Obesity-induced DNA hypermethylation of the adiponectin gene mediates insulin resistance
Adiponectin plays a key role in the regulation of the whole-body energy homeostasis by modulating glucose and lipid metabolism. Although obesity-induced reduction of adiponectin expression is primarily ascribed to a transcriptional regulation failure, the underlying mechanisms are largely undefined. Here we show that DNA hypermethylation of a particular region of the adiponectin promoter suppresses adiponectin expression through epigenetic control and, in turn, exacerbates metabolic diseases in obesity. Obesity-induced, pro-inflammatory cytokines promote DNMT1 expression and its enzymatic activity. Activated DNMT1 selectively methylates and stimulates compact chromatin structure in the adiponectin promoter, impeding adiponectin expression. Suppressing DNMT1 activity with a DNMT inhibitor resulted in the amelioration of obesity-induced glucose intolerance and insulin resistance in an adiponectin-dependent manner. These findings suggest a critical role of adiponectin gene epigenetic control by DNMT1 in governing energy homeostasis, implying that modulating DNMT1 activity represents a new strategy for the treatment of obesity-related diseases.
A. Young Kim,1 Yoon Jeong Park,1,2 Xuebo Pan,3 Kyung Cheul Shin,1,4 Soo-Heon Kwak,5 Abdulelah F. Bassas,6 Reem M. Sallam,6 Kyong Soo Park,5,7 Assim A. Alfadda,6,8 Aimin Xu,3,9,10 and Jae Bum Kima,1,4
Evidence of a sex-dependent restrictive epigenome in schizophrenia.
When compared to women, men have a higher incidence of schizophrenia, with increases in negative and cognitive symptoms, and an overall poorer disease course. Schizophrenia is conceptualized as a disorder of aberrant gene transcription and regulation. Thus, epigenetics, the study of environmentally induced changes in gene regulation, could advance our understanding of the molecular underpinnings of schizophrenia. Peripheral histone methyltransferase (HMT) mRNA levels have been previously shown to be significantly increased in patients with schizophrenia and correlate with symptomology. In this independent study, peripheral lymphocytes were extracted and clinical symptoms were measured on 74 participants, (40 patients with schizophrenia (19 women, 21 men) and 34 healthy individuals (19 women, 15 men)). HMT (G9α, SETDB1 and GLP) mRNA levels and their resulting histone modification H3K9me2 were measured with RT-PCR and ELISA respectively. Plasma estradiol levels were also measured via ELISA and correlated with HMT mRNA. Clinical symptoms were measured utilizing the Positive and Negative Syndrome Scale (PANSS) and the Heinrichs Carpenter Quality of Life Scale (QLS). The results indicate that men with schizophrenia expressed the highest levels of G9α, SETDB1 mRNA and H3K9me2 protein levels. Additionally, higher levels of symptom presentation and an overall poorer quality of life were correlated with higher HMT mRNA and H3K9me2 protein levels in a sex-dependent pattern. These data support the hypothesis of a sex-dependent restrictive epigenome contributing towards the etiology of schizophrenia. The histone methyltransferases measured here could be potential future therapeutic targets for small molecule pharmacology.
Chase KA1, Rosen C1, Rubin LH1, Feiner B1, Bodapati AS1, Gin H1, Hu E1, Sharma RP2.
Author information
1The Psychiatric Institute, University of Illinois at Chicago, 1601 W. Taylor St., Chicago, IL 60612, USA.
2The Psychiatric Institute, University of Illinois at Chicago, 1601 W. Taylor St., Chicago, IL 60612, USA; Jesse Brown Veterans Affairs Medical Center, 820 South Damen Avenue (M/C 151), Chicago, IL 60612, USA. Electronic address: rsharma@psych.uic.edu.
J Psychiatr Res. 2015 Apr 18. pii: S0022-3956(15)00108-9. doi: 10.1016/j.jpsychires.2015.04.005. [Epub ahead of print]
Stress In Utero: Prenatal Programming of Brain Plasticity and Cognition.
Bock J(1), Wainstock T(2), Braun K(1), Segal M(3).
Animal studies confirm earlier anecdotal observations in humans to indicate that
early life experience has a profound impact on adult behavior, years after the
original experience has vanished. These studies also highlight the role of early
life adversaries in the shaping of a disordered brain. Evidence is accumulating
to indicate that the epigenome, through which the environment regulates gene
expression, is responsible for long-lasting effects of stress during pregnancy on
brain and behavior. A possible differential effect of the environment on the
epigenome may underlie the observation that only a small fraction of a population
with similar genetic background deteriorates into mental disorders. Considerable
progress has been made in the untangling of the epigenetic mechanisms that
regulate emotional brain development. The present review focuses on the lasting
effects of prenatal stress on brain plasticity and cognitive functions in human
and rodent models. Although human studies stress the significance of early life
experience in functional maturation, they lack the rigor inherent in controlled
animal experiments. Furthermore, the analysis of molecular and cellular
mechanisms affected by prenatal stress is possible only in experimental animals.
The present review attempts to link human and animal studies while proposing
molecular mechanisms that interfere with functional brain development.
Author information:
(1)Otto von Guericke University Magdeburg (JB, KB), Magdeburg, Germany.
(2)Rollins School of Public Health (TW), Emory University, Atlanta, Georgia.
(3)Department of Neurobiology (MS) Weizmann Institute, Rehovot, Israel.
Electronic address: menahem.segal@weizmann.ac.il.
Biol Psychiatry. 2015 Mar 6. pii: S0006-3223(15)00162-6. doi:
10.1016/j.biopsych.2015.02.036. [Epub ahead of print]
Longevity determined by paternal ancestors’ nutrition during their slow growth period
Lars Olov Bygren, Gunnar Kaati and Soren Edvinsson
Department of Community Medicine and Rehabilitation, Umea University, Sweden
http://depts.washington.edu/lairdlab/pdfs/BygrenEtAl2001.pdf
Male-line transgenerational responses in humans
Hum Fertil (Camb). 2010 Dec;13(4):268-71. doi: 10.3109/14647273.2010.524721.
Pembrey ME.
Clinical and Molecular Genetics Unit, Institute of Child Health, University College, London, UK. m.pembrey@bristol.ac.uk
Genomic imprinting – Wikipedia link
Imprinting and transgenerational modulation of gene expression; human growth as a model
Pembrey M.
Institute of Child Health, University of London, United Kingdom.
Acta Genet Med Gemellol (Roma). 1996;45(1-2):111-25.
Sex-specific, male-line transgenerational responses in humans
Pembrey ME, Bygren LO, Kaati G, Edvinsson S, Northstone K, Sjöström M, Golding J; ALSPAC Study Team.
Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, England, UK. M.Pembrey@bristol.ac.uk
Eur J Hum Genet. 2006 Feb;14(2):159-66.
Germ cells carry the epigenetic benefits of grandmother’s diet
Craig A. Cooney
Proc Natl Acad Sci U S A. 2006 November 14; 103(46): 17071–17072.
Ten Putative Contributors to the Obesity Epidemic
Emily J. McAllister,1 Nikhil V. Dhurandhar,1 Scott W. Keith,2 Louis J. Aronne,3 Jamie Barger,4,5 Monica Baskin,6Ruth M. Benca,7 Joseph Biggio,8 Mary M. Boggiano,9 Joe C. Eisenmann,10 Mai Elobeid,2 Kevin R. Fontaine,11Peter Gluckman,12 Erin C. Hanlon,13 Peter Katzmarzyk,14 Angelo Pietrobelli,15 David T. Redden,2 Douglas M. Ruden,16 Chenxi Wang,17 Robert A. Waterland,18 Suzanne M. Wright,3 and David B. Allison2
Crit Rev Food Sci Nutr. 2009 November; 49(10): 868–913.
Methyl donor supplementation prevents transgenerational amplification of obesity
RA Waterland,1 M Travisano,2,3 KG Tahiliani,1 MT Rached,1 and S Mirza1
Int J Obes (Lond). 2008 September; 32(9): 1373–1379.
Published online 2008 July 15. doi: 10.1038/ijo.2008.100
DNA methylation, an epigenetic mechanism connecting folate to healthy embryonic development and aging
Kyong-chol Kim,1,2 Simonetta Friso,3 and Sang-Woon Choi1,
J Nutr Biochem. 2009 December; 20(12): 917–926.
Published online 2009 September 4. doi: 10.1016/j.jnutbio.2009.06.008
Food as exposure: Nutritional epigenetics and the new metabolism
Hannah Landecker
Biosocieties. 2011 June; 6(2): 167–194.
Published online 2011 March 7. doi: 10.1057/biosoc.2011.1
The agouti mouse model: an epigenetic biosensor for nutritional and environmental alterations on the fetal epigenome
Dana C Dolinoy
Nutr Rev. Author manuscript; available in PMC 2010 February 16.
Nutr Rev. 2008 August; 66(Suppl 1): S7–11.
doi: 10.1111/j.1753-4887.2008.00056.x
Mismatch – The Lifestyle diseases Timebomb
Peter Gluckman and Mark Hanson
Persistence of iodine deficiency 25 years after initial correction efforts in the Khumbu region of Nepal
Murdoch DR, Harding EG, Dunn JT.
Kunde Hospital, Solukhumbu District, Nepal. murdo005@mc.duke.edu
N Z Med J. 1999 Jul 23;112(1092):266-8.
Why are immigrants at increased risk for psychosis? Vitamin D insufficiency, epigenetic mechanisms, or both?
Dealberto MJ.
Department of Psychiatry, Ottawa Hospital and University of Ottawa, General Campus, 501 Smyth Road, Ottawa, Ont., Canada K1H 8L6. dealbert@uottawa.ca
Med Hypotheses. 2007;68(2):259-67. Epub 2006 Oct 2.
The environment and susceptibility to schizophrenia
Brown AS.
Department of Psychiatry, College of Physicians and Surgeons of Columbia University, New York State Psychiatric Institute, New York, NY 10032, USA. asb11@columbia.edu
Prog Neurobiol. 2011 Jan;93(1):23-58. doi: 10.1016/j.pneurobio.2010.09.003. Epub 2010 Oct 16.
Epigenetic regulation in obesity
Drummond EM, Gibney ER.
UCD Institute of Food and Health, University College Dublin, Belfield, Dublin, Ireland.
Curr Opin Clin Nutr Metab Care. 2013 Jul;16(4):392-7. doi: 10.1097/MCO.0b013e3283620f45.
Environmental epigenetics: a role in endocrine disease?
Abby F Fleisch, Robert O Wright and Andrea A Baccarelli
Departments of Endocrinology and Health Services Research, Children’s Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA
Epigenetic diet: impact on the epigenome and cancer
Hardy TM, Tollefsbol TO.
Department of Biology, University of Alabama at Birmingham, 1300 University Boulevard, Birmingham, AL 35294, USA.
Epigenomics. 2011 Aug;3(4):503-18. doi: 10.2217/epi.11.71.
Epigenetic inheritance and evolution: a paternal perspective on dietary influences.
Soubry A
Epidemiology Research Group, Department of Public Health and Primary Care, Faculty of Medicine, Leuven, Belgium.
Prog Biophys Mol Biol. 2015 Mar 10. pii: S0079-6107(15)00033-4. doi: 10.1016/j.pbiomolbio.2015.02.008. [Epub ahead of print]
Abstract
The earliest indications for paternally induced transgenerational effects from the environment to future generations were based on a small number of long-term epidemiological studies and some empirical observations. Only recently have experimental animal models and a few analyses on human data explored the transgenerational nature of phenotypic changes observed in offspring. Changes include multiple metabolic disorders, cancer and other chronic diseases. These phenotypes cannot always be explained by Mendelian inheritance, DNA mutations or genetic damage. Hence, a new compelling theory on epigenetic inheritance is gaining interest, providing new concepts that extend Darwin’s evolutionary theory. Epigenetic alterations or “epimutations” are being considered to explain transgenerational inheritance of parentally acquired traits. The responsible mechanisms for these epimutations include DNA methylation, histone modification, and RNA-mediated effects. This review explores the literature on a number of time-dependent environmentally induced epigenetic alterations, specifically those from dietary exposures. We suggest a role for the male germ line as one of nature’s tools to capture messages from our continuously changing environment and to transfer this information to subsequent generations. Further, we open the discussion that the paternally inherited epigenetic information may contribute to evolutionary adaptation.
