DOCSLIB.ORG

TNF- Is a Predictor of Insulin Resistance in Human Pregnancy

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
TNF- Is a Predictor of Insulin Resistance in Human Pregnancy TNF-␣ Is a Predictor of Insulin Resistance in Human Pregnancy John P. Kirwan,1,2 Sylvie Hauguel-De Mouzon,3 Jacques Lepercq,3 Jean-Claude Challier,4 Larraine Huston-Presley,1 Jacob E. Friedman,5 Satish C. Kalhan,6 and Patrick M. Catalano1,6 Historically, insulin resistance during pregnancy has most significant independent predictor of insulin sensi- ؊0.67, P < 0.0001), even after adjustment for؍ tivity (r ؍ -been ascribed to increased production of placental hor mones and cortisol. The purpose of this study was to fat mass by covariance (r 0.46, P < 0.01). These test this hypothesis by correlating the longitudinal observations challenge the view that the classical repro- changes in insulin sensitivity during pregnancy with ductive hormones are the primary mediators of change in insulin sensitivity during gestation and provide the changes in placental hormones, cortisol, leptin, and ␣ tumor necrosis factor (TNF)-␣. Insulin resistance was basis for including TNF- in a new paradigm to explain assessed in 15 women (5 with gestational diabetes insulin resistance in pregnancy. Diabetes 51:2207–2213, mellitus [GDM] and 10 with normal glucose tolerance) 2002 using the euglycemic-hyperinsulinemic clamp proce- dure, before pregnancy (pregravid) and during early (12–14 weeks) and late (34–36 weeks) gestation. Body composition, plasma TNF-␣, leptin, cortisol, and repro- regnancy is a period marked by profound ductive hormones (human chorionic gonadotropin, es- changes in a woman’s hormonal status and me- tradiol, progesterone, human placental lactogen, and tabolism. The ability to regulate nutrient balance prolactin) were measured in conjunction with the during this period is critical to the health of the ␣ P clamps. Placental TNF- was measured in vitro using mother and the growing fetus. Insulin is one of the key dually perfused human placental cotyledon from five regulators of metabolism, and significant changes in insu- additional subjects. Compared with pregravid, insulin lin sensitivity and its ability to control glucose, fat, and resistance was evident during late pregnancy in all protein during pregnancy have been well documented women (12.4 ؎ 1.2 vs. 8.1 ؎ 0.8 10؊2 mg ⅐ kg؊1 fat-free ؊ ؊ ؊ (1–4). Previous reports have also shown that maternal mass ⅐ min 1 ⅐ ␮U 1 ⅐ ml 1). TNF-␣, leptin, cortisol, all reproductive hormones, and fat mass were increased in insulin resistance plays an important role in the regulation late pregnancy (P < 0.001). In vitro, most of the placen- of maternal energy metabolism, fat accretion, and fetal tal TNF-␣ (94%) was released into the maternal circu- growth (5,6). In gestational diabetes mellitus (GDM), lation; 6% was released to the fetal side. During late greater insulin resistance may lead to abnormal blood pregnancy, TNF-␣ was inversely correlated with insulin glucose and fetal macrosomia, may increase the likelihood -؊0.69, P < 0.006). Furthermore, among of obstetric complications, and in some cases, may in؍ sensitivity (r all of the hormonal changes measured in this study, the crease the risk of stillbirth. The cellular mediators of change in TNF-␣ from pregravid to late pregnancy was insulin resistance in late pregnancy have long been as- the only significant predictor of the change in insulin ؊ cribed to alterations in cortisol and placental-derived؍ sensitivity (r 0.60, P < 0.02). The placental repro- hormones including human placental lactogen (HPL), pro- ductive hormones and cortisol did not correlate with insulin sensitivity in late pregnancy. Multivariate step- gesterone, and estrogen (7–9). To our knowledge, how- wise regression analysis revealed that TNF-␣ was the ever, the changes in insulin sensitivity during gestation have not yet been correlated with hormonal changes using a prospective longitudinal design. From the 1Department of Reproductive Biology, Case Western Reserve Recently, investigators have focused on several new University School of Medicine at MetroHealth Medical Center, Cleveland, Ohio; the 2Department of Nutrition, Case Western Reserve University School potential mediators of insulin resistance including the of Medicine at MetroHealth Medical Center, Cleveland, Ohio; the 3De´parte- cytokine tumor necrosis factor (TNF)-␣, the anti-obesity ment d’Endocrinologie, Institut Cochin de Ge´ne´tique Mole´culaire, Paris, France; the 4Service de Gyne´cologie-Obste´trique, Hoˆ pital Cochin-Saint Vin- hormone leptin, and adipose-derived resistin, adiponectin, cent-de-Paul, Paris, France; the 5Departments of Pediatrics, Biochemistry, and and free fatty acids (10,11). Among these candidates, Molecular Genetics, University of Colorado Health Sciences Center, Denver, TNF-␣ and leptin are known to be produced in the Colorado; and the 6Schwartz Center for Metabolism and Nutrition, Case Western Reserve University School of Medicine at MetroHealth Medical placenta and therefore could play a central role in insulin Center, Cleveland, Ohio. resistance during pregnancy (12–14). Although increased Address correspondence and reprint requests to John P. Kirwan, Depart- circulating TNF-␣ levels have been associated with insulin ments of Reproductive Biology and Nutrition, Case Western Reserve University School of Medicine at MetroHealth Medical Center, Bell Greve resistance in obesity, aging, sepsis, muscle damage, and Bldg., Rm. G-232E, 2500 MetroHealth Dr., Cleveland, OH 44109-1998. preeclamptic pregnancy, reports of change in levels during E-mail: [email protected]. Received for publication 1 March 2002 and accepted in revised form 3 April normal pregnancy and GDM are equivocal (15–22). Fur- 2002. thermore, because TNF-␣ is synthesized and secreted FFM, fat-free mass; GDM, gestational diabetes mellitus; hCG, human from the placenta and adipose tissue, the origin of circu- chorionic gonadotropin; HPL, human placental lactogen; IRS, insulin receptor substrate; NGT, normal glucose tolerance; RIA, radioimmunoassay; TNF, lating levels during pregnancy remains largely unknown. tumor necrosis factor. Leptin was first identified as a product of the ob gene in DIABETES, VOL. 51, JULY 2002 2207 TNF-␣ AND INSULIN RESISTANCE DURING PREGNANCY TABLE 1 recirculation period were recorded, and the media were stored at Ϫ20°C for Subject characteristics and glucose tolerance pregravid and later analysis. To estimate TNF-␣ release into the fetal (Qf ϭ Cf ϫ Vf) and during late pregnancy maternal (Qm ϭ Cm ϫ Vm) circulation, TNF-␣ concentrations were measured in fetal (Cf) and maternal (Cm) media. These values were divided by the Lean NGT Obese NGT GDM duration of the perfusion (t ϭ 120 min) to give the rates of TNF-␣ release toward the fetal and maternal side of the placental circulation. TNF-␣ was also Age (years) 33 Ϯ 230Ϯ 129Ϯ 2 assessed on triplicate tissue samples in the placenta, before (Qti), and at the Parity 1.2 Ϯ 0.4 0.8 Ϯ 0.2 1.0 Ϯ 0.3 end of (Qte) the perfusion to evaluate changes in placental TNF-␣ (Q ϭ Qte Ϫ Weight (kg) 53.5 Ϯ 1.4 76.8 Ϯ 7.4* 83.3 Ϯ 9.4* Qti). The rate of placental TNF-␣ synthesis was estimated as PLS ϭ Qf ϩ Qm BMI (kg/m2) 19.8 Ϯ 1.0 27.3 Ϯ 2.4* 30.8 Ϯ 2.8* ϩ Q divided by the duration of the perfusion for one cotyledon, and as TPS ϭ Body fat (%) 25.0 Ϯ 1.6 36.6 Ϯ 3.2* 40.1 Ϯ 3.2* PLS ϫ P/l, where P/l is the placenta/lobule weight ratio, for the whole 2-h Glucose, placenta. ␣ pregravid 102.6 Ϯ 17.8 106.6 Ϯ 2.8 141.0 Ϯ 6.5 Analytical procedures. All samples for TNF- , leptin, cortisol, and the ␣ 2-h Glucose, during reproductive hormones were run in duplicate in a single assay. Plasma TNF- Ϯ Ϯ Ϯ concentrations were measured by enzyme-linked immunosorbent assay late pregnancy 125.0 8.3 145.6 8.1† 173.4 4.9*† (Quantikine HS; R&D Systems, Minneapolis, MN). The intra-assay coefficient Data are means Ϯ SE; n ϭ 5 per group. *Significantly different from of variation was 14%, the minimum detectable limit of the assay was 0.18 lean NGT group, P Ͻ 0.02. †Significantly different from pregravid, pg/ml, and the lowest standard was 0.5 pg/ml. Plasma glucose concentrations P Ͻ 0.03. were measured by the glucose oxidase method (Yellow Springs Instruments, Yellow Springs, OH). Blood samples for insulin measurements were centri- fuged at 4°C, and the plasma was stored at –70°C for subsequent analysis by adipose tissue and is thought to regulate energy balance a double-antibody radioimmunoassay (RIA) as previously described (27). through central hypothalamic pathways, but it may also Plasma cortisol, estradiol, HPL, and progesterone were determined by RIA play a role in insulin resistance by promoting lipid oxida- (Diagnostic Products, Los Angeles, CA). Plasma leptin samples were also measured by RIA (Linco Research, St. Charles, MO). Plasma hCG was tion and inhibiting lipid synthesis (23–25). There are determined by immunoradiometric assay (Diagnostic Products). Plasma pro- several reports of increased circulating leptin during preg- lactin was measured by RIA (Nichols Institute Diagnostics, San Juan Capist- nancy, due in part to placental secretion (13,14,26). rano, CA) 2 The primary purpose of this prospective study was to The [6,6- H2]glucose in the plasma samples was isolated by ion-exchange relate the longitudinal changes in concentrations of repro- chromatography. A penta-acetate derivative of glucose was prepared accord- ing to Tserng and Kalhan (33). Plasma enrichment was determined using a gas ductive hormones (HPL, progesterone, human chorionic chromatograph mass spectrometer (model 5985B; Hewlett-Packard, Palo Alto, gonadotropin [hCG], prolactin, and estradiol), TNF-␣, lep- CA). tin, and cortisol with the corresponding changes in mater- Calculations and statistical analysis. The insulin sensitivity index from the nal insulin sensitivity as measured by the euglycemic- clamp procedure was estimated as the glucose infusion rate plus endogenous hyperinsulinemic clamp. To further elucidate the role of glucose output divided by the mean insulin concentration during the clamp and is expressed as 10Ϫ2 milligrams per kilogram fat-free mass (FFM) per TNF-␣ as a mediator of maternal insulin resistance, we Ϫ Ϫ Ϫ Ϫ minute per microunit per milliliter (10 2 mg ⅐ kg 1 FFM ⅐ min 1/␮U ⅐ ml 1).
Load more

Recommended publications
  • Strategies to Increase ß-Cell Mass Expansion
    This electronic thesis or dissertation has been downloaded from the King’s Research Portal at https://kclpure.kcl.ac.uk/portal/ Strategies to increase -cell mass expansion Drynda, Robert Lech Awarding institution: King's College London The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without proper acknowledgement. END USER LICENCE AGREEMENT Unless another licence is stated on the immediately following page this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence. https://creativecommons.org/licenses/by-nc-nd/4.0/ You are free to copy, distribute and transmit the work Under the following conditions: Attribution: You must attribute the work in the manner specified by the author (but not in any way that suggests that they endorse you or your use of the work). Non Commercial: You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. Take down policy If you believe that this document breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 02. Oct. 2021 Strategies to increase β-cell mass expansion A thesis submitted by Robert Drynda For the degree of Doctor of Philosophy from King’s College London Diabetes Research Group Division of Diabetes & Nutritional Sciences Faculty of Life Sciences & Medicine King’s College London 2017 Table of contents Table of contents .................................................................................................
    [Show full text]
  • Associations Between Serum Leptin Level and Bone Turnover in Kidney Transplant Recipients
    Associations between Serum Leptin Level and Bone Turnover in Kidney Transplant Recipients ʈ ʈ ʈ Csaba P. Kovesdy,*† Miklos Z. Molnar,‡§ Maria E. Czira, Anna Rudas, Akos Ujszaszi, Laszlo Rosivall,‡ Miklos Szathmari,¶ Adrian Covic,** Andras Keszei,†† Gabriella Beko,‡‡ ʈ Peter Lakatos,¶ Janos Kosa,¶ and Istvan Mucsi §§ *Division of Nephrology, Salem Veterans Affairs Medical Center, Salem, Virginia; †Division of Nephrology, University of Virginia, Charlottesville, Virginia; ‡Institute of Pathophysiology, Semmelweis University, Budapest, Hungary; §Harold Simmons Center for Chronic Disease Research & Epidemiology, Los Angeles Biomedical Research Institute at ʈ Harbor-University of California–Los Angeles Medical Center, Torrance, California; Institute of Behavioral Sciences, Semmelweis University, Budapest, Hungary; ¶First Department of Internal Medicine, Semmelweis University, Budapest, Hungary; **University of Medicine Gr T Popa, Iasi, Romania; ††Department of Epidemiology, Maastricht University, Maastricht, Netherlands; ‡‡Central Laboratory, Semmelweis University, Budapest, Hungary; and §§Division of Nephrology, Department of Medicine, McGill University Health Center, Montreal, Quebec, Canada Background and objectives: Obesity is associated with increased parathyroid hormone (PTH) in the general population and in patients with chronic kidney disease (CKD). A direct effect of adipose tissue on bone turnover through leptin production has been suggested, but such an association has not been explored in kidney transplant recipients. Design, setting, participants, & measurements: This study examined associations of serum leptin with PTH and with biomarkers of bone turnover (serum beta crosslaps [CTX, a marker of bone resorption] and osteocalcin [OC, a marker of bone formation]) in 978 kidney transplant recipients. Associations were examined in multivariable regression models. Path analyses were used to determine if the association of leptin with bone turnover is independent of PTH.
    [Show full text]
  • Resistin Levels and Inflammatory Markers in Patients with Morbid Obesity
    Nutr Hosp. 2010;25(4):630-634 ISSN 0212-1611 • CODEN NUHOEQ S.V.R. 318 Original Resistin levels and inflammatory markers in patients with morbid obesity D. A. De Luis, M. González Sagrado, R. Conde, R. Aller and O. Izaola Instituto de Endocrinología y Nutrición Clínica. Medicine School and Unit of Investigation. Hospital Rio Hortega. RD-056/0013 RETICEF. University of Valladolid. Valladolid. Spain. Abstract NIVELES DE RESISTINA Y MARCADORES INFLAMATORIOS EN PACIENTES Background: The aim of the present study was to CON OBESIDAD MÓRBIDA explore the relationship of resistin levels with inflamma- tory markers and anthropometric parameters in morbid obese patients. Resumen Subjects: A population of 46 morbid obese was ana- lyzed. A complete nutritional and biochemical evaluation Introducción: El objetivo del presente estudio es eva- was performed. Patients were divided in two groups by luar la relación entre los niveles de resistina con los mar- median resistin value (3.49 ng/ml), group I (low values, cadores inflamatorios y parámetros antropométricos en average value 2.60 ± 0.5) and group II (high values, aver- pacientes obesos morbidos. age value 5.71 ± 2.25). Sujetos y métodos: Una muestra de 46 obesos morbidos Results: Patients in the group II had higher weight, fue analizada. Se realizó una valoración nutricional y bio- BMI, fat mass, waist circumference, LDL-cholesterol, química completa. Los pacientes fueron divididos en dos triglycerides, fibrinogen and C reactive protein than grupos en función de la mediana de resistina (3,49 ng/ml), patients in group I. In the multivariate analysis with age- grupo I (valores bajos, media del valor 2,60 ± 0,5 ng/ml) y and sex-adjusted basal resistin concentration as a depen- grupo II (valores altos, media del valor 5,71 ± 2,25 ng/ml).
    [Show full text]
  • Placental Growth Hormone-Related Proteins and Prolactin-Related Proteins
    Placental Growth Hormone-Related Proteins and Prolactin-Related Proteins The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Haig, D. 2008. Placental growth hormone-related proteins and prolactin-related proteins. Placenta 29: 36-41. Published Version doi:10.1016/j.placenta.2007.09.010 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:11148777 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Placental growth hormone-related proteins and prolactin-related proteins. David Haig Department of Organismic and Evolutionary Biology, Harvard University, 26 Oxford Street, Cambridge MA 02138. e-mail: [email protected] phone: 617-496-5125 fax: 617-495-5667 Keywords: GH, PRL, placenta, endometrial glands, placental lactogen The placentas of ruminants and muroid rodents express prolactin (PRL)-related genes whereas the placentas of anthropoid primates express growth hormone (GH)-related genes. The evolution of placental expression is associated with acclerated evolution of the corresponding pituitary hormone and destabilization of conserved endocrine systems. In particular, placental hormones often evolve novel interactions with new receptors. The adaptive functions of some placental hormones may be revealed only under conditions of physiological stress. Introduction Placental hormones are produced by offspring, but act on receptors of mothers. As such, placental hormones and maternal receptors are prime candidates for the expression of parent-offspring conflict [1,2].
    [Show full text]
  • (Title of the Thesis)*
    THE PHYSIOLOGICAL ACTIONS OF ADIPONECTIN IN CENTRAL AUTONOMIC NUCLEI: IMPLICATIONS FOR THE INTEGRATIVE CONTROL OF ENERGY HOMEOSTASIS by Ted Donald Hoyda A thesis submitted to the Department of Physiology In conformity with the requirements for the degree of Doctor of Philosophy Queen‟s University Kingston, Ontario, Canada (September, 2009) Copyright © Ted Donald Hoyda, 2009 ABSTRACT Adiponectin regulates feeding behavior, energy expenditure and autonomic function through the activation of two receptors present in nuclei throughout the central nervous system, however much remains unknown about the mechanisms mediating these effects. Here I investigate the actions of adiponectin in autonomic centers of the hypothalamus (the paraventricular nucleus) and brainstem (the nucleus of the solitary tract) through examining molecular, electrical, hormonal and physiological consequences of peptidergic signalling. RT-PCR and in situ hybridization experiments demonstrate the presence of AdipoR1 and AdipoR2 mRNA in the paraventricular nucleus. Investigation of the electrical consequences following receptor activation in the paraventricular nucleus indicates that magnocellular-oxytocin cells are homogeneously inhibited while magnocellular-vasopressin neurons display mixed responses. Single cell RT-PCR analysis shows oxytocin neurons express both receptors while vasopressin neurons express either both receptors or one receptor. Co-expressing oxytocin and vasopressin neurons express neither receptor and are not affected by adiponectin. Median eminence projecting corticotropin releasing hormone neurons, brainstem projecting oxytocin neurons, and thyrotropin releasing hormone neurons are all depolarized by adiponectin. Plasma adrenocorticotropin hormone concentration is increased following intracerebroventricular injections of adiponectin. I demonstrate that the nucleus of the solitary tract, the primary cardiovascular regulation site of the medulla, expresses mRNA for AdipoR1 and AdipoR2 and mediates adiponectin induced hypotension.
    [Show full text]
  • Resistin, Is There Any Role in the Mediation of Obesity, Insulin Resistance and Type-II Diabetes Mellitus?
    Review Article JOJ Case Stud Volume 6 Issue 3 - March 2018 Copyright © All rights are reserved by Rajeev Pandey DOI: 10.19080/JOJCS.2018.06.555686 Resistin, Is There any Role in the Mediation of Obesity, Insulin Resistance and Type-II Diabetes Mellitus? Rajeev Pandey1* and Gurumurthy2 1Department of Biochemistry, Spartan Health Science University, West Indies 2Department of Neurosciences, Spartan Health Science University, West Indies Submission: February 21, 2018; Published: March 05, 2018 *Corresponding author: Rajeev Pandey, Department of Biochemistry, Spartan Health Science University, St. Lucia, West Indies, Email: Abstract Resistin is a member of a class of cystein-rich proteins collectively termed as resistin-like molecules. Resistin has been implicated in tothe date pathogenesis there has ofbeen obesity-mediated considerable controversy insulin resistance surrounding and T2DM this 12.5kDa(Type II polypeptidediabetes mellitus). in understanding In addition, its resistin physiological also appears relevance to be in a bothpro- inflammatory cytokine. Taken together, resistin, like many other adipocytokines, may possess a dual role in contributing to disease risk. However, involvementhuman and rodent of resistin systems. molecule Furthermore, in the causation this has and led progression question, ofwhether obesity resistin and type represents II diabetes an mellitus important and pathogenicfactors associated factor within the alteration etiology inof theT2DM expression or not. Inof this magicreview, molecule authors athave physiological made an attemptand genetic to discuss levels. the key controversies and developments made so far towards the Keywords: Resistin; Obesity; T2DM; Insulin resistance Introduction Adipose tissue is known to produce a vast array of In addition, we will highlight the continuing complexity of the adipocyte-derived factors, known as adipocytokines.
    [Show full text]
  • Pathophysiology of Gestational Diabetes Mellitus: the Past, the Present and the Future
    6 Pathophysiology of Gestational Diabetes Mellitus: The Past, the Present and the Future Mohammed Chyad Al-Noaemi1 and Mohammed Helmy Faris Shalayel2 1Al-Yarmouk College, Khartoum, 2National College for Medical and Technical Studies, Khartoum, Sudan 1. Introduction It is just to remember that “Pathophysiology” refers to the study of alterations in normal body function (physiology and biochemistry) which result in disease. E.g. changes in the normal thyroid hormone level causes either hyper or hypothyroidism. Changes in insulin level as a decrease in its blood level or a decrease in its action will cause hyperglycemia and finally diabetes mellitus. Scientists agreed that gestational diabetes mellitus (GDM) is a condition in which women without previously diagnosed diabetes exhibit high blood glucose levels during pregnancy. From our experience most women with GDM in the developing countries are not aware of the symptoms (i.e., the disease will be symptomless). While some of the women will have few symptoms and their GDM is most commonly diagnosed by routine blood examinations during pregnancy which detect inappropriate high level of glucose in their blood samples. GDM should be confirmed by doing fasting blood glucose and oral glucose tolerance test (OGTT), according to the WHO diagnostic criteria for diabetes. A decrease in insulin sensitivity (i.e. an increase in insulin resistance) is normally seen during pregnancy to spare the glucose for the fetus. This is attributed to the effects of placental hormones. In a few women the physiological changes during pregnancy result in impaired glucose tolerance which might develop diabetes mellitus (GDM). The prevalence of GDM ranges from 1% to 14% of all pregnancies depending on the population studied and the diagnostic tests used.
    [Show full text]
  • Low Ambient Temperature Lowers Cholecystokinin and Leptin Plasma Concentrations in Adult Men Monika Pizon, Przemyslaw J
    The Open Nutrition Journal, 2009, 3, 5-7 5 Open Access Low Ambient Temperature Lowers Cholecystokinin and Leptin Plasma Concentrations in Adult Men Monika Pizon, Przemyslaw J. Tomasik*, Krystyna Sztefko and Zdzislaw Szafran Department of Clinical Biochemistry, University Children`s Hospital, Krakow, Poland Abstract: Background: It is known that the low ambient temperature causes a considerable increase of appetite. The mechanisms underlying the changes of the amounts of the ingested food in relation to the environmental temperature has not been elucidated. The aim of this study was to investigate the effect of the short exposure to low ambient temperature on the plasma concentration of leptin and cholecystokinin. Methods: Sixteen healthy men, mean age 24.6 ± 3.5 years, BMI 22.3 ± 2.3 kg/m2, participated in the study. The concen- trations of plasma CCK and leptin were determined twice – before and after the 30 min. exposure to + 4 °C by using RIA kits. Results: The mean value of CCK concentration before the exposure to low ambient temperature was 1.1 pmol/l, and after the exposure 0.6 pmol/l (p<0.0005 in the paired t-test). The mean values of leptin before exposure (4.7 ± 1.54 μg/l) were also significantly lower than after the exposure (6.4 ± 1.7 μg/l; p<0.0005 in the paired t-test). However no significant cor- relation was found between CCK and leptin concentrations, both before and after exposure to low temperature. Conclusions: It has been known that a fall in the concentration of CCK elicits hunger and causes an increase in feeding activity.
    [Show full text]
  • Leptin Replacement Reestablishes Brain Insulin Action in The
    Diabetes Care 1 Sabine Frank-Podlech,1–3 Leptin Replacement Reestablishes Julia von Schnurbein,4 Ralf Veit,1–3 Martin Heni,2,3 Jurgen¨ Machann,2,5 Brain Insulin Action in the Jaana M. Heinze,2,3 Stephanie Kullmann,2,3 Jaida Manzoor,6 Hypothalamus in Congenital Saqib Mahmood,7 Hans-Ulrich Haring,¨ 2,3 fi Hubert Preissl,2,3,8,9 Martin Wabitsch,4 Leptin De ciency and Andreas Fritsche2,3 https://doi.org/10.2337/dc17-1867 OBJECTIVE Human obesity is associated with impaired central insulin signaling, and in very rare cases, severe obesity can be caused by congenital leptin deficiency. In such patients, leptin replacement results in substantial weight loss and improvement in peripheral 1 metabolism. Institute for Medical Psychology and Behaviou- ral Neurobiology, University of Tubingen,¨ Tubingen,¨ Germany RESEARCH DESIGN AND METHODS 2 Institute for Diabetes Research and Metabolic In a leptin-deficient patient, we investigated the impact of leptin substitution on Diseases of the Helmholtz Center Munich at the central insulin action, as quantified by changes in neuronal activity after intranasal University of Tubingen,¨ German Center for Dia- insulin application. This was assessed before and during the 1st year of metreleptin betes Research, Tubingen,¨ Germany 3Department of Internal Medicine IV, University substitution. Hospital, Tubingen,¨ Germany 4Division of Pediatric Endocrinology and Diabe- RESULTS tes, Department of Pediatrics and Adolescent After only 1 year, treatment with metreleptin reestablishes brain insulin sensitivity, Medicine, University of Ulm, Ulm, Germany 5 particularly in the hypothalamus and, to a lesser degree, in the prefrontal cortex. Section on Experimental Radiology, Depart- ment of Diagnostic and Interventional Radiol- Results are depicted in comparison with a control group.
    [Show full text]
  • Metabolic Regulation of Fertility Through Presynaptic and Postsynaptic Signaling to Gonadotropin-Releasing Hormone Neurons
    8578 • The Journal of Neuroscience, September 17, 2003 • 23(24):8578–8585 Behavioral/Systems/Cognitive Metabolic Regulation of Fertility through Presynaptic and Postsynaptic Signaling to Gonadotropin-Releasing Hormone Neurons Shannon D. Sullivan, R. Anthony DeFazio, and Suzanne M. Moenter 1Internal Medicine and Cell Biology, University of Virginia, Charlottesville, Virginia 22908 Gonadotropin-releasing hormone (GnRH) neurons form the final common pathway for the central regulation of reproduction and are inhibited by negative energy balance. In normal adults, these neurons maintain elevated intracellular chloride so that GABAA receptor activation is excitatory. We hypothesized that fasting alters homeostatic mechanisms to eliminate excitatory responses to GABA but rejected this hypothesis when brief, local GABA application elicited action currents in GnRH neurons from fed and fasted mice. This response was specific to GABAA receptors, because glycine elicited no response. We next found that fasting reduced the frequency of spontaneous GABAergic postsynaptic currents (PSCs) and that this was reversed by in vivo treatment with leptin during the fast. In the presence of tetrodotoxin to minimize presynaptic actions, leptin also potentiated the postsynaptic response of these cells to GABAA receptor activation. Postsynaptic effects of leptin on GABAergic miniature PSCs were eliminated by inhibiting JAK2/3 (Janus kinase), the tyrosine kinase through which leptin receptors signal. In all experiments, elimination of PSCs at ECl or by treatment with the GABAA receptor antagonist bicuculline confirmed that PSCs were specifically mediated by GABAA receptor chloride channels. These data dem- onstrate that fasting and leptin act presynaptically and postsynaptically to alter GABAergic drive to GnRH neurons, providing evidence for GABAergic communication of metabolic cues to GnRH neurons, and suggest the possibility for functional leptin receptors on GnRH neurons.
    [Show full text]
  • IL-33, Diet-Induced Obesity, and Pulmonary Responses to Ozone David I
    Kasahara and Shore Respiratory Research (2020) 21:98 https://doi.org/10.1186/s12931-020-01361-9 RESEARCH Open Access IL-33, diet-induced obesity, and pulmonary responses to ozone David I. Kasahara and Stephanie A. Shore* Abstract Background: Obesity augments pulmonary responses to ozone. We have reported that IL-33 contributes to these effects of obesity in db/db mice. The purpose of this study was to determine whether IL-33 also contributes to obesity-related changes in the response to ozone in mice with diet-induced obesity. Methods: Male wildtype C57BL/6 mice and mice deficient in ST2, the IL-33 receptor, were placed on chow or high fat diets for 12 weeks from weaning. Because the microbiome has been implicated in obesity-related changes in the pulmonaryresponsetoozone,micewereeitherhousedwithothermiceofthesamegenotype(samehoused)orwith mice of the opposite genotype (cohoused). Cohousing transfers the gut microbiome from one mouse to its cagemates. Results: Diet-induced increases in body mass were not affected by ST2 deficiency or cohousing. In same housed mice, ST2 deficiency reduced ozone-induced airway hyperresponsiveness and neutrophil recruitment in chow-fed but not HFD- fed mice even though ST2 deficiency reduced bronchoalveolar lavage IL-5 in both diet groups. In chow-fed mice, cohousing abolished ST2-related reductions in ozone-induced airway hyperresponsiveness and neutrophil recruitment, butinHFD-fedmice,noeffectofcohousingontheseresponsestoozonewasobserved.Inchow-fedmice,ST2 deficiency and cohousing caused changes in the gut microbiome. High fat diet-feeding caused marked changes in the gut microbiome and overrode both ST2-related and cohousing-related differences in the gut microbiome observed in chow-fed mice.
    [Show full text]
  • Fetal Growth Signals
    Arch Dis Child: first published as 10.1136/adc.64.1_Spec_No.53 on 1 January 1989. Downloaded from Archives of Disease in Childhood, 1989, 64, 53-57 Current topic Fetal growth signals R D G MILNER AND D J HILL Department of Paediatrics, Children's Hospital, Sheffield Human fetal growth is not uniform. Tissue patterns growth factor fi like peptide is found in the vegetal and organ primordia are established during embryo- pole ectoderm of the early Xenopus embryo and is genesis, then from the end of the first trimester and transcribed by a maternally derived gene designated throughout the second the fetus undergoes massive Vgl. An ectodermal cell line, XTC, from the meta- hyperplasia. In the third trimester further organ morphosing tadpole releases a transforming growth modelling and functional maturation occur in pre- factor I8 like peptide in vitro.5 In the 11-18 day fetal paration for extrauterine life. Each aspect ofdevelop- mouse transforming growth factor 3 can be detected ment requires orchestrated intercellular signalling at in bone and connective tissue, particularly that two levels. The release of peptide growth factors derived from neural crest such as palate, larynx, and the modulation of an extracellular matrix are facial mesenchyme, and teeth.6 Staining was most paracrine actions that occur within cell populations intense at sites of tissue morphogenesis affecting and between adjacent germ layers. In contrast, mesodermal and epithelial interaction such as hair endocrine hormones may stimulate growth non- follicles, teeth, and secondary palate. copyright. specifically or promote specific maturational events. Recently both fibroblast growth factor and trans- The interactions between paracrinology, endocrino- forming growth factor i have been shown to exert logy, and environmental constraints to growth remarkable effects on embryonal morphology.
    [Show full text]