Obesity is associated with a decrease in expression but not with the hypermethylation of thermogenesis-related genes in adipose tissues

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Abstract

Background

Impaired thermogenesis can promote obesity. Therefore, the aim of this study was to investigate whether the expression of thermogenesis-related genes is altered in adipose tissues of obese individuals and whether excessive methylation of their promoters is involved in this phenomenon.

Methods

The expression of genes encoding β adrenergic receptors ( ADRBs), thyroid hormone receptors ( THRs), 5’-iodothyronine deiodinases ( DIOs), and uncoupling proteins ( UCPs) was measured by real-time PCR in visceral and in subcutaneous adipose tissues of 58 obese (BMI >40 kg/m ²) and 50 slim (BMI 20-24.9 kg/m ²) individuals. The methylation status of these genes was studied by the methylation-sensitive digestion/real-time PCR method.

Results

The expression of ADRB2, ADRB3, THRA, THRB, DIO2, UCP2 was significantly lower in the adipose tissues of obese patients than in tissues of normal-weight individuals (P < 0.00001). In the obese, the expression of ADRB2, ADRB3, DIO2 was lower in visceral adipose tissue than in subcutaneous adipose tissue (P = 0.008, P = 0.002, P = 0.001, respectively). However, the mean methylation of CpG islands of these genes was similar in tissues with their high and low expression, and there was no correlation between the level of expression and the level of methylation.

Conclusions

Decreased expression of thermogenesis-related genes in adipose tissues of obese patients might result in the reduced reactivity to both hormonal and adrenergic stimuli and therefore in a lower potential to activate thermogenesis.

Electronic supplementary material

The online version of this article (doi:10.1186/s12967-015-0395-2) contains supplementary material, which is available to authorized users.

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Most cited references 40

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betaAR signaling required for diet-induced thermogenesis and obesity resistance.

Eric Bachman, Harveen Dhillon, Chen-Yu Zhang … (2002)

Excessive caloric intake is thought to be sensed by the brain, which then activates thermogenesis as a means of preventing obesity. The sympathetic nervous system, through beta-adrenergic receptor (betaAR) action on target tissues, is likely the efferent arm of this homeostatic mechanism. To test this hypothesis, we created mice that lack the three known betaARs (beta-less mice). beta-less mice on a Chow diet had a reduced metabolic rate and were slightly obese. On a high-fat diet, beta-less mice, in contrast to wild-type mice, developed massive obesity that was due entirely to a failure of diet-induced thermogenesis. These findings establish that betaARs are necessary for diet-induced thermogenesis and that this efferent pathway plays a critical role in the body's defense against diet-induced obesity.

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Thermogenic mechanisms and their hormonal regulation.

J. Silva (2006)

Increased heat generation from biological processes is inherent to homeothermy. Homeothermic species produce more heat from sustaining a more active metabolism as well as from reducing fuel efficiency. This article reviews the mechanisms used by homeothermic species to generate more heat and their regulation largely by thyroid hormone (TH) and the sympathetic nervous system (SNS). Thermogenic mechanisms antecede homeothermy, but in homeothermic species they are activated and regulated. Some of these mechanisms increase ATP utilization (same amount of heat per ATP), whereas others increase the heat resulting from aerobic ATP synthesis (more heat per ATP). Among the former, ATP utilization in the maintenance of ionic gradient through membranes seems quantitatively more important, particularly in birds. Regulated reduction of the proton-motive force to produce heat, originally believed specific to brown adipose tissue, is indeed an ancient thermogenic mechanism. A regulated proton leak has been described in the mitochondria of several tissues, but its precise mechanism remains undefined. This leak is more active in homeothermic species and is regulated by TH, explaining a significant fraction of its thermogenic effect. Homeothermic species generate additional heat, in a facultative manner, when obligatory thermogenesis and heat-saving mechanisms become limiting. Facultative thermogenesis is activated by the SNS but is modulated by TH. The type II iodothyronine deiodinase plays a critical role in modulating the amount of the active TH, T(3), in BAT, thereby modulating the responses to SNS. Other hormones affect thermogenesis in an indirect or permissive manner, providing fuel and modulating thermogenesis depending on food availability, but they do not seem to have a primary role in temperature homeostasis. Thermogenesis has a very high energy cost. Cold adaptation and food availability may have been conflicting selection pressures accounting for the variability of thermogenesis in humans.

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UCP1-independent thermogenesis in white adipose tissue of cold-acclimated Ucp1-/- mice.

Jozef Ukropec, Rea Anunciado, Yann Ravussin … (2006)

Apart from UCP1-based nonshivering thermogenesis in brown adipocytes, the identity of thermogenic mechanisms that can be activated to reduce a positive energy balance is largely unknown. To identify potentially useful mechanisms, we have analyzed physiological and molecular mechanisms that enable mice, genetically deficient in UCP1 and sensitive to acute exposure to the cold at 4 degrees C, to adapt to long term exposure at 4 degrees C. UCP1-deficient mice that can adapt to the cold have increased oxygen consumption and show increased oxidation of both fat and glucose as indicated from serum metabolite levels and liver glycogen content. Enhanced energy metabolism in inguinal fat was also indicated by increased oxygen consumption and fat oxidation in tissue suspensions and increased AMP kinase activity in dissected tissues. Analysis of gene expression in skeletal muscle showed surprisingly little change between cold-adapted Ucp1+/+ and Ucp1-/- mice, whereas in inguinal fat a robust induction occurred for type 2 deiodinase, sarcoendoplasmic reticulum Ca2+-ATPase, mitochondrial glycerol 3-phosphate dehydrogenase, PGC1alpha, CoxII, and mitochondrial DNA content. Western blot analysis showed an induction of total phospholamban and its phosphorylated form in inguinal fat and other white fat depots, but no induction was apparent in muscle. We conclude that alternative thermogenic mechanisms, based in part upon the enhanced capacity for ion and substrate cycling associated with brown adipocytes in white fat depots, are induced in UCP1-deficient mice by gradual cold adaptation.

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Author and article information

Contributors

Alina Kurylowicz: akurylowicz@imdik.pan.pl

Marta Jonas: martajonas@imdik.pan.pl

Wojciech Lisik: wojciech.lisik@wum.edu.pl

Maurycy Jonas: morjon@poczta.onet.pl

Zofia Agnieszka Wicik: zwicik@imdik.pan.pl

Zbigniew Wierzbicki: zbigniew-wierzbicki@wp.pl

Andrzej Chmura: andrzejchmura@geil.pl

Monika Puzianowska-Kuznicka: mpuzianowska@wum.edu.pl

Journal

Journal ID (nlm-ta): J Transl Med

Journal ID (iso-abbrev): J Transl Med

Title: Journal of Translational Medicine

Publisher: BioMed Central (London )

ISSN (Electronic): 1479-5876

Publication date (Electronic): 27 January 2015

Publication date PMC-release: 27 January 2015

Publication date Collection: 2015

Volume: 13

Issue: 1

Electronic Location Identifier: 31

Affiliations

[ ]Department of Human Epigenetics, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, 02-106 Warsaw, Poland

[ ]Department of General and Transplantation Surgery, Medical University of Warsaw, 59 Nowogrodzka Street, 02-005 Warsaw, Poland

[ ]Department of Geriatrics and Gerontology, Medical Centre of Postgraduate Education, 99 Marymoncka Street, 01-813 Warsaw, Poland

Article

Publisher ID: 395

DOI: 10.1186/s12967-015-0395-2

PMC ID: 4314800

PubMed ID: 25622596

SO-VID: 9de58e2e-6909-4b44-bc97-cee4a64738ff

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 22 September 2014

Date accepted : 14 January 2015

Custom metadata

ScienceOpen disciplines: Medicine

Keywords: obesity,adrenergic receptors,thyroid hormone receptors,5’-iodothyronine deiodinases,uncoupling proteins,methylation

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ScienceOpen disciplines: Medicine

Keywords: obesity, adrenergic receptors, thyroid hormone receptors, 5’-iodothyronine deiodinases, uncoupling proteins, methylation

Obesity is associated with a decrease in expression but not with the hypermethylation of thermogenesis-related genes in adipose tissues

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Most cited references 40

betaAR signaling required for diet-induced thermogenesis and obesity resistance.

Thermogenic mechanisms and their hormonal regulation.

UCP1-independent thermogenesis in white adipose tissue of cold-acclimated Ucp1-/- mice.

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