title: Participation of HIFs in the regulation of Sertoli cell lactate production.
abstract: Hypoxia Inducible Factors (HIFs) are master regulators of glycolytic metabolism. HIFs consist of a constitutive HIFbeta (HIFβ) subunit and a HIFalpha (HIFα) subunit, whose half-life depends on prolyl-hydroxylases activity. Inhibition of prolyl-hydroxylases by hypoxia or transition metals, or augmentation of HIFα subunit levels by hormonal stimuli lead to a higher HIF transcriptional activity. On the other hand, it is well known that lactate produced by Sertoli cells is delivered to and used by germ cells as an energy substrate. The aim of this work was to investigate whether HIFs participate in the regulation of lactate production in rat Sertoli cells and whether they are involved in the FSH mechanism of action. In order to reach a higher HIF transcriptional activity, Sertoli cells were treated with CoCl2. We observed that a higher HIF transcriptional activity leads to an augmentation of: lactate production, glucose uptake and LDH activity. Besides, an increase in Glut1, Pkm2 and Ldha mRNA levels was observed. These findings suggested that HIFs may participate in the modulation of Sertoli cell nutritional function. As FSH regulates lactate production, we evaluated whether HIFs were involved in FSH action. Sertoli cells were stimulated with FSH in the absence or presence of LW6, a drug which promotes HIFα subunit degradation. On the one hand, we observed that FSH increases HIF1α protein, Hif1α and Hif2α mRNA levels and, on the other hand, that LW6 inhibits FSH-stimulated lactate production, glucose uptake, Glut1, Pkm2 and Ldha expression. It is proposed that HIFs are key components of the intricate pathways utilized by FSH to regulate the provision of lactate for germ cells. Considering that FSH is the master endocrine regulator of Sertoli cells, it is not surprising that this hormone may employ several regulatory mechanisms to fulfill the nourishing functions of this cell type.
authors.affiliation: Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE) CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Gallo 1330, C1425EFD, Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: María Noel
authors.initials: MN
authors.lastname: Galardo
authors.affiliation: Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE) CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Gallo 1330, C1425EFD, Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: Agostina
authors.initials: A
authors.lastname: Gorga
authors.affiliation: Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE) CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Gallo 1330, C1425EFD, Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: Joaquín Pedro
authors.initials: JP
authors.lastname: Merlo
authors.affiliation: Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE) CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Gallo 1330, C1425EFD, Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: Mariana
authors.initials: M
authors.lastname: Regueira
authors.affiliation: Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE) CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Gallo 1330, C1425EFD, Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: Eliana Herminia
authors.initials: EH
authors.lastname: Pellizzari
authors.affiliation: Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE) CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Gallo 1330, C1425EFD, Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: Selva Beatriz
authors.initials: SB
authors.lastname: Cigorraga
authors.affiliation: Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE) CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Gallo 1330, C1425EFD, Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: María Fernanda
authors.initials: MF
authors.lastname: Riera
authors.affiliation: Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE) CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Gallo 1330, C1425EFD, Ciudad Autónoma de Buenos Aires, Argentina. Electronic address: smeroni@cedie.org.ar.
authors.forename: Silvina Beatriz
authors.initials: SB
authors.lastname: Meroni
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics* / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003035:Cobalt / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D007773:Lactates / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012708:Sertoli Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013963:Thyroid Hormones / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D000083:Acetanilides; D000218:Adamantane; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D002352:Carrier Proteins; D003035:Cobalt; D005640:Follicle Stimulating Hormone; D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007773:Lactates; D008565:Membrane Proteins; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C000607696:LW6 compound; C495679:Slc2a1 protein, rat; C018021:cobaltous chloride
keywords: FSH; HIFs; Lactate; Sertoli cell