping. Analysis was continued throughout the first 2 years of life.

Results: A 32% C. difficile colonization rate during the first 2 years of life and an in-hospital colonization rate of 8% was found in a cohort of 190 VLBWI. C. difficile colonization occurred mainly in the first 6 months of life, which was similar to term neonates. In-hospital colonization accounted for only a small percentage of cases with no detection of hypervirulent strains. Also, C. difficile colonization was not related to an adverse outcome in this VLBWI cohort. Oral lactoferrin of bovine origin and treatment with piperacillin/tazobactam were negatively correlated with C. difficile colonization in our study.

Conclusions: C. difficile colonization in our cohort of VLBWI was significantly lower than has been described in the literature and was not related to an adverse outcome.
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http://dx.doi.org/10.1159/000488025DOI Listing
September 2019

Administration of Fortifier by Finger Feeder During Breastfeeding in Preterm Infants.

J Obstet Gynecol Neonatal Nurs 2017 Sep - Oct;46(5):748-754. Epub 2017 Jul 12.

Objective: To evaluate the acceptance, adherence, and feasibility of fortifier administration by finger feeder during breastfeeding and to determine weight, length, and head circumference gains after discharge for preterm infants.

Design: Observational pilot study.

Setting: A Level III NICU and its outpatient clinic in Vienna, Austria.

Participants: Infants born at younger than 34 weeks gestation were included.

Methods: Mothers were screened in a tertiary NICU and trained by certified lactation consultants to administer fortifier with a finger feeder during breastfeeding. Data on finger feeder use at home were collected by self-reported feeding diaries and questionnaires.

Results: In total, data from 24 mother-infant dyads were analyzed. The acceptance rate was 67%. In 41.7%, more than 50% of meals were fortified. Mothers did not report problems in preparation, but 33% of the infants stopped latching on or drooled milk during finger feeder use.

Conclusion: Use of a finger feeder to administer fortifier to preterm infants enabled mothers to exclusively breastfeed their infants and meet their nutritional needs. The development of further methods to augment preterm infant nutrition that do not interfere with breastfeeding is of great interest.
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http://dx.doi.org/10.1016/j.jogn.2017.05.005DOI Listing
May 2018

Insulin Receptor Signaling in POMC, but Not AgRP, Neurons Controls Adipose Tissue Insulin Action.

Diabetes 2017 06 6;66(6):1560-1571. Epub 2017 Apr 6.

Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY

Insulin is a key regulator of adipose tissue lipolysis, and impaired adipose tissue insulin action results in unrestrained lipolysis and lipotoxicity, which are hallmarks of the metabolic syndrome and diabetes. Insulin regulates adipose tissue metabolism through direct effects on adipocytes and through signaling in the central nervous system by dampening sympathetic outflow to the adipose tissue. Here we examined the role of insulin signaling in agouti-related protein (AgRP) and pro-opiomelanocortin (POMC) neurons in regulating hepatic and adipose tissue insulin action. Mice lacking the insulin receptor in AgRP neurons (AgRP IR KO) exhibited impaired hepatic insulin action because the ability of insulin to suppress hepatic glucose production (hGP) was reduced, but the ability of insulin to suppress lipolysis was unaltered. To the contrary, in POMC IR KO mice, insulin lowered hGP but failed to suppress adipose tissue lipolysis. High-fat diet equally worsened glucose tolerance in AgRP and POMC IR KO mice and their respective controls but increased hepatic triglyceride levels only in POMC IR KO mice, consistent with impaired lipolytic regulation resulting in fatty liver. These data suggest that although insulin signaling in AgRP neurons is important in regulating glucose metabolism, insulin signaling in POMC neurons controls adipose tissue lipolysis and prevents high-fat diet-induced hepatic steatosis.
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http://dx.doi.org/10.2337/db16-1238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440019PMC
June 2017

Maternal immune activation transgenerationally modulates maternal care and offspring depression-like behavior.

Brain Behav Immun 2017 Jul 17;63:127-136. Epub 2016 Oct 17.

Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Austria. Electronic address:

Gestational infection is increasingly being recognized for its involvement as causative mechanism in severe developmental brain abnormalities and its contribution to the pathogenesis of psychopathologies later in life. First observations in the widely accepted maternal immune activation (MIA) model based upon the systemic administration of the viral mimetic Polyinosinic:polycytidylic acid (poly(I:C)) have recently suggested a transmission of behavioral and transcriptional traits across generations. Although maternal care behavior (MCB) is known as essential mediator of the transgenerational effects of environmental challenges on offspring brain function and behavior, the possible propagation of alterations of MCB resulting from MIA to following generations has not yet been examined. Here we show that poly(I:C) stimulation at embryonic day 12.5 (E12.5) leads to aberrant MCB and that this effect is transmitted to the female F1 offspring. The transgenerational effects on MCB are paralleled by enhanced depression-like behavior in the second generation F2 offspring with contributions of both maternal and paternal heritages. Examination of offspring hippocampal expression of genes known as targets of MCB and relevant for ensuing non-genetic transmission of altered brain function and behavior revealed transgenerationally conserved and modified expressional patterns in the F1 and F2 generation. Collectively these data firstly demonstrate the transgenerational transmission of the impact of gestational immune activation on the reproductive care behavior of the mother. Behavioral and molecular characteristics of first and second generation offspring suggest transgenerationally imprinted consequences of gestational infection on psychopathological traits related to mood disorders which remain to be examined in future cross-fostering experiments.
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http://dx.doi.org/10.1016/j.bbi.2016.10.016DOI Listing
July 2017

Increased susceptibility to metabolic dysregulation in a mouse model of Alzheimer's disease is associated with impaired hypothalamic insulin signaling and elevated BCAA levels.

Alzheimers Dement 2016 08 28;12(8):851-61. Epub 2016 Feb 28.

Department of Medicine, Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

Introduction: Epidemiologic studies have demonstrated an association between diabetes and dementia. Insulin signaling within the brain, in particular within the hypothalamus regulates carbohydrate, lipid, and branched chain amino acid (BCAA) metabolism in peripheral organs such as the liver and adipose tissue. We hypothesized that cerebral amyloidosis impairs central nervous system control of metabolism through disruption of insulin signaling in the hypothalamus, which dysregulates glucose and BCAA homeostasis resulting in increased susceptibility to diabetes.

Methods: We examined whether APP/PS1 mice exhibit increased susceptibility to aging or high-fat diet (HFD)-induced metabolic impairment using metabolic phenotyping and insulin-signaling studies.

Results: APP/PS1 mice were more susceptible to high-fat feeding and aging-induced metabolic dysregulation including disrupted BCAA homeostasis and exhibited impaired hypothalamic insulin signaling.

Discussion: Our data suggest that AD pathology increases susceptibility to diabetes due to impaired hypothalamic insulin signaling, and that plasma BCAA levels could serve as a biomarker of hypothalamic insulin action in patients with AD.
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http://dx.doi.org/10.1016/j.jalz.2016.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358328PMC
August 2016

Insulin Regulates Hepatic Triglyceride Secretion and Lipid Content via Signaling in the Brain.

Diabetes 2016 06 9;65(6):1511-20. Epub 2016 Feb 9.

Departments of Medicine and Neuroscience, Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY

Hepatic steatosis is common in obesity and insulin resistance and results from a net retention of lipids in the liver. A key mechanism to prevent steatosis is to increase secretion of triglycerides (TG) packaged as VLDLs. Insulin controls nutrient partitioning via signaling through its cognate receptor in peripheral target organs such as liver, muscle, and adipose tissue and via signaling in the central nervous system (CNS) to orchestrate organ cross talk. While hepatic insulin signaling is known to suppress VLDL production from the liver, it is unknown whether brain insulin signaling independently regulates hepatic VLDL secretion. Here, we show that in conscious, unrestrained male Sprague Dawley rats the infusion of insulin into the third ventricle acutely increased hepatic TG secretion. Chronic infusion of insulin into the CNS via osmotic minipumps reduced the hepatic lipid content as assessed by noninvasive (1)H-MRS and lipid profiling independent of changes in hepatic de novo lipogenesis and food intake. In mice that lack the insulin receptor in the brain, hepatic TG secretion was reduced compared with wild-type littermate controls. These studies identify brain insulin as an important permissive factor in hepatic VLDL secretion that protects against hepatic steatosis.
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http://dx.doi.org/10.2337/db15-1552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878422PMC
June 2016

Mitochondrial shape governs BAX-induced membrane permeabilization and apoptosis.

Mol Cell 2015 Jan 4;57(1):69-82. Epub 2014 Dec 4.

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Department of Dermatology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA. Electronic address:

Proapoptotic BCL-2 proteins converge upon the outer mitochondrial membrane (OMM) to promote mitochondrial outer membrane permeabilization (MOMP) and apoptosis. Here we investigated the mechanistic relationship between mitochondrial shape and MOMP and provide evidence that BAX requires a distinct mitochondrial size to induce MOMP. We utilized the terminal unfolded protein response pathway to systematically define proapoptotic BCL-2 protein composition after stress and then directly interrogated their requirement for a productive mitochondrial size. Complementary biochemical, cellular, in vivo, and ex vivo studies reveal that Mfn1, a GTPase involved in mitochondrial fusion, establishes a mitochondrial size that is permissive for proapoptotic BCL-2 family function. Cells with hyperfragmented mitochondria, along with size-restricted OMM model systems, fail to support BAX-dependent membrane association and permeabilization due to an inability to stabilize BAXα9·membrane interactions. This work identifies a mechanistic contribution of mitochondrial size in dictating BAX activation, MOMP, and apoptosis.
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http://dx.doi.org/10.1016/j.molcel.2014.10.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289414PMC
January 2015

Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism.

Cell Metab 2014 Nov 9;20(5):898-909. Epub 2014 Oct 9.

Diabetes, Obesity, and Metabolism Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA. Electronic address:

Circulating branched-chain amino acid (BCAA) levels are elevated in obesity/diabetes and are a sensitive predictor for type 2 diabetes. Here we show in rats that insulin dose-dependently lowers plasma BCAA levels through induction of hepatic protein expression and activity of branched-chain α-keto acid dehydrogenase (BCKDH), the rate-limiting enzyme in the BCAA degradation pathway. Selective induction of hypothalamic insulin signaling in rats and genetic modulation of brain insulin receptors in mice demonstrate that brain insulin signaling is a major regulator of BCAA metabolism by inducing hepatic BCKDH. Short-term overfeeding impairs the ability of brain insulin to lower BCAAs in rats. High-fat feeding in nonhuman primates and obesity and/or diabetes in humans is associated with reduced BCKDH protein in liver. These findings support the concept that decreased hepatic BCKDH is a major cause of increased plasma BCAAs and that hypothalamic insulin resistance may account for impaired BCAA metabolism in obesity and diabetes.
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http://dx.doi.org/10.1016/j.cmet.2014.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254305PMC
November 2014

Perinatal exposure of mice to the pesticide DDT impairs energy expenditure and metabolism in adult female offspring.

PLoS One 2014 30;9(7):e103337. Epub 2014 Jul 30.

Metabolism Institute, Mount Sinai School of Medicine, New York, New York, United States of America; Division of Endocrinology, Diabetes and Bone Disease, Mount Sinai School of Medicine, New York, New York, United States of America.

Dichlorodiphenyltrichloroethane (DDT) has been used extensively to control malaria, typhus, body lice and bubonic plague worldwide, until countries began restricting its use in the 1970s. Its use in malaria control continues in some countries according to recommendation by the World Health Organization. Individuals exposed to elevated levels of DDT and its metabolite dichlorodiphenyldichloroethylene (DDE) have an increased prevalence of diabetes and insulin resistance. Here we hypothesize that perinatal exposure to DDT disrupts metabolic programming leading to impaired metabolism in adult offspring. To test this, we administered DDT to C57BL/6J mice from gestational day 11.5 to postnatal day 5 and studied their metabolic phenotype at several ages up to nine months. Perinatal DDT exposure reduced core body temperature, impaired cold tolerance, decreased energy expenditure, and produced a transient early-life increase in body fat in female offspring. When challenged with a high fat diet for 12 weeks in adulthood, female offspring perinatally exposed to DDT developed glucose intolerance, hyperinsulinemia, dyslipidemia, and altered bile acid metabolism. Perinatal DDT exposure combined with high fat feeding in adulthood further impaired thermogenesis as evidenced by reductions in core temperature and in the expression of numerous RNA that promote thermogenesis and substrate utilization in the brown adipose tissue of adult female mice. These observations suggest that perinatal DDT exposure impairs thermogenesis and the metabolism of carbohydrates and lipids which may increase susceptibility to the metabolic syndrome in adult female offspring.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0103337PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116186PMC
November 2015

Activating transcription factor 6 is necessary and sufficient for alcoholic fatty liver disease in zebrafish.

PLoS Genet 2014 29;10(5):e1004335. Epub 2014 May 29.

Department of Medicine - Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.

Fatty liver disease (FLD) is characterized by lipid accumulation in hepatocytes and is accompanied by secretory pathway dysfunction, resulting in induction of the unfolded protein response (UPR). Activating transcription factor 6 (ATF6), one of three main UPR sensors, functions to both promote FLD during acute stress and reduce FLD during chronic stress. There is little mechanistic understanding of how ATF6, or any other UPR factor, regulates hepatic lipid metabolism to cause disease. We addressed this using zebrafish genetics and biochemical analyses and demonstrate that Atf6 is necessary and sufficient for FLD. atf6 transcription is significantly upregulated in the liver of zebrafish with alcoholic FLD and morpholino-mediated atf6 depletion significantly reduced steatosis incidence caused by alcohol. Moreover, overexpression of active, nuclear Atf6 (nAtf6) in hepatocytes caused FLD in the absence of stress. mRNA-Seq and qPCR analyses of livers from five day old nAtf6 transgenic larvae revealed upregulation of genes promoting glyceroneogenesis and fatty acid elongation, including fatty acid synthase (fasn), and nAtf6 overexpression in both zebrafish larvae and human hepatoma cells increased the incorporation of 14C-acetate into lipids. Srebp transcription factors are key regulators of lipogenic enzymes, but reducing Srebp activation by scap morpholino injection neither prevented FLD in nAtf6 transgenics nor synergized with atf6 knockdown to reduce alcohol-induced FLD. In contrast, fasn morpholino injection reduced FLD in nAtf6 transgenic larvae and synergistically interacted with atf6 to reduce alcoholic FLD. Thus, our data demonstrate that Atf6 is required for alcoholic FLD and epistatically interacts with fasn to cause this disease, suggesting triglyceride biogenesis as the mechanism of UPR induced FLD.
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http://dx.doi.org/10.1371/journal.pgen.1004335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038464PMC
December 2014

Morbid obesity resulting from inactivation of the ciliary protein CEP19 in humans and mice.

Am J Hum Genet 2013 Dec 21;93(6):1061-71. Epub 2013 Nov 21.

Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA; Simon Winter Institute for Human Genetics, Bnai-Zion Medical Center, 31048 Haifa, Israel; Clalit Health Services Group, 30810 Sakhnin City, Israel. Electronic address:

Obesity is a major public health concern, and complementary research strategies have been directed toward the identification of the underlying causative gene mutations that affect the normal pathways and networks that regulate energy balance. Here, we describe an autosomal-recessive morbid-obesity syndrome and identify the disease-causing gene defect. The average body mass index of affected family members was 48.7 (range = 36.7-61.0), and all had features of the metabolic syndrome. Homozygosity mapping localized the disease locus to a region in 3q29; we designated this region the morbid obesity 1 (MO1) locus. Sequence analysis identified a homozygous nonsense mutation in CEP19, the gene encoding the ciliary protein CEP19, in all affected family members. CEP19 is highly conserved in vertebrates and invertebrates, is expressed in multiple tissues, and localizes to the centrosome and primary cilia. Homozygous Cep19-knockout mice were morbidly obese, hyperphagic, glucose intolerant, and insulin resistant. Thus, loss of the ciliary protein CEP19 in humans and mice causes morbid obesity and defines a target for investigating the molecular pathogenesis of this disease and potential treatments for obesity and malnutrition.
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http://dx.doi.org/10.1016/j.ajhg.2013.10.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3852924PMC
December 2013

Binge drinking induces whole-body insulin resistance by impairing hypothalamic insulin action.

Sci Transl Med 2013 Jan;5(170):170ra14

Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574, USA.

Individuals with a history of binge drinking have an increased risk of developing the metabolic syndrome and type 2 diabetes. Whether binge drinking impairs glucose homeostasis and insulin action is unknown. To test this, we treated Sprague-Dawley rats daily with alcohol (3 g/kg) for three consecutive days to simulate human binge drinking and found that these rats developed and exhibited insulin resistance even after blood alcohol concentrations had become undetectable. The animals were resistant to insulin for up to 54 hours after the last dose of ethanol, chiefly a result of impaired hepatic and adipose tissue insulin action. Because insulin regulates hepatic glucose production and white adipose tissue lipolysis, in part through signaling in the central nervous system, we tested whether binge drinking impaired brain control of nutrient partitioning. Rats that had consumed alcohol exhibited impaired hypothalamic insulin action, defined as the ability of insulin infused into the mediobasal hypothalamus to suppress hepatic glucose production and white adipose tissue lipolysis. Insulin signaling in the hypothalamus, as assessed by insulin receptor and AKT phosphorylation, decreased after binge drinking. Quantitative polymerase chain reaction showed increased hypothalamic inflammation and expression of protein tyrosine phosphatase 1B (PTP1B), a negative regulator of insulin signaling. Intracerebroventricular infusion of CPT-157633, a small-molecule inhibitor of PTP1B, prevented binge drinking-induced glucose intolerance. These results show that, in rats, binge drinking induces systemic insulin resistance by impairing hypothalamic insulin action and that this effect can be prevented by inhibition of brain PTP1B.
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http://dx.doi.org/10.1126/scitranslmed.3005123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3740748PMC
January 2013

Short term voluntary overfeeding disrupts brain insulin control of adipose tissue lipolysis.

J Biol Chem 2012 Sep 18;287(39):33061-9. Epub 2012 Jul 18.

Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.

Insulin controls fatty acid (FA) release from white adipose tissue (WAT) through direct effects on adipocytes and indirectly through hypothalamic signaling by reducing sympathetic nervous system outflow to WAT. Uncontrolled FA release from WAT promotes lipotoxicity, which is characterized by inflammation and insulin resistance that leads to and worsens type 2 diabetes. Here we tested whether early diet-induced insulin resistance impairs the ability of hypothalamic insulin to regulate WAT lipolysis and thus contributes to adipose tissue dysfunction. To this end we fed male Sprague-Dawley rats a 10% lard diet (high fat diet (HFD)) for 3 consecutive days, which is known to induce systemic insulin resistance. Rats were studied by euglycemic pancreatic clamps and concomitant infusion of either insulin or vehicle into the mediobasal hypothalamus. Short term HFD feeding led to a 37% increase in caloric intake and elevated base-line free FAs and insulin levels compared with rats fed regular chow. Overfeeding did not impair insulin signaling in WAT, but it abolished the ability of mediobasal hypothalamus insulin to suppress WAT lipolysis and hepatic glucose production as assessed by glycerol and glucose flux. HFD feeding also increased hypothalamic levels of the endocannabinoid 2-arachidonoylglycerol after only 3 days. In summary, overfeeding impairs hypothalamic insulin action, which may contribute to unrestrained lipolysis seen in human obesity and type 2 diabetes.
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http://dx.doi.org/10.1074/jbc.M111.307348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3463338PMC
September 2012

Brain insulin controls adipose tissue lipolysis and lipogenesis.

Cell Metab 2011 Feb;13(2):183-94

Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1055, New York, NY 10029-6574, USA.

White adipose tissue (WAT) dysfunction plays a key role in the pathogenesis of type 2 diabetes (DM2). Unrestrained WAT lipolysis results in increased fatty acid release, leading to insulin resistance and lipotoxicity, while impaired de novo lipogenesis in WAT decreases the synthesis of insulin-sensitizing fatty acid species like palmitoleate. Here, we show that insulin infused into the mediobasal hypothalamus (MBH) of Sprague-Dawley rats increases WAT lipogenic protein expression, inactivates hormone-sensitive lipase (Hsl), and suppresses lipolysis. Conversely, mice that lack the neuronal insulin receptor exhibit unrestrained lipolysis and decreased de novo lipogenesis in WAT. Thus, brain and, in particular, hypothalamic insulin action play a pivotal role in WAT functionality.
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http://dx.doi.org/10.1016/j.cmet.2011.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3061443PMC
February 2011
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