Opposite effects of 17-β estradiol and testosterone on mitochondrial biogenesis and adiponectin synthesis in white adipocytes.

Sexual dimorphism has been found in both mitochondrial functionality and adiponectin expression in white adipose tissue, with female rats presenting more functional mitochondria than males and greater adiponectin expression. However, little is known about the role of sex hormones in this dimorphism. The aim was to elucidate the role of sex hormones in mitochondrial biogenesis and dynamics and in adiponectin synthesis in white adipocytes, and also to provide new evidence of the link between these processes. 3T3-L1 preadipocytes were differentiated and treated either with 17-β estradiol (E₂; 10  nM), progesterone (Pg), testosterone (1  μM both), or a combination of Pg or testosterone with flutamide (FLT; 10  μM) or E₂ (1  μM). The markers of mitochondrial biogenesis and dynamics and adiponectin expression were analyzed. E₂ induced mitochondrial proliferation and differentiation in 3T3-L1, although testosterone showed opposite effects. Pg treatment stimulated proliferation but impaired differentiation. In concerns mitochondrial dynamics, these hormones promoted fusion over fission. FLT treatment indicated that Pg elicits its effects on mitochondrial dynamics through the androgen receptor. E₂ coadministration with testosterone or Pg reversed its effects. In conclusion, our results show that E₂ induces stimulation of mitochondrial biogenesis in white adipocytes in vitro, especially in situations that imply an impairment of mitochondrial function, whereas testosterone would have opposite effects. Moreover, testosterone and Pg alter mitochondrial dynamics by promoting fusion over fission, while E₂ stimulates both processes. All these alterations run in parallel with changes in adiponectin expression, thus suggesting the existence of a link between mitochondrial biogenesis and dynamics and adiponectin synthesis in white adipocytes.

[1]  D. Chan,et al.  Disruption of Fusion Results in Mitochondrial Heterogeneity and Dysfunction* , 2005, Journal of Biological Chemistry.

[2]  T. Nakayama,et al.  Platelet mitochondrial evaluation during cytochrome c and dichloroacetate treatments of MELAS. , 2005, Mitochondrion.

[3]  Yau-Huei Wei,et al.  Mitochondrial biogenesis and mitochondrial DNA maintenance of mammalian cells under oxidative stress. , 2005, The international journal of biochemistry & cell biology.

[4]  A. Proenza,et al.  Retroperitoneal white adipose tissue mitochondrial function and adiponectin expression in response to ovariectomy and 17β-estradiol replacement , 2012, Steroids.

[5]  O. Jänne,et al.  Progestins can mimic, inhibit and potentiate the actions of androgens. , 1983, Pharmacology & therapeutics.

[6]  B. Spiegelman,et al.  Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism. , 2006, Endocrine reviews.

[7]  D. Chan,et al.  Functions and dysfunctions of mitochondrial dynamics , 2007, Nature Reviews Molecular Cell Biology.

[8]  J. Eckel,et al.  Autocrine action of adiponectin on human fat cells prevents the release of insulin resistance-inducing factors. , 2005, Diabetes.

[9]  Marc Liesa,et al.  Mitochondrial dynamics in mammalian health and disease. , 2009, Physiological reviews.

[10]  V. Mootha,et al.  Mechanisms Controlling Mitochondrial Biogenesis and Respiration through the Thermogenic Coactivator PGC-1 , 1999, Cell.

[11]  M. M. Bradford.  A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. , 1976, Analytical biochemistry.

[12]  H. Ji,et al.  Mitochondrial development and the influence of its dysfunction during rat adipocyte differentiation , 2010, Molecular Biology Reports.

[13]  A. Proenza,et al.  Sex differences in the effect of high-fat diet feeding on rat white adipose tissue mitochondrial function and insulin sensitivity. , 2012, Metabolism: clinical and experimental.

[14]  R. Wood-Bradley,et al.  White adipocytes: more than just fat depots. , 2012, The international journal of biochemistry & cell biology.

[15]  D. Chan,et al.  Mitochondrial dynamics in mammals. , 2004, Current topics in developmental biology.

[16]  Min-Seon Kim,et al.  Essential Role of Mitochondrial Function in Adiponectin Synthesis in Adipocytes , 2007, Diabetes.

[17]  A. Proenza,et al.  High-fat diet feeding induces a depot-dependent response on the pro-inflammatory state and mitochondrial function of gonadal white adipose tissue. , 2013, The British journal of nutrition.

[18]  P. Puigserver,et al.  Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. , 2003, Endocrine reviews.

[19]  M. Matsuda,et al.  Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors. , 2003, Diabetes.

[20]  R. Handa,et al.  The androgen metabolite, 5α-androstane-3β,17β-diol (3β-diol), activates the oxytocin promoter through an estrogen receptor-β pathway. , 2013, Endocrinology.

[21]  T. Prolla,et al.  Mitochondrial Fusion Is Required for mtDNA Stability in Skeletal Muscle and Tolerance of mtDNA Mutations , 2010, Cell.

[22]  R. Scarpulla,et al.  Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. , 2011, Biochimica et biophysica acta.

[23]  Y. Yoon,et al.  Mitochondrial morphology in metabolic diseases. , 2013, Antioxidants & redox signaling.

[24]  E. Mannarino,et al.  The endocrine function of adipose tissue: an update , 2006, Clinical endocrinology.

[25]  F. Labrie,et al.  Mechanism of action and pure antiandrogenic properties of flutamide , 1993, Cancer.

[26]  M. Matsuda,et al.  Androgens decrease plasma adiponectin, an insulin-sensitizing adipocyte-derived protein. , 2002, Diabetes.

[27]  C. Klinge,et al.  Estradiol stimulates transcription of nuclear respiratory factor-1 and increases mitochondrial biogenesis. , 2008, Molecular endocrinology.

[28]  H. Harwood,et al.  The adipocyte as an endocrine organ in the regulation of metabolic homeostasis , 2012, Neuropharmacology.

[29]  G. Steinberg,et al.  Adipose tissue as an endocrine organ , 2010, Molecular and Cellular Endocrinology.

[30]  W. Garvey,et al.  Adiponectin promotes adipocyte differentiation, insulin sensitivity, and lipid accumulation Published, JLR Papers in Press, April 16, 2005. DOI 10.1194/jlr.M400373-JLR200 , 2005, Journal of Lipid Research.

[31]  R. Scarpulla.  Nuclear Control of Respiratory Chain Expression in Mammalian Cells , 1997, Journal of bioenergetics and biomembranes.

[32]  R. Wiesner,et al.  Transient overexpression of mitochondrial transcription factor A (TFAM) is sufficient to stimulate mitochondrial DNA transcription, but not sufficient to increase mtDNA copy number in cultured cells. , 2004, Nucleic acids research.

[33]  R. Youle,et al.  Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. , 2004, Molecular biology of the cell.

[34]  J. Enríquez,et al.  Replication and Transcription of Mammalian Mitochondrial Dna , 2003, Experimental physiology.

[35]  Marc Liesa,et al.  Role of mitochondrial dynamics proteins in the pathophysiology of obesity and type 2 diabetes. , 2009, The international journal of biochemistry & cell biology.

[36]  J. Bienkowska,et al.  Estrogen Receptors α and β Mediate Distinct Pathways of Vascular Gene Expression, Including Genes Involved in Mitochondrial Electron Transport and Generation of Reactive Oxygen Species , 2007 .

[37]  D. Roncari,et al.  Promotion of human adipocyte precursor replication by 17beta-estradiol in culture. , 1978, The Journal of clinical investigation.

[38]  G. Cho,et al.  Correlation between estrogens and serum adipocytokines in premenopausal and postmenopausal women , 2007, Menopause.

[39]  T. Work,et al.  Biogenesis of Mitochondria , 1966, Nature.

[40]  G. Shadel,et al.  Human mitochondrial transcription factor A and promoter spacing integrity are required for transcription initiation. , 1995, Biochimica et biophysica acta.

[41]  Yau-Huei Wei,et al.  Mitochondrial dysfunction leads to impairment of insulin sensitivity and adiponectin secretion in adipocytes , 2013, The FEBS journal.

[42]  A. Barnett,et al.  The effects of androgens and estrogens on preadipocyte proliferation in human adipose tissue: influence of gender and site. , 2001, The Journal of clinical endocrinology and metabolism.

[43]  Julie Takada,et al.  O tecido adiposo como órgão endócrino: da teoria à prática: [revisão] , 2007 .

[44]  M. Fonseca-Alaniz,et al.  Adipose tissue as an endocrine organ: from theory to practice. , 2007, Jornal de pediatria.

[45]  Kok Weng Chan,et al.  Testosterone Selectively Reduces the High Molecular Weight Form of Adiponectin by Inhibiting Its Secretion from Adipocytes* , 2005, Journal of Biological Chemistry.

[46]  B. Spiegelman.  Peroxisome Proliferator-Activated Receptor-Coactivator 1 ( PGC-1 ) : Transcriptional Coactivator and Metabolic Regulator , 2003 .

[47]  D. Clayton.  Transcription and replication of animal mitochondrial DNAs. , 1992, International review of cytology.

[48]  B. Spiegelman,et al.  Regulation of adipocyte gene expression in differentiation and syndromes of obesity/diabetes. , 1993, The Journal of biological chemistry.

[49]  P. Scherer,et al.  Adipose tissue-derived factors: impact on health and disease. , 2006, Endocrine reviews.

[50]  R. Wiesner,et al.  Import of mitochondrial transcription factor A (TFAM) into rat liver mitochondria stimulates transcription of mitochondrial DNA. , 2003, Nucleic acids research.

[51]  Min Wu,et al.  Fission and selective fusion govern mitochondrial segregation and elimination by autophagy , 2008, The EMBO journal.