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Freuer D, Meisinger C. Causal effects of time-varying body size on selected autoimmune disorders: a life course Mendelian randomisation study. RMD Open 2023; 9:e003633. [PMID: 37963678 PMCID: PMC10649873 DOI: 10.1136/rmdopen-2023-003633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 10/30/2023] [Indexed: 11/16/2023] Open
Abstract
BACKGROUND Based on Barker's hypothesis, some studies investigated the associations between birth weight and several disorders. Apart from issues with statistical power and well-known shortcomings of the observational study design, there are no studies accounting for changes in weight-related body size over the life course regarding rheumatoid arthritis, psoriasis, psoriatic arthritis and multiple sclerosis. METHODS Using genetic information of up to 806 834 participants, this study investigated the associations between time-varying weight-related body size from birth to adulthood and the mentioned autoimmune diseases. Performing Mendelian randomisation (MR), the radial inverse-variance weighted approach was used iteratively in primary analyses. Robustness of the results was confirmed in several sensitivity analyses. Potential time-dependent mediation mechanisms were identified through network-clustering and assessed using multivariable MR. RESULTS Genetically predicted birth weight (fetal effect) was positively associated with rheumatoid arthritis (OR 1.44; 95% CI 1.17 to 1.77; Padj =0.005) but not with psoriasis, psoriatic arthritis or multiple sclerosis. This association was found to be mediated by body mass index (BMI) in adulthood (OR 1.45; 95% CI 1.14 to 1.84; Padj =0.019) rather than childhood. The direct effect of birth weight attenuated (OR 1.19; 95% CI 0.88 to 1.62); Padj =1) after adjustment for time-varying BMI. CONCLUSION Increased birth weight appears to be a risk factor for later manifestation of rheumatoid arthritis due to both fetal genetic components and high BMI persisting into adulthood. Approaches to prevent and minimise the risk of rheumatoid arthritis could include preventing obesity in adults with high birth weight.
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Affiliation(s)
- Dennis Freuer
- Epidemiology, Medical Faculty, University of Augsburg, University Hospital of Augsburg, Augsburg, Germany
| | - Christa Meisinger
- Epidemiology, Medical Faculty, University of Augsburg, University Hospital of Augsburg, Augsburg, Germany
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2
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Giudice A, Aliberti SM, Barbieri A, Pentangelo P, Bisogno I, D'Arena G, Cianciola E, Caraglia M, Capunzo M. Potential Mechanisms by which Glucocorticoids Induce Breast Carcinogenesis through Nrf2 Inhibition. FRONT BIOSCI-LANDMRK 2022; 27:223. [PMID: 35866405 DOI: 10.31083/j.fbl2707223] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/20/2022] [Accepted: 06/30/2022] [Indexed: 01/03/2025]
Abstract
Breast cancer is the most common malignancy among women worldwide. Several studies indicate that, in addition to established risk factors for breast cancer, other factors such as cortisol release related to psychological stress and drug treatment with high levels of glucocorticoids may also contribute significantly to the initiation of breast cancer. There are several possible mechanisms by which glucocorticoids might promote neoplastic transformation of breast tissue. Among these, the least known and studied is the inhibition of the nuclear erythroid factor 2-related (Nrf2)-antioxidant/electrophile response element (ARE/EpRE) pathway by high levels of glucocorticoids. Specifically, Nrf2 is a potent transcriptional activator that plays a central role in the basal and inducible expression of many cytoprotective genes that effectively protect mammalian cells from various forms of stress and reduce the propensity of tissues and organisms to develop disease or malignancy including breast cancer. Consequently, a loss of Nrf2 in response to high levels of gluco-corticoids may lead to a decrease in cellular defense against oxidative stress, which plays an important role in the initiation of human mammary carcinogenesis. In the present review, we provide a comprehensive overview of the current state of knowledge of the cellular mechanisms by which both glucocorticoid pharmacotherapy and endogenous GCs (cortisol in humans and corticosterone in rodents) may contribute to breast cancer development through inhibition of the Nrf2-ARE/EpRE pathway and the protective role of melatonin against glucocorticoid-induced apoptosis in the immune system.
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Affiliation(s)
- Aldo Giudice
- Animal Facility, Istituto Nazionale Tumori - "Fondazione G. Pascale" - IRCCS, 80131 Naples, Italy
| | - Silvana Mirella Aliberti
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081 Salerno, Italy
| | - Antonio Barbieri
- Animal Facility, Istituto Nazionale Tumori - "Fondazione G. Pascale" - IRCCS, 80131 Naples, Italy
| | - Paola Pentangelo
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081 Salerno, Italy
| | - Ilaria Bisogno
- Department of Radiological, Oncological and Anatomo-Pathological Science, University of Rome "Sapienza", 00161 Rome, Italy
| | - Giovanni D'Arena
- Hematology Service, San Luca Hospital, ASL Salerno, 84124 Salerno, Italy
| | - Emidio Cianciola
- Anesthesia and Intensive Care Unit, "Immacolata di Sapri" Hospital- ASL Salerno, 84073 Salerno, Italy
| | - Michele Caraglia
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Mario Capunzo
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081 Salerno, Italy
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Jin S, Sun X, Liu Q, Liang H, Li C, Mao Z, Song C, Xia W, Li Y, Xu S. Steroid Hormones in Cord Blood Mediate the Association Between Maternal Prepregnancy BMI and Birth Weight. Obesity (Silver Spring) 2019; 27:1338-1346. [PMID: 31207092 DOI: 10.1002/oby.22524] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 04/19/2019] [Indexed: 11/11/2022]
Abstract
OBJECTIVE Maternal overweight has been associated with increasing offspring birth weight, but epidemiological data on potential biological mechanisms are limited. This study aimed to examine whether steroid hormones mediate the association between maternal prepregnancy BMI (pre-BMI) and birth weight. METHODS This study involving 2,039 participants was conducted from an ongoing cohort study in Wuhan, China. Mediation analysis was used to identify the extent to which steroid hormones mediated associations. RESULTS Each one-unit increase in pre-BMI was significantly associated with lower log2 -transformed cord blood levels of cortisol and corticosterone. Levels of cortisol and corticosterone were also negatively associated with birth weight. It was estimated that corticosterone mediated 3.48% of the association between pre-BMI and birth weight, and no significant mediation effect was observed in cortisol. After stratification by maternal gestational weight gain (GWG; within or in excess of the Institute of Medicine [IOM] guidelines), the associations of pre-BMI with cortisol and corticosterone levels were significant in the women with GWG > IOM but not in women with GWG ≤ IOM. When the mediation analysis in the women with GWG > IOM was limited, the mediation effects of cord blood cortisol and corticosterone were both significant (P < 0.05). CONCLUSIONS Cord blood cortisol and corticosterone partially mediate the association of increased maternal pre-BMI with higher birth weight.
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Affiliation(s)
- Shuna Jin
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, and State Key Laboratory of Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaojie Sun
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, and State Key Laboratory of Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qi Liu
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, and State Key Laboratory of Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Huifang Liang
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, and State Key Laboratory of Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Chunhui Li
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, and State Key Laboratory of Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhenxing Mao
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Chengwu Song
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, China
| | - Wei Xia
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, and State Key Laboratory of Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yuanyuan Li
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, and State Key Laboratory of Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shunqing Xu
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, and State Key Laboratory of Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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Marzano F, Faienza MF, Caratozzolo MF, Brunetti G, Chiara M, Horner DS, Annese A, D'Erchia AM, Consiglio A, Pesole G, Sbisà E, Inzaghi E, Cianfarani S, Tullo A. Pilot study on circulating miRNA signature in children with obesity born small for gestational age and appropriate for gestational age. Pediatr Obes 2018; 13:803-811. [PMID: 30160046 DOI: 10.1111/ijpo.12439] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Revised: 05/25/2018] [Accepted: 05/29/2018] [Indexed: 02/01/2023]
Abstract
BACKGROUND Children born small for gestational age (SGA) are at increased risk of metabolic dysfunction. Dysregulation of specific microRNAs (miRNAs) contributes to aberrant gene expression patterns underlying metabolic dysfunction. OBJECTIVE We aimed to determine and compare circulating miRNA (c-miRNA) profile of SGA and appropriate for gestational age (AGA) children with obesity and with normal weight, in order to identify biomarkers for early detection of increased risk of developing metabolic dysfunction in SGA and AGA children with obesity. METHODS Small non-coding RNAs from serum of 15 SGA children with obesity (OB-SGA), 10 SGA children with normal weight (NW-SGA), 17 AGA children with obesity (OB-AGA) and 12 AGA children with normal weight (NW-AGA) (mean age 11.2 ± 2.6) have been extracted and sequenced in order to detect and quantify miRNA expression profiles. RESULTS RNA-seq analyses showed 28 miRNAs dysregulated in OB-SGA vs. NW-SGA and 19 miRNAs dysregulated in OB-AGA vs. NW-AGA. Among these, miR-92a-3p, miR-122-5p, miR-423-5p, miR-484, miR-486-3p and miR-532-5p were up regulated, and miR-181b-5p was down regulated in both OB-SGA and OB-AGA compared with normal weight counterparts. Pathway analysis and miRNA target prediction suggested that these miRNAs were particularly involved in insulin signalling, glucose transport, insulin resistance, cholesterol and lipid metabolism. CONCLUSION We identified a specific profile of c-miRNAs in SGA and AGA children with obesity compared with SGA and AGA children with normal weight. These c-miRNAs could represent specific biomarkers for early detection of increased risk of developing metabolic dysfunction in SGA and AGA children with obesity.
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Affiliation(s)
- F Marzano
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies-IBIOM, CNR, Bari, Italy
| | - M F Faienza
- Department of Biomedical Sciences and Human Oncology, Section of Pediatrics, University of Bari "A. Moro,", Bari, Italy
| | - M F Caratozzolo
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies-IBIOM, CNR, Bari, Italy
| | - G Brunetti
- Department of Basic Medical Sciences, Neuroscience, and Sense Organs, Section of Human Anatomy and Histology, University of Bari "A. Moro", Bari, Italy
| | - M Chiara
- Department of Biosciences, University of Milan, Milan, Italy
| | - D S Horner
- Department of Biosciences, University of Milan, Milan, Italy
| | - A Annese
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies-IBIOM, CNR, Bari, Italy
| | - A M D'Erchia
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies-IBIOM, CNR, Bari, Italy.,Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari "Aldo Moro", Bari, Italy
| | - A Consiglio
- Institute for Biomedical Technologies of Bari - ITB, National Research Council, Bari, Italy
| | - G Pesole
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies-IBIOM, CNR, Bari, Italy
| | - E Sbisà
- Institute for Biomedical Technologies of Bari - ITB, National Research Council, Bari, Italy
| | - E Inzaghi
- Dipartimento Pediatrico Universitario Ospedaliero, "Bambino Gesu`" Children's Hospital - Tor Vergata University, Rome, Italy
| | - S Cianfarani
- Dipartimento Pediatrico Universitario Ospedaliero, "Bambino Gesu`" Children's Hospital - Tor Vergata University, Rome, Italy.,Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - A Tullo
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies-IBIOM, CNR, Bari, Italy
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Gohlke B, Wudy SA, Stutte S, Bartmann P, Hartmann MF, Woelfle J. Increased Steroid Excretion in Children with Extremely Low Birth Weight at a Median Age of 9.8 years. Horm Res Paediatr 2016; 84:331-7. [PMID: 26440939 DOI: 10.1159/000441031] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Accepted: 09/07/2015] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Events during foetal or early extrauterine life may affect bodily structure and/or functions and even pave the way for adult diseases. AIMS To find whether extremely low birth weight (ELBW) infants differ from healthy controls regarding the excretion of steroid metabolites. METHODS The study compared 17 female and 10 male ELBW infants, all prepubertal, aged 8-11 years, birth weight <1,000 g, with 27 age- and sex-matched controls. All were healthy at the time of the study. Height, weight and BMI did not differ between the groups. Results were adjusted according to body surface area. 36 urinary steroid metabolites were quantified by gas chromatography-mass spectrometry. RESULTS In the ELBW girls 33/36 steroid metabolites were higher (19 significantly) than in the controls. All 36 steroid metabolites were higher in the ELBW boys (9 significantly) than in the controls. Sums of mineralocorticoid precursors, metabolites descriptive for cortisol and parameters of adrenal androgen production were significantly higher in ELBW infants (both sexes). Only the sum of the metabolites known to be illustrative for adrenal 11β-hydroxysteroid dehydrogenase activity was not different. CONCLUSION Prepubertal ELBW children have an augmented urinary excretion of adrenal androgens, cortisol and mineralocorticoid precursors. These findings corroborate and help to explain the link between early-life adversity and subsequent adrenocortical function.
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Affiliation(s)
- Bettina Gohlke
- Paediatric Endocrinology Division, Children's Hospital, University of Bonn, Bonn, Germany
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Ma S, Li T, Guo K, Li X, An S, Hou S, Chen R, Yang B, Liu S, Fu J. Effective treatment with combination of peripheral 5-hydroxytryptamine synthetic inhibitor and 5-hydroxytryptamine 2 receptor antagonist on glucocorticoid-induced whole-body insulin resistance with hyperglycemia. J Diabetes Investig 2016; 7:833-844. [PMID: 27177506 PMCID: PMC5089945 DOI: 10.1111/jdi.12526] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 02/24/2016] [Accepted: 03/16/2016] [Indexed: 12/12/2022] Open
Abstract
AIMS/INTRODUCTION Our previous study found that dexamethasone-induced insulin resistance (IR) was involved in 5-hydroxytryptamine (5-HT) synthesis and 5-hydroxytryptamine 2 receptor (5-HT2 R) in the periphery. The present study examined the effects of inhibitions of both peripheral 5-HT synthesis and 5-HT2 R on dexamethasone-induced IR. MATERIALS AND METHODS Male rats were exposed to dexamethasone for 10 days, then treated with or without a 5-HT2 R antagonist, sarpogrelate, a 5-HT synthetic inhibitor, carbidopa, alone or in combination for 20 days. RESULTS Dexamethasone-induced whole-body IR, with glucose intolerance, decreased insulin sensitivity, hyperglycemia, hyperinsulinemia and dyslipidemia, could be effectively abolished by sarpogrelate or/and carbidopa, whereas IR-related actions of dexamethasone in tissues were accompanied by increased 5-HT synthesis in the liver and visceral adipose, and upregulated 5-HT2 R (5-HT2A R and 5-HT2B R) expression in these two tissues as well as in skeletal muscle. Sarpogrelate or/and carbidopa treatment significantly abolished dexamethasone-caused tissue-specific IR. In the liver, increased gluconeogenesis, triglycerides and very low-density lipoprotein syntheses with steatosis, and downregulated expression of plasmalemmal glucose transporter-2 were markedly reversed. In the visceral adipose and skeletal muscle, downregulated expression of plasmalemmal glucose transporter-4 was significantly reversed, and increased lipolysis was also reversed in the visceral adipose. Dexamethasone-induced activations of hepatic mammalian target of rapamycin serine2448 , and S6K threonine389/412 phosphorylation were also abolished markedly by sarpogrelate or/and carbidopa. Co-treatment with sarpogrelate and carbidopa showed a synergistic effect on suppressing dexamethasone actions. CONCLUSION Inhibitions of both peripheral 5-HT synthesis and 5-HT2 R are expected to be a dependable target for treatment of steroid-induced diabetes.
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Affiliation(s)
- Shaoxin Ma
- Postgraduates of China Pharmaceutical University, Nanjing, China
| | - Tao Li
- Postgraduates of China Pharmaceutical University, Nanjing, China
| | - Keke Guo
- Postgraduates of China Pharmaceutical University, Nanjing, China
| | - Xin Li
- Postgraduates of China Pharmaceutical University, Nanjing, China
| | - Shanshan An
- Postgraduates of China Pharmaceutical University, Nanjing, China
| | - Shanshan Hou
- Postgraduates of China Pharmaceutical University, Nanjing, China
| | - Ru Chen
- Postgraduates of China Pharmaceutical University, Nanjing, China
| | - Bo Yang
- Undergraduates of China Pharmaceutical University, Nanjing, China
| | - Siyu Liu
- Undergraduates of China Pharmaceutical University, Nanjing, China
| | - Jihua Fu
- Department of Physiology, China Pharmaceutical University, Nanjing, China.
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Kueper J, Beyth S, Liebergall M, Kaplan L, Schroeder JE. Evidence for the adverse effect of starvation on bone quality: a review of the literature. Int J Endocrinol 2015; 2015:628740. [PMID: 25810719 PMCID: PMC4355339 DOI: 10.1155/2015/628740] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Revised: 01/27/2015] [Accepted: 01/31/2015] [Indexed: 02/05/2023] Open
Abstract
Malnutrition and starvation's possible adverse impacts on bone health and bone quality first came into the spotlight after the horrors of the Holocaust and the ghettos of World War II. Famine and food restrictions led to a mean caloric intake of 200-800 calories a day in the ghettos and concentration camps, resulting in catabolysis and starvation of the inhabitants and prisoners. Severely increased risks of fracture, poor bone mineral density, and decreased cortical strength were noted in several case series and descriptive reports addressing the medical issues of these individuals. A severe effect of severely diminished food intake and frequently concomitant calcium- and Vitamin D deficiencies was subsequently proven in both animal models and the most common cause of starvation in developed countries is anorexia nervosa. This review attempts to summarize the literature available on the impact of the metabolic response to Starvation on overall bone health and bone quality.
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Affiliation(s)
- Janina Kueper
- Charité University of Medicine, Charitéplatz 1, 10117 Berlin, Germany
| | - Shaul Beyth
- Department of Orthopedic Surgery, Spine Surgery, Hadassah Medical Center, Kiryat Hadassah, P.O. Box 12000, 91120 Jerusalem, Israel
| | - Meir Liebergall
- Department of Orthopedic Surgery, Spine Surgery, Hadassah Medical Center, Kiryat Hadassah, P.O. Box 12000, 91120 Jerusalem, Israel
| | - Leon Kaplan
- Department of Orthopedic Surgery, Spine Surgery, Hadassah Medical Center, Kiryat Hadassah, P.O. Box 12000, 91120 Jerusalem, Israel
| | - Josh E. Schroeder
- Department of Orthopedic Surgery, Spine Surgery, Hadassah Medical Center, Kiryat Hadassah, P.O. Box 12000, 91120 Jerusalem, Israel
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de Guia RM, Rose AJ, Sommerfeld A, Seibert O, Strzoda D, Zota A, Feuchter Y, Krones-Herzig A, Sijmonsma T, Kirilov M, Sticht C, Gretz N, Dallinga-Thie G, Diederichs S, Klöting N, Blüher M, Berriel Diaz M, Herzig S. microRNA-379 couples glucocorticoid hormones to dysfunctional lipid homeostasis. EMBO J 2014; 34:344-60. [PMID: 25510864 DOI: 10.15252/embj.201490464] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
In mammals, glucocorticoids (GCs) and their intracellular receptor, the glucocorticoid receptor (GR), represent critical checkpoints in the endocrine control of energy homeostasis. Indeed, aberrant GC action is linked to severe metabolic stress conditions as seen in Cushing's syndrome, GC therapy and certain components of the Metabolic Syndrome, including obesity and insulin resistance. Here, we identify the hepatic induction of the mammalian conserved microRNA (miR)-379/410 genomic cluster as a key component of GC/GR-driven metabolic dysfunction. Particularly, miR-379 was up-regulated in mouse models of hyperglucocorticoidemia and obesity as well as human liver in a GC/GR-dependent manner. Hepatocyte-specific silencing of miR-379 substantially reduced circulating very-low-density lipoprotein (VLDL)-associated triglyceride (TG) levels in healthy mice and normalized aberrant lipid profiles in metabolically challenged animals, mediated through miR-379 effects on key receptors in hepatic TG re-uptake. As hepatic miR-379 levels were also correlated with GC and TG levels in human obese patients, the identification of a GC/GR-controlled miRNA cluster not only defines a novel layer of hormone-dependent metabolic control but also paves the way to alternative miRNA-based therapeutic approaches in metabolic dysfunction.
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Affiliation(s)
- Roldan M de Guia
- Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany
| | - Adam J Rose
- Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany
| | - Anke Sommerfeld
- Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany
| | - Oksana Seibert
- Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany
| | - Daniela Strzoda
- Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany
| | - Annika Zota
- Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany
| | - Yvonne Feuchter
- Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany
| | - Anja Krones-Herzig
- Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany
| | - Tjeerd Sijmonsma
- Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany
| | - Milen Kirilov
- Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany
| | - Carsten Sticht
- Medical Research Center, Klinikum Mannheim, Mannheim, Germany
| | - Norbert Gretz
- Medical Research Center, Klinikum Mannheim, Mannheim, Germany
| | | | - Sven Diederichs
- Helmholtz-University-Group Molecular RNA Biology and Cancer DKFZ, Heidelberg, Germany Institute of Pathology Heidelberg University, Heidelberg, Germany
| | - Nora Klöting
- Department of Medicine, University of Leipzig, Leipzig, Germany
| | - Matthias Blüher
- Department of Medicine, University of Leipzig, Leipzig, Germany
| | - Mauricio Berriel Diaz
- Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany
| | - Stephan Herzig
- Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany
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Altered adipocyte structure and function in nutritionally programmed microswine offspring. J Dev Orig Health Dis 2014; 3:198-209. [PMID: 25102010 DOI: 10.1017/s2040174412000232] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Adipose tissue (AT) dysfunction links obesity of any cause with cardiometabolic disease, but whether early-life nutritional deficiency can program adipocyte dysfunction independently of obesity is untested. In 3-5-month-old juvenile microswine offspring exposed to isocaloric perinatal maternal protein restriction (MPR) and exhibiting accelerated prepubertal fat accrual without obesity, we assessed markers of acquired obesity: adiponectin and tumor necrosis factor (TNF)-α messenger ribonucleic acid (mRNA) levels and adipocyte size in intra-abdominal (ABD-AT) and subcutaneous (SC-AT) adipose tissues. Plasma cortisol, leptin and insulin levels were measured in fetal, neonatal and juvenile offspring. In juvenile low-protein offspring (LPO), adipocyte size in ABD-AT was reduced 22% (P = 0.011 v. controls), whereas adipocyte size in SC-AT was increased in female LPO (P = 0.05) and normal in male LPO; yet, adiponectin mRNA in LPO was low in both sexes and in both depots (P < 0.001). Plasma leptin (P = 0.004) and cortisol (P < 0.05) were reduced only in neonatal LPO during MPR. In juveniles, correlations between % body fat and adiponectin mRNA, TNF-α mRNA or plasma leptin were significant in normal-protein offspring (NPO) but absent in LPO. Plasma glucose in juvenile LPO was increased in males but decreased in females (interaction, P = 0.023); plasma insulin levels and insulin sensitivity were unaffected. Findings support nutritional programming of adipocyte size and gene expression and subtly altered glucose homeostasis. Reduced adiponectin mRNA and adipokine dysregulation in juvenile LPO following accelerated growth occurred independently of obesity, adipocyte hypertrophy or inflammatory markers; thus, perinatal MPR and/or growth acceleration can alter adipocyte structure and disturb adipokine homeostasis in metabolically adverse patterns predictive of enhanced disease risk.
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Painter RC, Roseboom TJ, de Rooij SR. Long-term effects of prenatal stress and glucocorticoid exposure. ACTA ACUST UNITED AC 2014; 96:315-24. [PMID: 24203920 DOI: 10.1002/bdrc.21021] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2012] [Accepted: 11/07/2012] [Indexed: 12/13/2022]
Abstract
There is a growing body of evidence suggesting that events during prenatal life can have long-lasting effects on development and adult health. Stress during pregnancy is common and has been linked to increased incidence of a range of affective and behavioral outcomes in the offspring in later life and also some somatic outcomes. Glucocorticoids, and their actions on the fetus, which are regulated by placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), are hypothesized to mediate these effects. Animal studies have demonstrated long-term effects of stress and glucocorticoid administration on behavioral outcomes, as well as increased blood pressure, altered hypothalamic pituitary adrenal axis (HPA) function, and decreased glucose tolerance and brain size. In humans, licorice, which inhibits placental 11β-HSD2 when consumed during pregnancy, has been shown to increase the risk of behavioral problems linked to altered HPA activity. Synthetic glucocorticoids administered during pregnancy to improve fetal lung maturity in threatened preterm birth have been shown to reduce birth weight and head circumference, but have not been linked to gross changes in long-term health to date. It is important to consider the long-term consequences of stress, and medication that mimics stress, during pregnancy.
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Affiliation(s)
- Rebecca C Painter
- Department of Obstetrics and Gynaecology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
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11
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Rose AJ, Herzig S. Metabolic control through glucocorticoid hormones: an update. Mol Cell Endocrinol 2013; 380:65-78. [PMID: 23523966 DOI: 10.1016/j.mce.2013.03.007] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2012] [Revised: 02/21/2013] [Accepted: 03/08/2013] [Indexed: 01/28/2023]
Abstract
In the past decades, glucocorticoid (GC) hormones and their cognate, intracellular receptor, the glucocorticoid receptor (GR), have been well established as critical checkpoints in mammalian energy homeostasis. Whereas many aspects in healthy nutrient metabolism require physiological levels and/or action of GC, aberrant GC/GR signalling has been linked to severe metabolic dysfunction, including obesity, insulin resistance and type 2 diabetes. Consequently, studies of the molecular mechanisms within the GC signalling axis have become a major focus in biomedical research, up-to-date particularly focusing on systemic glucose and lipid handling. However, with the availability of novel high throughput technologies and more sophisticated metabolic phenotyping capabilities, as-yet non-appreciated, metabolic functions of GC have been recently discovered, including regulatory roles of the GC/GR axis in protein and bile acid homeostasis as well as metabolic inter-organ communication. Therefore, this review summarises recent advances in GC/GR biology, and summarises findings relevant for basic and translational metabolic research.
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Affiliation(s)
- Adam J Rose
- Joint Research Division, Molecular Metabolic Control, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH), Heidelberg University, Network Aging Research, University Hospital Heidelberg, Germany
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12
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Brunton PJ. Effects of maternal exposure to social stress during pregnancy: consequences for mother and offspring. Reproduction 2013; 146:R175-89. [DOI: 10.1530/rep-13-0258] [Citation(s) in RCA: 144] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
A suboptimalin uteroenvironment, for example, as a result of maternal stress, can have detrimental effects on the pregnancy and long-term adverse ‘programming’ effects on the offspring. This article focuses on the effects of prenatal social stress on the mother, her pregnancy and the offspring, since these issues have ethological relevance in both animals and humans. The consequences of social stress exposure depend on when during pregnancy the stress occurs, and many of the effects on the offspring are sex specific. Social stress during early pregnancy tends to result in pregnancy loss, whereas stress exposure later in pregnancy, when the mother has already invested considerable resources in the foetuses, results in programmed offspring of low birth weight: a risk factor for various adulthood diseases. Neuroendocrine and behavioural responses to stress in the offspring are particularly sensitive to foetal programming by prenatal stress, indicated by enhanced hypothalamo-pituitary–adrenal (HPA) axis responses and increased anxiety behaviour, which result from permanent changes in the offspring's brain. The dysregulation of HPA axis function may also interfere with other systems, for example, the hypothalamic–pituitary–gonadal axis, as there is evidence for alterations in steroidogenesis, reproductive potential and impaired reproductive/social behaviours in prenatally stressed offspring. Prenatal social stress also programmes future maternal behaviour, highlighting the potential for negative phenotypes to be transmitted to future generations. The possible mechanisms through which maternal stress during pregnancy is transmitted to the foetuses and the foetal brain is programmed by prenatal stress and the potential to overwrite programming of the offspring are discussed.
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13
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Kongsted AH, Husted SV, Thygesen MP, Christensen VG, Blache D, Tolver A, Larsen T, Quistorff B, Nielsen MO. Pre- and postnatal nutrition in sheep affects β-cell secretion and hypothalamic control. J Endocrinol 2013; 219:159-71. [PMID: 24096964 DOI: 10.1530/joe-13-0099] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Maternal undernutrition increases the risk of type 2 diabetes and metabolic syndrome later in life, particularly upon postnatal exposure to a high-energy diet. However, dysfunctions of, for example, the glucose-insulin axis are not readily detectable by conventional tests early in life, making it difficult to identify individuals at risk. Thus, other methods are required. We hypothesised that prenatally undernourished individuals (but not postnatally overnourished ones) are adapted to a life with limited food availability, which would be evident under conditions reflecting starvation, stress and short-term abundance of food. In this study, twin-pregnant sheep were fed diets meeting 100% (NORM) or 50% (LOW) of energy and protein requirements during the last trimester. Twin offspring were fed either a normal moderate (CONV) diet or a high-carbohydrate-high-fat (HCHF) diet from 3 days to 6 months of age (approximately puberty) and the same moderate diet thereafter until 2 years of age (young adulthood; only females), resulting in four groups: NORM-CONV, LOW-CONV, NORM-HCHF and LOW-HCHF. At the age of 6 months and 2 years respectively, they were subjected to fasting and propionate (nutrient abundance) and adrenalin challenges. At 6 months of age, postnatal HCHF diet exposure caused metabolic alterations, reflecting hypertriglyceridaemia and altered pancreatic β-cell secretion. Irrespective of postnatal diet, prenatal undernutrition was found to be associated with unexpected endocrine responses of leptin, IGF1 and cortisol during fasting (lack of or the opposite response compared with the controls) in 2-year-old adults. In conclusion, a HCHF diet interfered with β-cell function, whereas maternal undernutrition did not lead to any changes in the LOW offspring, except to abnormal hormone responses, suggesting that fetal programming interferes with hypothalamic integration of important endocrine axis.
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Affiliation(s)
- Anna H Kongsted
- Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Cook Medical Europe APS, Bjaeverskov, Denmark School of Animal Biology, University of Western Australia, Perth, Western Australia, Australia Department of Basic Sciences and Environment, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Department of Animal Science, Faculty of Science and Technology, Aarhus University, Aarhus, Denmark Department of Biomedical Sciences, Faculty of Health and Medical Sciences, Nuclear Magnetic Resonance Centre, University of Copenhagen, Copenhagen, Denmark
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14
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Duthie L, Reynolds RM. Changes in the maternal hypothalamic-pituitary-adrenal axis in pregnancy and postpartum: influences on maternal and fetal outcomes. Neuroendocrinology 2013; 98:106-15. [PMID: 23969897 DOI: 10.1159/000354702] [Citation(s) in RCA: 227] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2013] [Accepted: 07/19/2013] [Indexed: 11/19/2022]
Abstract
Overexposure of the developing fetus to glucocorticoids is hypothesised to be one of the key mechanisms linking early life development with later life disease. The maternal hypothalamic-pituitary-adrenal (HPA) axis undergoes dramatic changes during pregnancy and postpartum. Although cortisol levels rise threefold by the third trimester, the fetus is partially protected from high cortisol by activity of the enzyme 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2). Maternal HPA axis activity and activity of HSD11B2 may be modified by maternal stress and disease allowing greater transfer of glucocorticoids from mother to fetus. Here we review emerging data from human studies linking dysregulation of the maternal HPA axis to outcomes in both the mother and her offspring. For the offspring, greater glucocorticoid exposure is associated with lower birth weight and shorter gestation at delivery. In addition, evidence supports longer term consequences for the offspring including re-setting of the HPA axis and susceptibility to neurodevelopmental problems and cardiometabolic disease. For the mother, the changes in the HPA axis, particularly in the postpartum period, may increase vulnerability to mood disturbances. Further understanding of the changes in the HPA axis during pregnancy and the impact of these changes may ultimately allow early identification of those most at risk of future disease.
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Affiliation(s)
- Leanne Duthie
- Endocrinology Unit, University/British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
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15
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Abstract
Development of metabolic syndrome is attributed to genes, dietary intake, physical activity and environmental factors. Fetal programming due to maternal nutrition is also an important factor especially in developing countries where intrauterine growth retardation followed by excess nutrition postnatally is causing mismatch predisposing individuals to development of metabolic syndrome and its components. Several epidemiological and animal studies have provided evidence for the link between intrauterine growth retardation and adult metabolic diseases. Deficiency of macronutrients, protein and carbohydrates, during pregnancy and gestation results in lower infant birth weight, a surrogate marker of fetal growth and subsequently insulin resistance, glucose intolerance, hypertension and adiposity in adulthood. The role of micronutrients is less extensively studied but however gaining attention with several recent studies focusing on this aspect. Several mechanisms have been proposed to explain the developmental origin of adult diseases important among them being alteration of hypothalamic pituitary axis, epigenetic regulation of gene expression and oxidative stress. All of these mechanisms may be acting at different time during gestation and contributing to development of metabolic syndrome in adulthood.
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Affiliation(s)
- Ramakrishnan Lakshmy
- Department of Cardiac Biochemistry, All India Institute of Medical Sciences, New Delhi, 110049, India,
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Goosby BJ, Heidbrink C. Transgenerational Consequences of Racial Discrimination for African American Health. SOCIOLOGY COMPASS 2013; 7:630-643. [PMID: 24855488 PMCID: PMC4026365 DOI: 10.1111/soc4.12054] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/18/2023]
Abstract
Disparities in African American health remain pervasive and persist transgenerationally. There is a growing consensus that both structural and interpersonal racial discrimination are key mechanisms affecting African American health. The Biopsychosocial Model of Racism as a Stressor posits that the persistent stress of experiencing discrimination take a physical toll on the health of African Americans and is ultimately manifested in the onset of illness. However, the degree to which the health consequences of racism and discrimination can be passed down from one generation to the next is an important avenue of exploration. In this review, we discuss and link literature across disciplines demonstrating the harmful impact of racism on African American physical health and the health of their offspring.
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Affiliation(s)
- Bridget J. Goosby
- Department of Sociology, University of Nebraska Lincoln, 742 Oldfather Hall, Lincoln, NE 68588, United States
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Hajat A, Diez-Roux AV, Sánchez BN, Holvoet P, Lima JA, Merkin SS, Polak JF, Seeman T, Wu M. Examining the association between salivary cortisol levels and subclinical measures of atherosclerosis: the Multi-Ethnic Study of Atherosclerosis. Psychoneuroendocrinology 2013; 38:1036-46. [PMID: 23146655 PMCID: PMC4020284 DOI: 10.1016/j.psyneuen.2012.10.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2012] [Revised: 09/01/2012] [Accepted: 10/08/2012] [Indexed: 01/31/2023]
Abstract
OBJECTIVE To investigate the association between salivary cortisol and two markers of subclinical cardiovascular disease (CVD), coronary calcification (CAC), and ankle-brachial index (ABI). METHODS Data from an ancillary study to the Multi-Ethnic Study of Atherosclerosis (MESA), the MESA Stress Study, were used to analyze associations of salivary cortisol data collected six times per day over three days with CAC and ABI. The authors used mixed models with repeat cortisol measures nested within persons to determine if specific features of the cortisol profile were associated with CAC and ABI. RESULTS A total of 464 participants were included in the CAC analysis and 610 in the ABI analysis. The mean age of participants was 65.6 years. A 1-unit increase in log coronary calcium was associated with a 1.77% flatter early decline in cortisol (95% CI: 0.23, 3.34) among men and women combined. Among women low ABI was associated with a steeper early decline (-13.95% CI: -25.58, -3.39) and a marginally statistically significant flatter late decline (1.39% CI: -0.009, 2.81). The cortisol area under the curve and wake to bedtime slope were not associated with subclinical CVD. CONCLUSIONS This study provides weak support for the link between cortisol and measures of subclinical atherosclerosis. We found an association between some features of the diurnal cortisol profile and coronary calcification and ABI but associations were not consistent across subclinical measures. There are methodological challenges in detecting associations of cortisol measures at a point in time with health outcomes that develop over a lifetime. Studies of short-term mechanisms linking stress to physiological processes related to the development of early atherosclerosis may be more informative.
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Affiliation(s)
- Anjum Hajat
- University of Washington, Department of Environmental & Occupational Health Sciences, Seattle, WA 98102, United States.
| | | | | | - Paul Holvoet
- Katholieke Universiteit Leuven, Department of Cardiovascular Disease
| | - João A. Lima
- Johns Hopkins University, Department of Cardiology
| | | | - Joseph F. Polak
- Tufts University, School of Medicine, Department of Radiology
| | - Teresa Seeman
- University of California Los Angeles, Division of Geriatrics
| | - Meihua Wu
- University of Michigan, Department of Biostatistics
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18
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Devlin MJ, Grasemann C, Cloutier AM, Louis L, Alm C, Palmert MR, Bouxsein ML. Maternal perinatal diet induces developmental programming of bone architecture. J Endocrinol 2013; 217:69-81. [PMID: 23503967 PMCID: PMC3792707 DOI: 10.1530/joe-12-0403] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Maternal high-fat (HF) diet can alter offspring metabolism via perinatal developmental programming. This study tests the hypothesis that maternal HF diet also induces perinatal programming of offspring bone mass and strength. We compared skeletal acquisition in pups from C57Bl/6J mice fed HF or normal diet from preconception through lactation. Three-week-old male and female pups from HF (HF-N) and normal mothers (N-N) were weaned onto normal diet. Outcomes at 14 and 26 weeks of age included body mass, body composition, whole-body bone mineral content (WBBMC) via peripheral dual-energy X-ray absorptiometry, femoral cortical and trabecular architecture via microcomputed tomography, and glucose tolerance. Female HF-N had normal body mass and glucose tolerance, with lower body fat (%) but higher serum leptin at 14 weeks vs. N-N (P<0.05 for both). WBBMC was 12% lower at 14 weeks and 5% lower at 26 weeks, but trabecular bone volume fraction was 20% higher at 14 weeks in female HF-N vs. N-N (P<0.05 for all). Male HF-N had normal body mass and mildly impaired glucose tolerance, with lower body fat (%) at 14 weeks and lower serum leptin at 26 weeks vs. N-N (P<0.05 for both). Serum insulin was higher at 14 weeks and lower at 26 weeks in HF-N vs. N-N (P<0.05). Trabecular BV/TV was 34% higher and cortical bone area was 6% higher at 14 weeks vs. N-N (P<0.05 for both). These data suggest that maternal HF diet has complex effects on offspring bone, supporting the hypothesis that maternal diet alters postnatal skeletal homeostasis.
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Affiliation(s)
- M J Devlin
- Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
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19
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Johnsen L, Kongsted AH, Nielsen MO. Prenatal undernutrition and postnatal overnutrition alter thyroid hormone axis function in sheep. J Endocrinol 2013; 216:389-402. [PMID: 23287634 DOI: 10.1530/joe-12-0389] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Mounting evidence led us to hypothesize that i) function of the thyroid hormone (TH) axis can be programed by late gestation undernutrition (LG-UN) and ii) early-postnatal-life overnutrition (EL-ON) exacerbates the fetal impacts on TH axis function. In a 2 × 2 factorial experiment, 21 twin-bearing sheep were fed one of two diets during late gestation: NORM (fulfilling energy and protein requirements) or LOW (50% of NORM). From day 3 to 6 months after birth (around puberty), the twin lambs were assigned to each their diet: conventional (CONV) or high-carbohydrate, high-fat, where after half the lambs were killed. Remaining sheep (exclusively females) were fed the same moderate diet until 2 years of age (young adults). At 6 months and 2 years of age, fasting challenges were conducted and target tissues were collected at autopsy. LG-UN caused adult hyperthyroidism associated with increased thyroid expression of genes regulating TH synthesis and deiodination. In one or more of the target tissues, liver, cardiac muscle, and longissimus dorsi muscle, gene expressions were increased by LG-UN for TH receptors (THRA and THRB) and deiodinases but were decreased in visceral and subcutaneous adipose tissues. EL-ON increased TH levels in adolescent lambs, but this was reversed after diet correction and not evident in adulthood. We conclude that LG-UN programed TH axis function at the secretory level and differentially in target tissues, which was increasingly manifested with age. Differential TH signaling in adipose vs other tissues may be part of a mechanism whereby fetal malnutrition can predispose for obesity and other metabolic disorders.
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Affiliation(s)
- L Johnsen
- Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Groennegaardsvej 7, DK-1870 Frederiksberg, Denmark
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20
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Brenseke B, Prater MR, Bahamonde J, Gutierrez JC. Current thoughts on maternal nutrition and fetal programming of the metabolic syndrome. J Pregnancy 2013; 2013:368461. [PMID: 23476780 PMCID: PMC3586494 DOI: 10.1155/2013/368461] [Citation(s) in RCA: 88] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2012] [Accepted: 01/03/2013] [Indexed: 02/07/2023] Open
Abstract
Chronic diseases such as type 2 diabetes and cardiovascular disease are the leading cause of death and disability worldwide. Although the metabolic syndrome has been defined in various ways, the ultimate importance of recognizing this combination of disorders is that it helps identify individuals at high risk for both type 2 diabetes and cardiovascular disease. Evidence from observational and experimental studies links adverse exposures in early life, particularly relating to nutrition, to chronic disease susceptibility in adulthood. Such studies provide the foundation and framework for the relatively new field of developmental origins of health and disease (DOHaD). Although great strides have been made in identifying the putative concepts and mechanisms relating specific exposures in early life to the risk of developing chronic diseases in adulthood, a complete picture remains obscure. To date, the main focus of the field has been on perinatal undernutrition and specific nutrient deficiencies; however, the current global health crisis of overweight and obesity demands that perinatal overnutrition and specific nutrient excesses be examined. This paper assembles current thoughts on the concepts and mechanisms behind the DOHaD as they relate to maternal nutrition, and highlights specific contributions made by macro- and micronutrients.
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Affiliation(s)
- Bonnie Brenseke
- Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, VA 24061, USA
- Department of Pathology, Campbell University School of Osteopathic Medicine, Buies Creek, NC 27506, USA
| | - M. Renee Prater
- Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, VA 24061, USA
- Department of Biomedical Sciences, Edward Via College of Osteopathic Medicine, 2265 Kraft Drive, Blacksburg, VA 24060, USA
| | - Javiera Bahamonde
- Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, VA 24061, USA
| | - J. Claudio Gutierrez
- Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, VA 24061, USA
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21
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Mackenzie SD, Walker BR. Targeting endogenous glucocorticoids in degenerative disease. Clin Med (Lond) 2012. [DOI: 10.7861/clinmedicine.12-6-s58] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Pereira CD, Azevedo I, Monteiro R, Martins MJ. 11β-Hydroxysteroid dehydrogenase type 1: relevance of its modulation in the pathophysiology of obesity, the metabolic syndrome and type 2 diabetes mellitus. Diabetes Obes Metab 2012; 14:869-81. [PMID: 22321826 DOI: 10.1111/j.1463-1326.2012.01582.x] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Recent evidence strongly argues for a pathogenic role of glucocorticoids and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in obesity and the metabolic syndrome, a cluster of risk factors for atherosclerotic cardiovascular disease and type 2 diabetes mellitus (T2DM) that includes insulin resistance (IR), dyslipidaemia, hypertension and visceral obesity. This has been partially prompted not only by the striking clinical resemblances between the metabolic syndrome and Cushing's syndrome (a state characterized by hypercortisolism that associates with metabolic syndrome components) but also from monogenic rodent models for the metabolic syndrome (e.g. the leptin-deficient ob/ob mouse or the leptin-resistant Zucker rat) that display overall increased secretion of glucocorticoids. However, systemic circulating glucocorticoids are not elevated in obese patients and/or patients with metabolic syndrome. The study of the role of 11β-HSD system shed light on this conundrum, showing that local glucocorticoids are finely regulated in a tissue-specific manner at the pre-receptor level. The system comprises two microsomal enzymes that either activate cortisone to cortisol (11β-HSD1) or inactivate cortisol to cortisone (11β-HSD2). Transgenic rodent models, knockout (KO) for HSD11B1 or with HSD11B1 or HSD11B2 overexpression, specifically targeted to the liver or adipose tissue, have been developed and helped unravel the currently undisputable role of the enzymes in metabolic syndrome pathophysiology, in each of its isolated components and in their prevention. In the transgenic HSD11B1 overexpressing models, different features of the metabolic syndrome and obesity are replicated. HSD11B1 gene deficiency or HSD11B2 gene overexpression associates with improvements in the metabolic profile. In face of these demonstrations, research efforts are now being turned both into the inhibition of 11β-HSD1 as a possible pharmacological target and into the role of dietary habits on the establishment or the prevention of the metabolic syndrome, obesity and T2DM through 11β-HSD1 modulation. We intend to review and discuss 11β-HSD1 and obesity, the metabolic syndrome and T2DM and to highlight the potential of its inhibition for therapeutic or prophylactic approaches in those metabolic diseases.
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Affiliation(s)
- C D Pereira
- Department of Biochemistry (U38/FCT), Faculty of Medicine, University of Porto, Portugal
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Kinouchi R, Matsuzaki T, Iwasa T, Gereltsetseg G, Nakazawa H, Kunimi K, Kuwahara A, Yasui T, Irahara M. Prepubertal exposure to glucocorticoid delays puberty independent of the hypothalamic Kiss1‐GnRH system in female rats. Int J Dev Neurosci 2012; 30:596-601. [DOI: 10.1016/j.ijdevneu.2012.09.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2012] [Revised: 08/23/2012] [Accepted: 09/01/2012] [Indexed: 11/26/2022] Open
Affiliation(s)
- Riyo Kinouchi
- Department of Obstetrics and GynecologyThe University of Tokushima Graduate SchoolInstitute of Health Biosciences3‐18‐15 Kuramoto‐choTokushima770‐8503Japan
| | - Toshiya Matsuzaki
- Department of Obstetrics and GynecologyThe University of Tokushima Graduate SchoolInstitute of Health Biosciences3‐18‐15 Kuramoto‐choTokushima770‐8503Japan
| | - Takeshi Iwasa
- Department of Obstetrics and GynecologyThe University of Tokushima Graduate SchoolInstitute of Health Biosciences3‐18‐15 Kuramoto‐choTokushima770‐8503Japan
| | - Ganbat Gereltsetseg
- Department of Obstetrics and GynecologyThe University of Tokushima Graduate SchoolInstitute of Health Biosciences3‐18‐15 Kuramoto‐choTokushima770‐8503Japan
| | - Hiroshi Nakazawa
- Department of Obstetrics and GynecologyThe University of Tokushima Graduate SchoolInstitute of Health Biosciences3‐18‐15 Kuramoto‐choTokushima770‐8503Japan
| | - Kotaro Kunimi
- Department of Obstetrics and GynecologyThe University of Tokushima Graduate SchoolInstitute of Health Biosciences3‐18‐15 Kuramoto‐choTokushima770‐8503Japan
| | - Akira Kuwahara
- Department of Obstetrics and GynecologyThe University of Tokushima Graduate SchoolInstitute of Health Biosciences3‐18‐15 Kuramoto‐choTokushima770‐8503Japan
| | - Toshiyuki Yasui
- Department of Obstetrics and GynecologyThe University of Tokushima Graduate SchoolInstitute of Health Biosciences3‐18‐15 Kuramoto‐choTokushima770‐8503Japan
| | - Minoru Irahara
- Department of Obstetrics and GynecologyThe University of Tokushima Graduate SchoolInstitute of Health Biosciences3‐18‐15 Kuramoto‐choTokushima770‐8503Japan
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Pikwer M, Nilsson JÅ, Bergström U, Jacobsson LTH, Turesson C. Early menopause and severity of rheumatoid arthritis in women older than 45 years. Arthritis Res Ther 2012; 14:R190. [PMID: 22901865 PMCID: PMC3580586 DOI: 10.1186/ar4021] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2012] [Accepted: 08/17/2012] [Indexed: 12/12/2022] Open
Abstract
Introduction We aimed to investigate whether recognized hormonal predictors of rheumatoid arthritis (RA) also influence the severity of RA. Methods One hundred thirty-four incident RA cases identified by four different local and national registers, who had participated in a community-based health survey between 1991 and 1996, were included. By a retrospective structured review of the medical records, information on the use of disease-modifying antirheumatic drugs (DMARDs), erosions on radiographs, rheumatoid factor (RF) status, and disability measured by using the health assessment questionnaire (HAQ) were collected. The variables were added to the SPSS TwoStep Cluster Analysis to reveal natural groupings of RA severity. Known hormonal predictors analyzed were breastfeeding history, history of oral contraceptive (OC) use, and menopausal age. Results The mean age at RA diagnosis was 63.4 years; 72% were RF positive, and 28% had received biological treatment. Three clusters were identified, one with severe RA, one with mild/moderate RF-positive RA, and one with mild/moderate RF-negative RA. A significant difference (P = 0.005) was found in the distribution of clusters between patients with a history of early menopause compared with those with menopause after 45 years, with a higher proportion with mild/moderate RF-negative RA in the early-menopause subset. No major difference in severity of the disease was noted depending on OC use or history of breastfeeding. Conclusions Early menopause was associated with a milder form of RA. Hormonal changes may influence pathways that are distinct from those leading to severe, progressive disease.
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Pasquali R. The hypothalamic-pituitary-adrenal axis and sex hormones in chronic stress and obesity: pathophysiological and clinical aspects. Ann N Y Acad Sci 2012; 1264:20-35. [PMID: 22612409 PMCID: PMC3464358 DOI: 10.1111/j.1749-6632.2012.06569.x] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Obesity, particularly the abdominal phenotype, has been ascribed to an individual maladaptation to chronic environmental stress exposure mediated by a dysregulation of related neuroendocrine axes. Alterations in the control and action of the hypothalamic-pituitary-adrenal axis play a major role in this context, with the participation of the sympathetic nervous system. The ability to adapt to chronic stress may differ according to sex, with specific pathophysiological events leading to the development of stress-related chronic diseases. This seems to be influenced by the regulatory effects of sex hormones, particularly androgens. Stress may also disrupt the control of feeding, with some differences according to sex. Finally, the amount of experimental data in both animals and humans may help to shed more light on specific phenotypes of obesity, strictly related to the chronic exposure to stress. This challenge may potentially imply a different pathophysiological perspective and, possibly, a specific treatment.
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Affiliation(s)
- Renato Pasquali
- Division of Endocrinology, Department of Clinical Medicine, S. Orsola-Malpighi Hospital, University Alma Mater Studiorum of Bologna, Bologna, Italy.
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Schöpper H, Klaus T, Palme R, Ruf T, Huber S. Sex-specific impact of prenatal stress on growth and reproductive parameters of guinea pigs. J Comp Physiol B 2012; 182:1117-27. [DOI: 10.1007/s00360-012-0680-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2012] [Revised: 05/24/2012] [Accepted: 05/26/2012] [Indexed: 11/29/2022]
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Jang YM, Lee EJ, Kim DL, Kim SK, Song KH. The Association between Midnight Salivary Cortisol and Metabolic Syndrome in Korean Adults. Diabetes Metab J 2012; 36:245-50. [PMID: 22737665 PMCID: PMC3380129 DOI: 10.4093/dmj.2012.36.3.245] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2011] [Accepted: 02/16/2012] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND The common characteristics of metabolic syndrome (MetS) and Cushing's syndrome suggest that excess cortisol may be involved in the pathogenesis of MetS. Salivary cortisol measurements are simple and can be surrogates for plasma free cortisol, which is the most biologically active form. We evaluated the association between levels of midnight salivary cortisol and MetS in Korean adults. METHODS A total of 46 subjects, aged 20 to 70 years, who visited the Health Care Center at Konkuk University Hospital from August 2008 to August 2009 were enrolled. We compared the levels of midnight salivary cortisol in subjects with MetS with those in subjects without MetS. We analyzed the associations between midnight salivary cortisol levels and components of MetS. RESULTS Midnight salivary cortisol levels were higher in the MetS group (70±42.4 ng/dL, n=12) than that in the group without MetS (48.1±36.8 ng/dL, n=34) (P=0.001). Positive correlations were observed between midnight salivary cortisol levels and waist circumference, fasting blood glucose, and homeostasis model assessment of insulin resistance. The risk for MetS was significantly higher in subjects with midnight salivary cortisol levels ≥100 ng/dL than in those with levels <50 ng/dL (odds ratio, 5.9; 95% confidence interval, 2.35 to 36.4). CONCLUSION The results showed a positive correlation between midnight salivary cortisol levels and MetS, suggesting that hypercortisolism may be related to MetS.
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Affiliation(s)
- Yun-Mi Jang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Eun Jung Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Dong Lim Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Suk Kyeong Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Kee-Ho Song
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
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Gangestad SW, Caldwell Hooper AE, Eaton MA. On the function of placental corticotropin-releasing hormone: a role in maternal-fetal conflicts over blood glucose concentrations. Biol Rev Camb Philos Soc 2012; 87:856-73. [PMID: 22564253 DOI: 10.1111/j.1469-185x.2012.00226.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Throughout the second and third trimesters, the human placenta (and the placenta in other anthropoid primates) produces substantial quantities of corticotropin-releasing hormone (placental CRH), most of which is secreted into the maternal bloodstream. During pregnancy, CRH concentrations rise over 1000-fold. The advantages that led selection to favour placental CRH production and secretion are not yet fully understood. Placental CRH stimulates the production of maternal adrenocorticotropin hormone (ACTH) and cortisol, leading to substantial increases in maternal serum cortisol levels during the third trimester. These effects are puzzling in light of widespread theory that cortisol has harmful effects on the fetus. The maternal hypothalamic-pituitary-adrenal (HPA) axis becomes less sensitive to cortisol during pregnancy, purportedly to protect the fetus from cortisol exposure. Researchers, then, have often looked for beneficial effects of placental CRH that involve receptors outside the HPA system, such as the uterine myometrium (e.g. the placental clock hypothesis). An alternative view is proposed here: the beneficial effect of placental CRH to the fetus lies in the fact that it does stimulate the production of cortisol, which, in turn, leads to greater concentrations of glucose in the maternal bloodstream available for fetal consumption. In this view, maternal HPA insensitivity to placental CRH likely reflects counter-adaptation, as the optimal rate of cortisol production for the fetus exceeds that for the mother. Evidence pertaining to this proposal is reviewed.
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Affiliation(s)
- Steven W Gangestad
- Department of Psychology, University of New Mexico, Albuquerque, 87111, USA.
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Martinez-Aguayo A, Aglony M, Bancalari R, Avalos C, Bolte L, Garcia H, Loureiro C, Carvajal C, Campino C, Inostroza A, Fardella C. Birth weight is inversely associated with blood pressure and serum aldosterone and cortisol levels in children. Clin Endocrinol (Oxf) 2012; 76:713-8. [PMID: 22145676 DOI: 10.1111/j.1365-2265.2011.04308.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
CONTEXT Low birth weight has been independently associated with adult hypertension, and renin-angiotensin system (RAS) plays a role in this connection. OBJECTIVE To characterize the associations between birth weight (BW) and serum aldosterone (SA), serum cortisol, plasma renin activity (PRA) and blood pressure (BP). DESIGN Cross-sectional study. SUBJECTS Children from the community born at a gestational age >32 weeks. METHODS Systolic and diastolic BP indices (SBPi and DBPi) were calculated using the observed BP/50th percentile BP for gender, age and stature. BW was transformed to a standard deviation score (SDS) for gestational age, whereas SA, serum cortisol and PRA were transformed using the natural log. RESULTS We selected 288 subjects between the ages of 4·9 and 15·5 years (Females, 50%). After adjusting for body mass index (BMI) SDS and Tanner, multiple regression analysis revealed that BW (SDS) was both independently and inversely associated with the natural log of SA (β = -0·065; P = 0·039), the natural log of serum cortisol (β = -0·064; P = 0·009), SBPi (β = -0·012; P = 0·020) and DBPi (β = -0·023; P = 0·002). An association was not observed with PRA (P = 0·178) and aldosterone renin ratio (ARR) (P = 0·452). Serum cortisol levels were positively associated with SA (r = 0·125; P = 0·034), while an association with PRA (P = 0·251) and ARR (P = 0·052) was not observed. CONCLUSIONS The results of this study demonstrate an inverse association between birth weight and blood pressure and serum aldosterone and cortisol levels. This association is independent of BMI and Tanner, suggesting foetal programming of the hypothalamic-pituitary-adrenal axis.
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Affiliation(s)
- Alejandro Martinez-Aguayo
- Endocrinology Unit, Division of Paediatrics, Faculty of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
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Johansson M, Rasmussen F. Birthweight and Body Mass Index in Young Adulthood: The Swedish Young Male Twins Study. ACTA ACUST UNITED AC 2012. [DOI: 10.1375/twin.4.5.400] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
AbstractMany studies have found an inverse association between fetal growth and cardiovascular disease related to the metabolic syndrome in adulthood. Nevertheless, the relative importance of genetics and the intrauterine environment remain unclear. The objective of the study was to test the fetal origins hypothesis and the fetal insulin resistance hypothesis by studying the impact of fetal growth on Body Mass Index (BMI) in young adulthood. In a nationwide cohort study, the Swedish Medical Birth Register for the years 1973–1979 was linked with the Military Service Conscription Register for 1990–1999. In 1998 a questionnaire was mailed to all male twins, included in the two registers, who were alive and still resident in Sweden. The study covers the 923 male twin pairs for which full data were available. Mixed linear models were used to estimate within-pair and between-pair differences in birthweight and their relations to BMI. A weak positive association was found among the monozygotic twins for the withinpair difference in birthweight and BMI. No significant association was found among the monozygotic for the between-pair difference in birthweight and BMI. No significant associations were found for dizygotic twins. These findings do not seem to support either the fetal programming hypothesis or the fetal insulin resistance hypothesis.
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Phillips DI, Davies MJ, Robinson JS. Fetal Growth and the Fetal Origins Hypothesis in Twins — Problems and Perspectives. ACTA ACUST UNITED AC 2012. [DOI: 10.1375/twin.4.5.327] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
AbstractAlthough there is substantial evidence from studies of singletons that small size at birth is linked with long-term adverse health effects, until recently little was known as to whether these associations extend to twins. A review of published studies suggests that at present there is little consistent evidence that birthsize in twins is associated with increased morbidity or morality. While, these findings may reflect methodological limitations, it is also argued that they arise as a consequence of the substantially different biology of fetal growth in twins.
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Paternain L, Batlle MA, De la Garza AL, Milagro FI, Martínez JA, Campión J. Transcriptomic and epigenetic changes in the hypothalamus are involved in an increased susceptibility to a high-fat-sucrose diet in prenatally stressed female rats. Neuroendocrinology 2012; 96:249-60. [PMID: 22986707 DOI: 10.1159/000341684] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2011] [Accepted: 07/08/2012] [Indexed: 11/19/2022]
Abstract
Disturbances in the prenatal period are linked to metabolic disorders in adulthood, implying the hypothalamic systems of appetite and energy balance regulation. In order to analyze the central effects of a high-fat-sucrose (HFS) diet in prenatally stressed (PNS) female adult rats, Wistar dams were exposed to chronic-mild-stress during the third week of gestation and were then compared with unstressed controls. Adult female offspring were fed a chow or HFS diet for 10 weeks. Changes in body weight, adiposity as well as expression and methylation levels of selected hypothalamic genes were analyzed. PNS induced lower birthweight and body length with no changes in body fat mass. After the HFS diet, the expected overweight model was observed accompanied by higher adiposity and insulin resistance, which was worsened by PNS. The stress model induced higher energy intake in adulthood. Hypothalamic gene expression analysis revealed that the HFS diet decreased Slc6a3 (dopamine active transporter), NPY (neuropeptide Y) and IR (insulin receptor) and increased POMC (pro-opiomelanocortin). Hypothalamic DNA methylation levels in the promoter region of Slc6a3 revealed that Slc6a3 was hypermethylated by the HFS diet in CpG site -53 bp to the transcription start site. HFS diet also hypermethylated CpG site -167 bp of the POMC promoter only in nonstressed animals. No correlations were found between gene expression and DNA methylation levels. These results imply that early-life stress in females increased predisposition to diet-induced obesity in adulthood.
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Affiliation(s)
- L Paternain
- Department of Nutrition, Food Sciences and Physiology, University of Navarra, Pamplona, Spain.
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Yener S, Ertilav S, Secil M, Akinci B, Demir T, Kebapcilar L, Yesil S. Increased risk of unfavorable metabolic outcome during short-term follow-up in subjects with nonfunctioning adrenal adenomas. Med Princ Pract 2012; 21:429-34. [PMID: 22398948 DOI: 10.1159/000336589] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2011] [Accepted: 01/04/2012] [Indexed: 01/27/2023] Open
Abstract
OBJECTIVE To demonstrate long-term changes in the prevalence of several types of metabolic derangements in subjects with nonfunctioning adrenal adenomas. SUBJECTS AND METHODS 273 subjects with adrenal adenomas, including 231 with nonfunctioning adenoma and 42 with subclinical Cushing's syndrome (sCS), were evaluated with respect to anthropometric and laboratory characteristics and prevalence of type 2 diabetes mellitus (T2DM), hypertension, dyslipidemia, metabolic syndrome (MS), prediabetes and cardiovascular disease (CVD). Median duration was 24 months. Follow-up data of 114 participants with nonfunctioning adrenal adenomas are also presented while those of 117 were missing. Follow-up data regarding changes in anthropometric and laboratory parameters and prevalence rates of metabolic disturbances were obtained from the medical records. RESULTS The prevalence rates for both patients with nonfunctioning adenoma and sCS were: dyslipidemia: 161 (59%), hypertension: 147 (54%), MS: 128 (47%), prediabetes: 62 (23%), T2DM: 49 (18%), and CVD: 21 (8%). Hypertension and CVD were prevalent in subjects with sCS compared to participants with nonfunctioning adenoma. In follow-up, body mass index (p = 0.005), systolic blood pressure (p < 0.001), waist circumference (p = 0.005), homeostasis model assessment (p = 0.046), high-sensitivity C-reactive protein (p = 0.023), total cholesterol (p < 0.001) and low-density lipoprotein cholesterol (p < 0.001) and prevalence of hypertension (p < 0.001), dyslipidemia (p < 0.001), prediabetes (p < 0.001) and MS (p < 0.01) significantly increased in subjects with nonfunctioning adenoma. CONCLUSION The data showed that nonfunctioning adrenal adenomas were associated with the development or deterioration of atherosclerotic risk factors. Therefore, follow-up and management strategies should be developed to decrease atherosclerotic morbidity in those individuals.
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Affiliation(s)
- S Yener
- Division of Endocrinology and Metabolism, School of Medicine, Dokuz Eylul University, Izmir, Turkey
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Phillips DI, Matthews SG. Is perinatal neuroendocrine programming involved in the developmental origins of metabolic disorders? World J Diabetes 2011; 2:211-6. [PMID: 22174956 PMCID: PMC3238489 DOI: 10.4239/wjd.v2.i12.211] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2011] [Revised: 11/25/2011] [Accepted: 11/29/2011] [Indexed: 02/05/2023] Open
Abstract
The discovery that small size at birth and during infancy are associated with a higher risk of diabetes and related metabolic disease in later life has pointed to the importance of developmental factors in these conditions. The birth size associations are thought to reflect exposure to adverse environmental factors during early development but the mechanisms involved are still not fully understood. Animal and human work has pointed to the importance of changes in the set-point of a number of key hormonal systems controlling growth and development. These include the IGF-1/GH axis, gonadal hormones and, in particular, the systems mediating the classical stress response. Several studies show that small size at birth is linked with increased activity of the hypothalamic-pituitary-adrenal axis and sympathoadrenal system in adult life. More recent human studies have shown associations between specific adverse experiences during pregnancy, such as famine or the consumption of adverse diets, and enhanced stress responses many decades later. The mediators of these neuroendocrine responses are biologically potent and are likely to have a direct influence on the risk of metabolic disease. These neuroendocrine changes may also have an evolutionary basis being part of broader process, termed phenotypic plasticity, by which adverse environmental cues experienced during development modify the structure and physiology of the adult towards a phenotype adapted for adversity. The changes are clearly advantageous if they lead to a phenotype which is well-adapted for the adult environment, but may lead to disease if there is subsequent overnutrition or other unexpected environmental conditions.
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Affiliation(s)
- David Iw Phillips
- David IW Phillips, MRC Lifecourse Epidemiology Unit, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, United Kingdom
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Boguszewski MCS, Mericq V, Bergada I, Damiani D, Belgorosky A, Gunczler P, Ortiz T, Llano M, Domené HM, Calzada-León R, Blanco A, Barrientos M, Procel P, Lanes R, Jaramillo O. Latin American consensus: children born small for gestational age. BMC Pediatr 2011; 11:66. [PMID: 21771322 PMCID: PMC3163535 DOI: 10.1186/1471-2431-11-66] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2010] [Accepted: 07/19/2011] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Children born small for gestational age (SGA) experience higher rates of morbidity and mortality than those born appropriate for gestational age. In Latin America, identification and optimal management of children born SGA is a critical issue. Leading experts in pediatric endocrinology throughout Latin America established working groups in order to discuss key challenges regarding the evaluation and management of children born SGA and ultimately develop a consensus statement. DISCUSSION SGA is defined as a birth weight and/or birth length greater than 2 standard deviations (SD) below the population reference mean for gestational age. SGA refers to body size and implies length-weight reference data in a geographical population whose ethnicity is known and specific to this group. Ideally, each country/region within Latin America should establish its own standards and make relevant updates. SGA children should be evaluated with standardized measures by trained personnel every 3 months during year 1 and every 6 months during year 2. Those without catch-up growth within the first 6 months of life need further evaluation, as do children whose weight is ≤ -2 SD at age 2 years. Growth hormone treatment can begin in SGA children > 2 years with short stature (< -2.0 SD) and a growth velocity < 25th percentile for their age, and should continue until final height (a growth velocity below 2 cm/year or a bone age of > 14 years for girls and > 16 years for boys) is reached. Blood glucose, thyroid function, HbA1c, and insulin-like growth factor-1 (IGF-1) should be monitored once a year. Monitoring insulin changes from baseline and surrogates of insulin sensitivity is essential. Reduced fetal growth followed by excessive postnatal catch-up in height, and particularly in weight, should be closely monitored. In both sexes, gonadal function should be monitored especially during puberty. SUMMARY Children born SGA should be carefully followed by a multidisciplinary group that includes perinatologists, pediatricians, nutritionists, and pediatric endocrinologists since 10% to 15% will continue to have weight and height deficiency through development and may benefit from growth hormone treatment. Standards/guidelines should be developed on a country/region basis throughout Latin America.
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Affiliation(s)
- Margaret CS Boguszewski
- Department of Pediatrics, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil
| | - Veronica Mericq
- Institute of Maternal and Child Research, Faculty of Medicine, University of Chile, Santiago
| | - Ignacio Bergada
- División de Endocrinología, Hospital de Niños "Ricardo Gutiérrez," Buenos Aires, Argentina
| | - Durval Damiani
- Pediatric Endocrinology Unit, Instituto da Criança, São Paulo University Medical School, Brazil
| | | | - Peter Gunczler
- Unidad de Endocrinología Pediátrica, Hospital de Clínicas Caracas, Caracas, Venezuela
| | - Teresa Ortiz
- Universidad Militar Nueva Granada Hospital Militar Central, Bogotá, Colombia
| | - Mauricio Llano
- Department of Pediatrics, Universidad del Bosque, Bogotá, Colombia
| | - Horacio M Domené
- Centro de Investigaciones Endocrinológicas (CEDIE-CONICET), Hospital de Niños "Ricardo Gutiérrez," Buenos Aires, Argentina
| | - Raúl Calzada-León
- Endocrinology Services, Instituto Nacional de Pediatría, México City, México
| | | | | | - Patricio Procel
- Instituto Ecuatoriano de Endocrinología y Metabolismo, IEMYR, Quito, Ecuador
| | - Roberto Lanes
- Unidad de Endocrinología Pediátrica, Hospital de Clínicas Caracas, Caracas, Venezuela
| | - Orlando Jaramillo
- Servicio de Endocrinología, Hospital Nacional de Niños "Dr. Carlos Sáenz Herrera," San José, Costa Rica
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Is chromium from stainless steel utensils responsible for epidemic of type 2 diabetes? Med Hypotheses 2011; 77:84-6. [DOI: 10.1016/j.mehy.2011.03.032] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2010] [Accepted: 03/17/2011] [Indexed: 11/21/2022]
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Asiaei M, Solati J, Salari AA. Prenatal exposure to lps leads to long-lasting physiological consequences in male offspring. Dev Psychobiol 2011; 53:828-38. [DOI: 10.1002/dev.20568] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2010] [Accepted: 04/25/2011] [Indexed: 11/11/2022]
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Obulkasim M, Turdi A, Amat N, Haxim M, Eziz R, Haji H, Li L, Chen X, Upur H, Ren J. Neuroendocrine-immune disorder in type 2 diabetic patients with retinopathy. Clin Exp Pharmacol Physiol 2011; 38:229-32. [DOI: 10.1111/j.1440-1681.2011.05490.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Hernandez C, Matthews L, Oliver M, Bloomfield F, Harding J. Effects of sex, litter size and periconceptional ewe nutrition on offspring behavioural and physiological response to isolation. Physiol Behav 2010; 101:588-94. [DOI: 10.1016/j.physbeh.2010.08.020] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2009] [Revised: 07/06/2010] [Accepted: 08/27/2010] [Indexed: 11/30/2022]
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Abstract
Research investigating the early programming of adult metabolic disease has in recent years provided much mechanistic insight into how the early environment impacts on long-term health. It includes studies addressing the roles of intrauterine nutrient availability, which is determined by maternal nutrition, maternal exposure to oxygen, toxic events, and infection; the placental interface; and also the early postnatal environment. This review will explore the epidemiological evidence for programming of metabolic disease and provide an overview of the various studies using animals to model metabolic phenotypic outcome. It will also discuss evidence for the proposed molecular mechanisms and the potential for intervention.
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Affiliation(s)
- Denise S Fernandez-Twinn
- Department of Clinical Biochemistry, University of Cambridge, Metabolic Research Laboratories, Institute of Metabolic Sciences, Addenbrooke's Hospital, Cambridge, United Kingdom.
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Iwasa T, Matsuzaki T, Murakami M, Kinouchi R, Gereltsetseg G, Yamamoto S, Kuwahara A, Yasui T, Irahara M. Delayed puberty in prenatally glucocorticoid administered female rats occurs independently of the hypothalamic Kiss1–Kiss1r–GnRH system. Int J Dev Neurosci 2010; 29:183-8. [DOI: 10.1016/j.ijdevneu.2010.11.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2010] [Revised: 10/22/2010] [Accepted: 11/03/2010] [Indexed: 11/26/2022] Open
Affiliation(s)
- Takeshi Iwasa
- Department of Obstetrics and GynecologyThe University of Tokushima Graduate SchoolInstitute of Health Biosciences3‐18‐15 Kuramoto‐ChoTokushima770‐8503Japan
| | - Toshiya Matsuzaki
- Department of Obstetrics and GynecologyThe University of Tokushima Graduate SchoolInstitute of Health Biosciences3‐18‐15 Kuramoto‐ChoTokushima770‐8503Japan
| | - Masahiro Murakami
- Department of Obstetrics and GynecologyThe University of Tokushima Graduate SchoolInstitute of Health Biosciences3‐18‐15 Kuramoto‐ChoTokushima770‐8503Japan
| | - Riyo Kinouchi
- Department of Obstetrics and GynecologyThe University of Tokushima Graduate SchoolInstitute of Health Biosciences3‐18‐15 Kuramoto‐ChoTokushima770‐8503Japan
| | - Ganbat Gereltsetseg
- Department of Obstetrics and GynecologyThe University of Tokushima Graduate SchoolInstitute of Health Biosciences3‐18‐15 Kuramoto‐ChoTokushima770‐8503Japan
| | - Satoshi Yamamoto
- Department of Obstetrics and GynecologyThe University of Tokushima Graduate SchoolInstitute of Health Biosciences3‐18‐15 Kuramoto‐ChoTokushima770‐8503Japan
| | - Akira Kuwahara
- Department of Obstetrics and GynecologyThe University of Tokushima Graduate SchoolInstitute of Health Biosciences3‐18‐15 Kuramoto‐ChoTokushima770‐8503Japan
| | - Toshiyuki Yasui
- Department of Obstetrics and GynecologyThe University of Tokushima Graduate SchoolInstitute of Health Biosciences3‐18‐15 Kuramoto‐ChoTokushima770‐8503Japan
| | - Minoru Irahara
- Department of Obstetrics and GynecologyThe University of Tokushima Graduate SchoolInstitute of Health Biosciences3‐18‐15 Kuramoto‐ChoTokushima770‐8503Japan
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Reynolds RM. Corticosteroid-mediated programming and the pathogenesis of obesity and diabetes. J Steroid Biochem Mol Biol 2010; 122:3-9. [PMID: 20117209 DOI: 10.1016/j.jsbmb.2010.01.009] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2009] [Revised: 12/21/2009] [Accepted: 01/20/2010] [Indexed: 01/23/2023]
Abstract
Epidemiological studies have shown that low birthweight is associated with increased risk of development of diabetes and obesity in later life. Over-exposure of the developing fetus to glucocorticoids is one of the major hypotheses that has been proposed to explain this association. In animal models, a range of manipulations that increase fetal glucocorticoid load, 'programme' permanent changes in glucose and insulin metabolism and adiposity. This may be mediated by alterations in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. In humans, low birthweight is associated with increased circulating glucocorticoid levels, and an increased cortisol response to physiological and psychosocial stressors, in child- and adulthood. This activation of the HPA axis is also associated with increased risk of development of diabetes and obesity in later life.
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Affiliation(s)
- Rebecca M Reynolds
- Endocrinology Unit, Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom.
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Rose AJ, Vegiopoulos A, Herzig S. Role of glucocorticoids and the glucocorticoid receptor in metabolism: insights from genetic manipulations. J Steroid Biochem Mol Biol 2010; 122:10-20. [PMID: 20170729 DOI: 10.1016/j.jsbmb.2010.02.010] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2009] [Revised: 12/14/2009] [Accepted: 02/10/2010] [Indexed: 12/21/2022]
Abstract
Since the discovery of the beneficial effects of adrenocortical extracts for treating adrenal insufficiency more than 80 years ago, glucocorticoids and their cognate, intracellular receptor, the glucocorticoid receptor have been characterized as critical checkpoints in the delicate hormonal control of energy homeostasis in mammals. Whereas physiological levels of glucocorticoids are required for proper metabolic control, aberrant glucocorticoid action has been linked to a variety of pandemic metabolic diseases, such as type II diabetes and obesity. Based on its importance for human health, studies of the molecular mechanisms of within the glucocorticoid signaling axis have become a major focus in biomedical research. In particular, the understanding of tissue-specific functions of the glucocorticoid receptor pathway has been proven to be of substantial value for the development of novel therapies in the treatment of chronic metabolic disorders. Therefore, this review focuses on the consequences of endogenous and experimental modulation of glucocorticoid receptor expression for metabolic homeostasis and dysregulation, particularly emphasizing tissue-specific contributions of the glucocorticoid pathway to the control of energy metabolism.
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Affiliation(s)
- Adam J Rose
- Molecular Metabolic Control, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany
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Gudmundsson P, Andersson S, Gustafson D, Waern M, Ostling S, Hällström T, Palsson S, Skoog I, Hulthen L. Depression in Swedish women: relationship to factors at birth. Eur J Epidemiol 2010; 26:55-60. [PMID: 20857177 DOI: 10.1007/s10654-010-9508-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2010] [Accepted: 09/03/2010] [Indexed: 10/19/2022]
Abstract
Depression is a common and serious disorder that may have developmental origins. Birth-related factors have been related to childhood and adult occurrence of somatic as well as psychiatric disorders, but studies on the relationship between birth-related factors and depression are few and show mixed results. In addition, varying methods have been used to assess depression. Standardized clinical criteria to diagnose depression, combined with birth data collected from midwife records have not been used in most studies. Participants in the Prospective Population Study of Women in Sweden (803 women), born 1914, 1918, 1922 and 1930, provide information on birth factors and depression. Women participated from 1968 at mid-life ages of 38-60 years, to 2000, when they were age 78-92 years. Original birth records containing birth weight, length, head circumference, and gestational time, as well as social factors were obtained. Lifetime depression was diagnosed via multiple information sources. Symptoms were assessed using the Comprehensive Psychopathological Rating Scale and diagnoses were based on DSM-III-R criteria. Over their lifetime, 44.6% of women in this sample experienced depression. Birth weights ≤ 3500 g [odds ratio (OR), age-adjusted = 1.72; 95% CI 1.29-2.28, P < 0.001] and shorter gestational time (OR, age-adjusted = 1.13; 95% CI 1.04-1.24, P = 0.005) were independently associated with a higher odds of lifetime depression in a logistic regression model adjusted for age. Lower than median birth weights and shorter gestational time were related to lifetime depression in women. Both neurodevelopmental and environmental contributions to lifetime depression may be considered.
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Affiliation(s)
- Pia Gudmundsson
- Institute of Neuroscience and Physiology, Section for Psychiatry and Neurochemistry, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
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Kajantie E, Räikkönen K. Early life predictors of the physiological stress response later in life. Neurosci Biobehav Rev 2010; 35:23-32. [DOI: 10.1016/j.neubiorev.2009.11.013] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2009] [Revised: 10/26/2009] [Accepted: 11/14/2009] [Indexed: 11/27/2022]
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Emery Thompson M, Muller MN, Kahlenberg SM, Wrangham RW. Dynamics of social and energetic stress in wild female chimpanzees. Horm Behav 2010; 58:440-9. [PMID: 20546741 PMCID: PMC3951729 DOI: 10.1016/j.yhbeh.2010.05.009] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2010] [Revised: 05/12/2010] [Accepted: 05/17/2010] [Indexed: 11/17/2022]
Abstract
Stress hormone measurements can reinforce and refine hypotheses about the costs of particular contexts or behaviors in wild animals. For social species, this is complicated because potential stressors may come from the physical environment, social environment, or some combination of both, while the stress response itself is generalized. Here, we present a multivariate examination of urinary cortisol dynamics over 6 years in the lives of wild female chimpanzees in the Kanyawara community of Kibale National Park, Uganda. We hypothesized that chimpanzee socioecology provides strong indications of both energetic and social stress to females, but that the salience of these stressors might vary over a female's life history in accordance with their changing reproductive costs and social interactions. Using linear mixed models, we found that urinary cortisol levels increased significantly with age but were also elevated in young immigrants to the community. Across reproductive states, cycling, non-estrous females had relatively low cortisol compared to lactating, estrous, or pregnant females. Aggression from males led to higher cortisol levels among estrous females, frequent targets of aggressive sexual coercion. In contrast, energetic stress was most salient to lactating females, who experienced higher cortisol during months of low fruit consumption. Low dominance rank was associated with increased cortisol, particularly during the energetically demanding period of lactation. The effects of female conflict were felt widely, even among those who were the primary aggressors, providing further evidence that long-term resource competition, while apparently muted, exerts a far-reaching impact on the lives of chimpanzee females.
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Gustafsson PE, Janlert U, Theorell T, Hammarström A. Is body size at birth related to circadian salivary cortisol levels in adulthood? Results from a longitudinal cohort study. BMC Public Health 2010; 10:346. [PMID: 20553630 PMCID: PMC2908578 DOI: 10.1186/1471-2458-10-346] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2009] [Accepted: 06/17/2010] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The hypothesis of fetal origins of adult disease has during the last decades received interest as an explanation of chronic, e.g. cardiovascular, disease in adulthood stemming from fetal environmental conditions. Early programming and enduring dysregulations of the hypothalamic-pituitary-adrenal (HPA axis), with cortisol as its end product, has been proposed as a possible mechanism by which birth weight influence later health status. However, the fetal origin of the adult cortisol regulation has been insufficiently studied. The present study aims to examine if body size at birth is related to circadian cortisol levels at 43 years. METHODS Participants were drawn from a prospective cohort study (n = 752, 74.5%). Salivary cortisol samples were collected at four times during one day at 43 years, and information on birth size was collected retrospectively from delivery records. Information on body mass during adolescence and adulthood and on health behavior, medication and medical conditions at 43 years was collected prospectively by questionnaire and examined as potential confounders. Participants born preterm or < 2500 g were excluded from the main analyses. RESULTS Across the normal spectrum, size at birth (birth weight and ponderal index) was positively related to total (area under the curve, AUC) and bedtime cortisol levels in the total sample. Results were more consistent in men than in women. Descriptively, participants born preterm or < 2500 g also seemed to display elevated evening and total cortisol levels. No associations were found for birth length or for the cortisol awakening response (CAR). CONCLUSIONS These results are contradictory to previously reported negative associations between birth weight and adult cortisol levels, and thus tentatively question the assumption that only low birth weight predicts future physiological dysregulations.
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Affiliation(s)
- Per E Gustafsson
- Dept of Public Health and Clinical Medicine, Family Medicine, Umeå University, Umeå, Sweden.
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Hellemans KG, Sliwowska J, Verma P, Weinberg J. Prenatal alcohol exposure: fetal programming and later life vulnerability to stress, depression and anxiety disorders. Neurosci Biobehav Rev 2010; 34:791-807. [PMID: 19545588 PMCID: PMC5518679 DOI: 10.1016/j.neubiorev.2009.06.004] [Citation(s) in RCA: 248] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2008] [Revised: 06/01/2009] [Accepted: 06/11/2009] [Indexed: 01/21/2023]
Abstract
Children with fetal alcohol spectrum disorder (FASD) exhibit cognitive, neuropsychological and behavioral problems, and numerous secondary disabilities including depression and anxiety disorders. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is common in depression/anxiety, reflected primarily in increased HPA tone or activity. Prenatal alcohol exposure (PAE) increases HPA tone and results in HPA dysregulation throughout life, paralleling many of the HPA changes in depression/anxiety. We review data demonstrating altered HPA function and increased depression/anxiety in FASD. In the context of the stress-diathesis model, we discuss the hypothesis that fetal programming of the HPA axis by PAE alters neuroadaptive mechanisms that mediate the stress response, thus sensitizing the organism to stressors encountered later in life, and mediating, at least partly, the increased vulnerability to depression/anxiety disorders. Furthermore, we present evidence demonstrating sex-specific alterations in both hormonal and behavioral responsiveness to tasks measuring depressive- and anxiety-like behaviors in PAE offspring. Overall, the research suggests that the stress-diathesis model provides a powerful approach for elucidating mechanisms underlying the increased vulnerability to mental illness among individuals with FASD, and developing appropriate treatments for these individuals. Dr. Seymour Levine's seminal work on the long-term consequences of early life experiences formed a framework for the development of the research described in this review.
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Affiliation(s)
- Kim G.C. Hellemans
- Department of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, V6T 1Z3
- Department of Psychology, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario, Canada K1S 5B6
| | - Joanne Sliwowska
- Department of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, V6T 1Z3
| | - Pamela Verma
- Department of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, V6T 1Z3
| | - Joanne Weinberg
- Department of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, V6T 1Z3
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Murray L, Halligan SL, Goodyer I, Herbert J. Disturbances in early parenting of depressed mothers and cortisol secretion in offspring: a preliminary study. J Affect Disord 2010; 122:218-23. [PMID: 19632727 DOI: 10.1016/j.jad.2009.06.034] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2009] [Revised: 06/24/2009] [Accepted: 06/25/2009] [Indexed: 01/24/2023]
Abstract
BACKGROUND Disturbances in cortisol secretion are associated with risk for psychiatric disorder, including depression. Animal research indicates that early care experiences influence hypothalamic-pituitary-adrenal (HPA) axis functioning in offspring. Similar effects are suggested in human development, but evidence of longitudinal associations between observed early parenting and offspring cortisol secretion is extremely limited. We studied associations between parenting disturbances occurring in the context of maternal postnatal depression (PND), and elevations in morning cortisol secretion in the adolescent offspring of PND mothers. METHODS We observed maternal parenting behaviour on four occasions through the first year and at five-year follow-up in postnatally depressed (n=29) and well (n=20) mothers. Observations were coded for maternal sensitivity and withdrawn behaviour. Basal offspring salivary cortisol secretion was measured at 13-years, using collections over 10-days. RESULTS Postnatal, but not five-year, maternal withdrawal predicted elevated mean and maximum morning cortisol secretion in 13-year-old offspring. There were no significant associations between maternal sensitivity and offspring cortisol secretion. LIMITATIONS The sample size was relatively small, and effects tended to be reduced to trend level when covariates were considered. The correlational nature of the study (albeit longitudinal) limits conclusions regarding causality. CONCLUSIONS Individual differences in early maternal parenting behaviour may influence offspring cortisol secretion, and thereby risk for depression. Parenting interventions that facilitate active maternal engagement with the infant may be indicated for high-risk populations.
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Affiliation(s)
- Lynne Murray
- Department of Clinical Neuroscience, Cambridge University, Cambridge, UK
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Li L, Messina JL. Acute insulin resistance following injury. Trends Endocrinol Metab 2009; 20:429-35. [PMID: 19800814 PMCID: PMC2939005 DOI: 10.1016/j.tem.2009.06.004] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2009] [Revised: 06/15/2009] [Accepted: 06/16/2009] [Indexed: 02/08/2023]
Abstract
Hyperglycemia and insulin resistance often occur following injury and/or critical illness. Whereas intensive insulin treatment reduces hyperglycemia, mortality and morbidity in certain patients, little is known regarding the pathophysiology of acute insulin resistance following injury and infection. Studies suggest that acute insulin resistance is complex and might differ in a tissue-specific manner, involving multiple causative factors and intracellular signaling pathways. Therefore, the advantages of intensive insulin therapy might not be uniform to all injuries or critical illnesses. Clearly, the increased incidence of hypoglycemic incidents following intensive insulin therapy indicates a need for understanding the underlying molecular mechanisms of the acute development of insulin resistance, which will allow a more targeted approach to treat altered glucose metabolism of critically ill patients.
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Affiliation(s)
- Li Li
- Department of Pathology, Division of Molecular and Cellular Pathology, The University of Alabama at Birmingham, Birmingham, AL, 35294
| | - Joseph L. Messina
- Department of Pathology, Division of Molecular and Cellular Pathology, The University of Alabama at Birmingham, Birmingham, AL, 35294
- Veterans Affairs Medical Center, Birmingham, Alabama 35233
- Correspondence: Joseph L. Messina, Ph.D., Department of Pathology, Division of Molecular and Cellular Pathology, The University of Alabama at Birmingham, VH G019J, 1530 3rd Ave S, Birmingham, AL, 35294-0019,
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