Skip to main content
Top
Published in: Obesity Surgery 1/2012

01-01-2012 | Physiology Research

Sexual Dimorphism in Clock Genes Expression in Human Adipose Tissue

Authors: P. Gómez-Abellán, J. A. Madrid, J. A. Luján, M. D. Frutos, R. González, O. Martínez-Augustín, F. Sánchez de Medina, J. M. Ordovás, M. Garaulet

Published in: Obesity Surgery | Issue 1/2012

Login to get access

Abstract

Background

This study was carried out to investigate whether sex-related differences exist in the adipocyte expression of clock genes from subcutaneous abdominal and visceral fat depots in severely obese patients.

Methods

We investigated 16 morbidly obese patients, eight men and eight women (mean age 45 ± 20 years; mean BMI 46 ± 6 kg/m2), undergoing laparoscopic gastric bypass surgery. Biopsies were taken as paired samples [subcutaneous and visceral adipose tissue (AT)] at the beginning of the surgical process at 11:00 h in the morning. Metabolic syndrome features such as waist circumference, plasma glucose, triglycerides, total cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were also studied. The expression of clock genes (PER2, BMAL1, and CRY1) was measured by quantitative real-time PCR, Western blot, and immunohistochemical analysis.

Results

Gene expression was significantly higher in women than in men for the three genes studied in both ATs (P < 0.05). In visceral fat, these differences were more marked. (P < 0.001). Western blot analysis partially confirmed these results since statistical differences were observed for PER2 in both ATs and for CRY1 in subcutaneous adipose tissue. There were no differences in BMAL1 protein expression. Interestingly, clock gene expression level was correlated with LDL-C and HDL-C (P < 0.05). Moreover, we found significant associations with body fat mass in women and with age in men.

Conclusions

Clock genes expression is sex dependent in human adipose tissue from morbidly obese subjects and correlates to a decreased in metabolic syndrome-related traits. These preliminary results make necessary to go deep into the knowledge of the molecular basis of the sexual dimorphism in chronobiology.
Literature
1.
go back to reference Garaulet M, Gómez-Abellán P, Madrid JA. Chronobiology and obesity: the orchestra out of tune. Clin Lipidol. 2010;5(2):181–8. Review.CrossRef Garaulet M, Gómez-Abellán P, Madrid JA. Chronobiology and obesity: the orchestra out of tune. Clin Lipidol. 2010;5(2):181–8. Review.CrossRef
2.
go back to reference Marcheva B, Ramsey KM, Affinati A, et al. Clock genes and metabolic disease. J Appl Physiol. 2009;107(5):1638–46. Review.PubMedCrossRef Marcheva B, Ramsey KM, Affinati A, et al. Clock genes and metabolic disease. J Appl Physiol. 2009;107(5):1638–46. Review.PubMedCrossRef
3.
go back to reference Garaulet M, Madrid JA. Chronobiology, genetics and metabolic syndrome. Curr Opin Lipidol. 2009;20(2):127–34.PubMedCrossRef Garaulet M, Madrid JA. Chronobiology, genetics and metabolic syndrome. Curr Opin Lipidol. 2009;20(2):127–34.PubMedCrossRef
4.
go back to reference Whitehead JP, Richards AA, Hickman IJ, et al. Adiponectin—a key adipokine in the metabolic syndrome. Diabetes Obes Metab. 2006;8:264–80.PubMedCrossRef Whitehead JP, Richards AA, Hickman IJ, et al. Adiponectin—a key adipokine in the metabolic syndrome. Diabetes Obes Metab. 2006;8:264–80.PubMedCrossRef
5.
go back to reference Gómez-Abellán P, Hernández-Morante JJ, Luján JA, et al. Clock genes are implicated in the human metabolic syndrome. Int J Obes. 2008;32(1):121–8.CrossRef Gómez-Abellán P, Hernández-Morante JJ, Luján JA, et al. Clock genes are implicated in the human metabolic syndrome. Int J Obes. 2008;32(1):121–8.CrossRef
6.
go back to reference Klaus S, Keijer J. Gene expression profiling of adipose tissue: individual, depot-dependent, and sex-dependent variabilities. Nutrition. 2004;20(1):115–20.PubMedCrossRef Klaus S, Keijer J. Gene expression profiling of adipose tissue: individual, depot-dependent, and sex-dependent variabilities. Nutrition. 2004;20(1):115–20.PubMedCrossRef
7.
go back to reference Garaulet M, Pérez-Llamas F, Fuente T, et al. Anthropometric, computed tomography and fat cell data in an obese population: relationship with insulin, leptin, tumor necrosis factor-alpha, sex hormone-binding globulin and sex hormones. Eur J Endocrinol. 2000;143(5):657–66.PubMedCrossRef Garaulet M, Pérez-Llamas F, Fuente T, et al. Anthropometric, computed tomography and fat cell data in an obese population: relationship with insulin, leptin, tumor necrosis factor-alpha, sex hormone-binding globulin and sex hormones. Eur J Endocrinol. 2000;143(5):657–66.PubMedCrossRef
8.
go back to reference Ramis JM, Salinas R, García-Sanz JM, et al. Depot- and gender-related differences in the lipolytic pathway of adipose tissue from severely obese patients. Cell Physiol Biochem. 2006;17(3–4):173–80.PubMedCrossRef Ramis JM, Salinas R, García-Sanz JM, et al. Depot- and gender-related differences in the lipolytic pathway of adipose tissue from severely obese patients. Cell Physiol Biochem. 2006;17(3–4):173–80.PubMedCrossRef
9.
go back to reference Adan A, Natale V. Gender differences in morningness–eveningness preference. Chronobiol Int. 2002;19(4):709–20.PubMedCrossRef Adan A, Natale V. Gender differences in morningness–eveningness preference. Chronobiol Int. 2002;19(4):709–20.PubMedCrossRef
10.
go back to reference Lévi F, Filipski E, Iurisci I, et al. Cross-talks between circadian timing system and cell division cycle determine cancer biology and therapeutics. Cold Spring Harb Symp Quant Biol. 2007;72:465–75.PubMedCrossRef Lévi F, Filipski E, Iurisci I, et al. Cross-talks between circadian timing system and cell division cycle determine cancer biology and therapeutics. Cold Spring Harb Symp Quant Biol. 2007;72:465–75.PubMedCrossRef
11.
go back to reference Mongrain V, Lavoie S, Selmaoui B, et al. Phase relationships between sleep–wake cycle and underlying circadian rhythms in morningness–eveningness. J Biol Rhythms. 2004;19(3):248–57.PubMedCrossRef Mongrain V, Lavoie S, Selmaoui B, et al. Phase relationships between sleep–wake cycle and underlying circadian rhythms in morningness–eveningness. J Biol Rhythms. 2004;19(3):248–57.PubMedCrossRef
12.
go back to reference Sopowski MJ, Hampton SM, Ribeiro DC, et al. Postprandial triacylglycerol responses in simulated night and day shift: gender differences. J Biol Rhythms. 2001;16(3):272–6.PubMed Sopowski MJ, Hampton SM, Ribeiro DC, et al. Postprandial triacylglycerol responses in simulated night and day shift: gender differences. J Biol Rhythms. 2001;16(3):272–6.PubMed
13.
go back to reference Panda S, Antoch MP, Miller BH, et al. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell. 2002;109:307–20.PubMedCrossRef Panda S, Antoch MP, Miller BH, et al. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell. 2002;109:307–20.PubMedCrossRef
14.
go back to reference Storch KF, Lipan O, Leykin I, et al. Extensive and divergent circadian gene expression in liver and heart. Nature. 2002;417:78–83.PubMedCrossRef Storch KF, Lipan O, Leykin I, et al. Extensive and divergent circadian gene expression in liver and heart. Nature. 2002;417:78–83.PubMedCrossRef
15.
go back to reference Yoo SH, Yamazaki S, Lowrey PL, et al. PERIOD2:LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proc Natl Acad Sci USA. 2004;101:5339–46.PubMedCrossRef Yoo SH, Yamazaki S, Lowrey PL, et al. PERIOD2:LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proc Natl Acad Sci USA. 2004;101:5339–46.PubMedCrossRef
16.
go back to reference Ando H, Yanagihara H, Hayashi Y, et al. Rhythmic mRNA expression of clock genes and adipocytokines in mouse visceral adipose tissue. Endocrinology. 2005;146(12):5631–6.PubMedCrossRef Ando H, Yanagihara H, Hayashi Y, et al. Rhythmic mRNA expression of clock genes and adipocytokines in mouse visceral adipose tissue. Endocrinology. 2005;146(12):5631–6.PubMedCrossRef
17.
go back to reference Teboul M, Barrat-Petit MA, Li XM, et al. Atypical patterns of circadian clock gene expression in human peripheral blood mononuclear cells. J Mol Med. 2005;83:693–9.PubMedCrossRef Teboul M, Barrat-Petit MA, Li XM, et al. Atypical patterns of circadian clock gene expression in human peripheral blood mononuclear cells. J Mol Med. 2005;83:693–9.PubMedCrossRef
18.
go back to reference Sociedad Española para el Estudio de la Obesidad (SEEDO). Consenso SEEDO 2007 para la evaluación del sobrepeso y la obesidad y el establecimiento de criterios de intervención terapéutica [article in Spanish]. Med Clin (Barc). 2007;128:184–96.CrossRef Sociedad Española para el Estudio de la Obesidad (SEEDO). Consenso SEEDO 2007 para la evaluación del sobrepeso y la obesidad y el establecimiento de criterios de intervención terapéutica [article in Spanish]. Med Clin (Barc). 2007;128:184–96.CrossRef
19.
go back to reference Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 2001;25:402–8.PubMedCrossRef Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 2001;25:402–8.PubMedCrossRef
20.
go back to reference Alberti KGMM, Zimmet P, Shaw J. Metabolic syndrome a new world-wide definition. A consensus statement from the International Diabetes Federation. Diabet Med. 2006;23:469–80.PubMedCrossRef Alberti KGMM, Zimmet P, Shaw J. Metabolic syndrome a new world-wide definition. A consensus statement from the International Diabetes Federation. Diabet Med. 2006;23:469–80.PubMedCrossRef
21.
go back to reference Yang X, Zhang YK, Esterly N, et al. Gender disparity of hepatic lipid homoeostasis regulated by the circadian clock. J Biochem. 2009;145(5):609–23.PubMedCrossRef Yang X, Zhang YK, Esterly N, et al. Gender disparity of hepatic lipid homoeostasis regulated by the circadian clock. J Biochem. 2009;145(5):609–23.PubMedCrossRef
22.
go back to reference Metz RP, Qu X, Laffin B, et al. Circadian clock and cell cycle gene expression in mouse mammary epithelial cells and in the developing mouse mammary gland. Dev Dyn. 2006;235:263–71.PubMedCrossRef Metz RP, Qu X, Laffin B, et al. Circadian clock and cell cycle gene expression in mouse mammary epithelial cells and in the developing mouse mammary gland. Dev Dyn. 2006;235:263–71.PubMedCrossRef
23.
go back to reference Miller BH, Olson SL, Turek FW, et al. Circadian clock mutation disrupts estrous cyclicity and maintenance of pregnancy. Curr Biol. 2004;14:1367–73.PubMedCrossRef Miller BH, Olson SL, Turek FW, et al. Circadian clock mutation disrupts estrous cyclicity and maintenance of pregnancy. Curr Biol. 2004;14:1367–73.PubMedCrossRef
24.
go back to reference Albers HE. Gonadal hormones organize and modulate the circadian system of the rat. Am J Physiol. 1981;241:R62–6.PubMed Albers HE. Gonadal hormones organize and modulate the circadian system of the rat. Am J Physiol. 1981;241:R62–6.PubMed
25.
go back to reference Wiegand SJ, Terasawa E. Discrete lesions reveal functional heterogeneity of suprachiasmatic structures in regulation of gonadotropin secretion in the female rat. Neuroendocrinology. 1982;34:395–404.PubMedCrossRef Wiegand SJ, Terasawa E. Discrete lesions reveal functional heterogeneity of suprachiasmatic structures in regulation of gonadotropin secretion in the female rat. Neuroendocrinology. 1982;34:395–404.PubMedCrossRef
26.
go back to reference Wiegand SJ, Terasawa E, Bridson WE. Persistent estrus and blockade of progesterone-induced LH release follows lesions which do not damage the suprachiasmatic nucleus. Endocrinology. 1978;102:1645–8.PubMedCrossRef Wiegand SJ, Terasawa E, Bridson WE. Persistent estrus and blockade of progesterone-induced LH release follows lesions which do not damage the suprachiasmatic nucleus. Endocrinology. 1978;102:1645–8.PubMedCrossRef
27.
go back to reference Perrin JS, Segall LA, Harbour VL, et al. The expression of the clock protein PER2 in the limbic forebrain is modulated by the estrous cycle. Proc Natl Acad Sci USA. 2006;103(14):5591–6.PubMedCrossRef Perrin JS, Segall LA, Harbour VL, et al. The expression of the clock protein PER2 in the limbic forebrain is modulated by the estrous cycle. Proc Natl Acad Sci USA. 2006;103(14):5591–6.PubMedCrossRef
28.
go back to reference Van Dongen HPA. Inter- and intra-individual differences in circadian phase. The Netherlands: Leiden University Press; 1998. Van Dongen HPA. Inter- and intra-individual differences in circadian phase. The Netherlands: Leiden University Press; 1998.
29.
go back to reference Wever RA. Characteristics of circadian rhythms in human functions. In Journal of Neural Transmission (Suppl.) Melatonin in Humans; Wurtman RJ, Waldhause F, Eds.; Springer, New York, 1986; 323–335. Wever RA. Characteristics of circadian rhythms in human functions. In Journal of Neural Transmission (Suppl.) Melatonin in Humans; Wurtman RJ, Waldhause F, Eds.; Springer, New York, 1986; 323–335.
30.
go back to reference Maywood ES, O'Brien JA, Hastings MH. Expression of mCLOCK and other circadian clock-relevant proteins in the mouse suprachiasmatic nuclei. J Neuroendocrinol. 2003;15(4):329–34.PubMedCrossRef Maywood ES, O'Brien JA, Hastings MH. Expression of mCLOCK and other circadian clock-relevant proteins in the mouse suprachiasmatic nuclei. J Neuroendocrinol. 2003;15(4):329–34.PubMedCrossRef
31.
go back to reference Shende VR, Goldrick MM, Ramani S, et al. Expression and rhythmic modulation of circulating microRNAs targeting the clock gene Bmal1 in mice. PLoS One. 2011;6(7):e22586.PubMedCrossRef Shende VR, Goldrick MM, Ramani S, et al. Expression and rhythmic modulation of circulating microRNAs targeting the clock gene Bmal1 in mice. PLoS One. 2011;6(7):e22586.PubMedCrossRef
32.
go back to reference Lee J, Lee Y, Lee MJ, et al. Dual modification of BMAL1 by SUMO2/3 and ubiquitin promotes circadian activation of the CLOCK/BMAL1 complex. Mol Cell Biol. 2008;28(19):6056–65.PubMedCrossRef Lee J, Lee Y, Lee MJ, et al. Dual modification of BMAL1 by SUMO2/3 and ubiquitin promotes circadian activation of the CLOCK/BMAL1 complex. Mol Cell Biol. 2008;28(19):6056–65.PubMedCrossRef
33.
go back to reference Cnop M, Havel PJ, Utzschneider KM, et al. Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex. Diabetologia. 2003;46(4):459–69.PubMed Cnop M, Havel PJ, Utzschneider KM, et al. Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex. Diabetologia. 2003;46(4):459–69.PubMed
34.
go back to reference Saad MF, Riad-Gabriel MG, Khan A, et al. Diurnal and ultradian rhythmicity of plasma leptin: effects of gender and adiposity. J Clin Endocrinol Metab. 1998;83(2):453–9.PubMedCrossRef Saad MF, Riad-Gabriel MG, Khan A, et al. Diurnal and ultradian rhythmicity of plasma leptin: effects of gender and adiposity. J Clin Endocrinol Metab. 1998;83(2):453–9.PubMedCrossRef
35.
go back to reference Bur IM, Cohen-Solal AM, Carmignac D, et al. The circadian clock components CRY1 and CRY2 are necessary to sustain sex dimorphism in mouse liver metabolism. J Biol Chem. 2009;284(14):9066–73.PubMedCrossRef Bur IM, Cohen-Solal AM, Carmignac D, et al. The circadian clock components CRY1 and CRY2 are necessary to sustain sex dimorphism in mouse liver metabolism. J Biol Chem. 2009;284(14):9066–73.PubMedCrossRef
36.
go back to reference Pilorz V, Steinlechner S, Oster H. Age and oestrus cycle-related changes in glucocorticoid excretion and wheel-running activity in female mice carrying mutations in the circadian clock genes Per1 and Per2. Physiol Behav. 2009;96(1):57–63.PubMedCrossRef Pilorz V, Steinlechner S, Oster H. Age and oestrus cycle-related changes in glucocorticoid excretion and wheel-running activity in female mice carrying mutations in the circadian clock genes Per1 and Per2. Physiol Behav. 2009;96(1):57–63.PubMedCrossRef
37.
go back to reference Garaulet M, Corbalán MD, Madrid JA, et al. PER2 variants are associated with abdominal obesity, psycho-behavioral factors and attrition in the dietary treatment of obesity. J Am Diet Assoc. 2010;110(6):917–21.PubMedCrossRef Garaulet M, Corbalán MD, Madrid JA, et al. PER2 variants are associated with abdominal obesity, psycho-behavioral factors and attrition in the dietary treatment of obesity. J Am Diet Assoc. 2010;110(6):917–21.PubMedCrossRef
38.
go back to reference Yang S, Liu A, Weidenhammer A, et al. The role of mPer2 clock gene in glucocorticoid and feeding rhythm. Endocrinology. 2009;150(5):2153–60.PubMedCrossRef Yang S, Liu A, Weidenhammer A, et al. The role of mPer2 clock gene in glucocorticoid and feeding rhythm. Endocrinology. 2009;150(5):2153–60.PubMedCrossRef
39.
go back to reference Armitage R, Smith C, Thompson S, et al. Sex differences in slow-wave activity in response to sleep deprivation. Sleep Res Online. 2001;4:33–41. Armitage R, Smith C, Thompson S, et al. Sex differences in slow-wave activity in response to sleep deprivation. Sleep Res Online. 2001;4:33–41.
40.
go back to reference Manber R, Armitage R. Sex, steroids, and sleep: a review. Sleep. 1999;22:540–55.PubMed Manber R, Armitage R. Sex, steroids, and sleep: a review. Sleep. 1999;22:540–55.PubMed
41.
go back to reference Ando H, Ushijima K, Kumazaki M, et al. Influence of age on clock gene expression in peripheral blood cells of healthy women. J Gerontol A Biol Sci Med Sci. 2010;65(1):9–13.PubMedCrossRef Ando H, Ushijima K, Kumazaki M, et al. Influence of age on clock gene expression in peripheral blood cells of healthy women. J Gerontol A Biol Sci Med Sci. 2010;65(1):9–13.PubMedCrossRef
42.
go back to reference Kohsaka A, Laposky AD, Ramsey KM, et al. High-fat diet disrupts behavioral and molecular circadian rhythms in mice. Cell Metab. 2007;6(5):414–21.PubMedCrossRef Kohsaka A, Laposky AD, Ramsey KM, et al. High-fat diet disrupts behavioral and molecular circadian rhythms in mice. Cell Metab. 2007;6(5):414–21.PubMedCrossRef
43.
go back to reference Karlsson B, Knutsson A, Lindahl B. Is there an association between shift work and having a metabolic syndrome? Results from a population based study of 27,485 people. Occup Environ Med. 2001;58:747–52.PubMedCrossRef Karlsson B, Knutsson A, Lindahl B. Is there an association between shift work and having a metabolic syndrome? Results from a population based study of 27,485 people. Occup Environ Med. 2001;58:747–52.PubMedCrossRef
Metadata
Title
Sexual Dimorphism in Clock Genes Expression in Human Adipose Tissue
Authors
P. Gómez-Abellán
J. A. Madrid
J. A. Luján
M. D. Frutos
R. González
O. Martínez-Augustín
F. Sánchez de Medina
J. M. Ordovás
M. Garaulet
Publication date
01-01-2012
Publisher
Springer-Verlag
Published in
Obesity Surgery / Issue 1/2012
Print ISSN: 0960-8923
Electronic ISSN: 1708-0428
DOI
https://doi.org/10.1007/s11695-011-0539-2

Other articles of this Issue 1/2012

Obesity Surgery 1/2012 Go to the issue