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1. Severe Hyperprolactinemia Promotes Brown Adipose Tissue Whitening and Aggravates High Fat Diet Induced Metabolic Imbalance

Author

Felicitas Lopez-Vicchi, Catalina De Winne, Ana Maria Ornstein, Eleonora Sorianello, Judith Toneatto, and Damasia Becu-Villalobos

Subjects
prolactin, brown adipose tissue, thermogenic markers, whitening, UCP1, PGC1 alpha, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

BackgroundThe association of high serum prolactin and increased body weight is positive but controversial, therefore we hypothesized that additional factors such as diets and the impact of prolactin on brown adipose tissue may condition its metabolic effects.MethodsWe used LacDrd2KO females with lifelong severe hyperprolactinemia due dopamine-D2 receptor deletion from lactotropes, and slow onset of metabolic disturbances, and compared them to their respective controls (Drd2 loxP/loxP). Food intake, and binge eating was evaluated. We then challenged mice with a High Fat (HFD) or a Control Diet (CD) for 8 weeks, beginning at 3 months of age, when no differences in body weight are found between genotypes. At the end of the protocol brown and white adipose tissues were weighed, and thermogenic and lipogenic markers studied, using real time PCR (Ucp1, Cidea, Pgc1a, Lpl, adiponectin, Prlr) or immunohistochemistry (UCP1). Histochemical analysis of brown adipose tissue, and glucose tolerance tests were performed.ResultsHyperprolactinemic mice had increased food intake and binge eating behavior. Metabolic effects induced by a HFD were exacerbated in lacDrd2KO mice. Hyperprolactinemia aggravated HFD-induced body weight gain and glucose intolerance. In brown adipose tissue pronounced cellular whitening as well as decreased expression of the thermogenic markers Ucp1 and Pgc1a were observed in response to high prolactin levels, regardless of the diet, and furthermore, hyperprolactinemia potentiated the decrease in Cidea mRNA expression induced by HFD. In subcutaneous white adipose tissue hyperprolactinemia synergistically increased tissue weight, while decreasing Prlr, Adiponectin and Lpl mRNA levels regardless of the diet.ConclusionsPathological hyperprolactinemia has a strong impact in brown adipose tissue, lowering thermogenic markers and evoking tissue whitening. Furthermore, it modifies lipogenic markers in subcutaneous white adipose, and aggravates HFD-induced glucose intolerance and Cidea decrease. Therefore, severe high prolactin levels may target BAT function, and furthermore represent an adjuvant player in the development of obesity induced by high fat diets.

Published
2022
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3. Angiogenesis in Pituitary Adenomas: Human Studies and New Mutant Mouse Models

Author

Carolina Cristina, Guillermina María Luque, Gianina Demarchi, Felicitas Lopez Vicchi, Lautaro Zubeldia-Brenner, Maria Ines Perez Millan, Sofia Perrone, Ana Maria Ornstein, Isabel M. Lacau-Mengido, Silvia Inés Berner, and Damasia Becu-Villalobos

Subjects
Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

The role of angiogenesis in pituitary tumor development has been questioned, as pituitary tumors have been usually found to be less vascularized than the normal pituitary tissue. Nevertheless, a significantly higher degree of vasculature has been shown in invasive or macropituitary prolactinomas when compared to noninvasive and microprolactinomas. Many growth factors and their receptors are involved in pituitary tumor development. For example, VEGF, FGF-2, FGFR1, and PTTG, which give a particular vascular phenotype, are modified in human and experimental pituitary adenomas of different histotypes. In particular, vascular endothelial growth factor, VEGF, the central mediator of angiogenesis in endocrine glands, was encountered in experimental and human pituitary tumors at different levels of expression and, in particular, was higher in dopamine agonist resistant prolactinomas. Furthermore, several anti-VEGF techniques lowered tumor burden in human and experimental pituitary adenomas. Therefore, even though the role of angiogenesis in pituitary adenomas is contentious, VEGF, making permeable pituitary endothelia, might contribute to adequate temporal vascular supply and mechanisms other than endothelial cell proliferation. The study of angiogenic factor expression in aggressive prolactinomas with resistance to dopamine agonists will yield important data in the search of therapeutical alternatives.

Published
2014
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4. Epigenetic modifications in the GH-dependent Prlr, Hnf6, Cyp7b1, Adh1 and Cyp2a4 genes

Author

Ana Maria Ornstein, Belen Brie, Damasia Becu-Villalobos, I.M. Lacau-Mengido, and Maria Cecilia Ramirez

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, LIVER, CIENCIAS MÉDICAS Y DE LA SALUD, Receptors, Prolactin, Cytochrome P450 Family 7, 030209 endocrinology & metabolism, Biology, MIRNA, Epigenesis, Genetic, Mice, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Internal medicine, microRNA, Gene expression, medicine, Animals, Epigenetics, Cytochrome P450 Family 2, Promoter Regions, Genetic, Molecular Biology, Gene, Mice, Knockout, Sex Characteristics, Prolactin receptor, PRLR, Alcohol Dehydrogenase, METHYLATION, Otras Medicina Básica, Promoter, Methylation, GH, Mice, Inbred C57BL, Sexual dimorphism, Hepatocyte Nuclear Factor 6, Medicina Básica, 030104 developmental biology, Gene Expression Regulation, Liver, Growth Hormone, Steroid Hydroxylases, Female, Aryl Hydrocarbon Hydroxylases, Signal Transduction
Abstract

Many sex differences in liver gene expression originate in the brain, depend on GH secretion and may underlie sex disparities in hepatic disease. Because epigenetic mechanisms may contribute, we studied promoter methylation and microRNA abundance in the liver, associated with expression of sexual dimorphic genes in mice with selective disruption of the dopamine D2 receptor in neurons (neuroDrd2KO), which decreases hypothalamic Ghrh, pituitary GH, and serum IGFI and in neonatally androgenized female mice which have increased pituitary GH content and serum IGFI. We evaluated mRNA levels of the female predominant genes prolactin receptor (Prlr), alcohol dehydrogenase 1 (Adh1), Cyp2a4, and hepatocyte nuclear transcription factor 6 (Hnf6) and the male predominant gene, Cyp7b1. Female predominant genes had higher mRNA levels compared to males, but lower methylation was only detected in the Prlr and Cyp2a4 female promoters. In neuroDrd2KO mice, sexual dimorphism was lost for all genes; the upregulation (feminization) of Prlr and Cyp2a4 in males correlated with decreased methylation of their promoters, and the downregulation (masculinization) of Hnf-6 mRNA in females correlated inversely with its promoter methylation. Neonatal androgenization of females evoked a loss of sexual dimorphism only for the female predominant Hnf6 and Adh1 genes, but no differences in promoter methylation were found. Finally, mmumiR-155-5p, predicted to target Cyp7b1 expression, was lower in males in association with higher Cyp7b1 mRNA levels compared to females and was not modified in neuroDrd2KO or TP mice. Our results suggest specific regulation of gene sexually dimorphic expression in the liver by methylation or miRNAs. Fil: Brie, Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Ornstein, Ana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Ramirez, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Lacau Mengido, Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Becu Villalobos, Damasia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina

Published
2020
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5. Neuroendocrine Control of Brown Adipocytes: Functions, Beiging, Whitening and Autophagy

Author

Ana Maria Ornstein, I.M. Lacau-Mengido, Felicitas Lopez-Vicchi, Damasia Becu-Villalobos, Eleonora Sorianello, Catalina De Winne, and Luz Etcheverry Boneo

Subjects
Brown Adipocytes, Autophagy, Biology, Cell biology
Abstract

Adipose tissue has emerged as a fundamental player in metabolic and energy processes. Beyond its fat storage capacity, it displays adaptive mechanisms to react to metabolic challenges throughout life. Three types of adipocytes, white, brown and beige, share common and yet fundamentally different roles and molecular regulation. This review focuses on brain and endocrine control of the function and plasticity of brown and beige adipocytes. The involvement of brain circuits controlling brown adipocytes and thermogenesis via the sympathetic nervous system is described. This autonomic control is mainly exerted by the hypothalamus and brainstem, and noradrenaline released from sympathetic efferent postganglionic fibers interacts with brown or beige b3 adrenoreceptors (b3Adr) to trigger a cascade of events favorable to thermogenesis. Metabolic plasticity in response to environmental or hormonal cues, such as high fat diets, temperature, or hormones and aging, has been identified as a hallmark feature of brown/beige adipocytes. Besides the plastic response of WAT beiging, which is the generation of brown-like adipocytes within white adipose depots, diet-induced obesity and other cues evoke vascular remodeling and functional hypoxia in BAT leading to a whitening phenotype, characterized by mitochondrial dysfunction and loss, lipid droplet accumulation, and decreased thermogenesis. A detailed analysis of the participation of autophagy, and the endocrine signals relied by prolactin and growth hormone uncovers potential avenues of intervention to improve the metabolic function of BAT. Because BAT dysfunction in rodents is linked to fat gain, and glucose and lipid disorders, targeting BAT function and WAT beiging holds promise for obesity prevention and metabolic improvement.

Published
2021
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6. Galectin-1 impacts on glucose homeostasis by modulating pancreatic insulin release

Author

Ana Maria Ornstein, Montana N Manselle Cocco, Gabriel A. Rabinovich, Victoria Sundblad, Sabrina G. Gatto, Damasia Becu-Villalobos, Verónica Candela Martínez Allo, Isabel García-Tornadú, Rosa M. Morales, Diego O. Croci, Julián Gambarte Tudela, and Rodrigo Antonio Lorenzo

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Galectin 1, medicine.medical_treatment, 030209 endocrinology & metabolism, Endogeny, Carbohydrate metabolism, Biochemistry, 03 medical and health sciences, Mice, 0302 clinical medicine, Diabetes mellitus, Internal medicine, Insulin Secretion, medicine, Glucose homeostasis, Animals, Homeostasis, Insulin, business.industry, Type 2 Diabetes Mellitus, medicine.disease, 030104 developmental biology, Endocrinology, Glucose, Basal (medicine), Blood sugar regulation, Female, Insulin Resistance, business
Abstract

Type-2 diabetes mellitus (T2DM) is an expanding global health problem, involving defective insulin secretion by pancreatic β-cells and peripheral insulin resistance, leading to impaired glucose regulation. Galectin-1—an endogenous lectin with affinity for N-acetyllactosamine (LacNAc)-containing glycans—has emerged as a regulator of inflammatory and metabolic disorders. However, the role of galectin-1 in glucose homeostasis and pancreatic β-cell function, independently of hypercaloric diets, has not been explored. Here, we identified a phenotype compatible with T2DM, involving alterations in glucose metabolism and pancreatic insulin release, in female but not male mice lacking galectin-1 (Lgals1−/−). Compared with age-matched controls, Lgals1−/− female mice exhibited higher body weight and increased food intake ad libitum as well as after fasting and acute re-feeding. Although fasted serum insulin levels and insulin sensitivity were similar in both genotypes, Lgals1−/− female mice presented altered glucose tolerance and higher basal glucose levels depending on the fasting period. Insulin response to glucose overload was impaired, while pancreatic insulin content was enhanced in the absence of galectin-1. Accordingly, recombinant galectin-1 enhanced glucose-stimulated insulin release in vitro. Our study identifies a role for galectin-1 in regulating glucose metabolism through modulation of pancreatic insulin secretion, highlighting novel opportunities to control T2DM.

Published
2020

7. Chronic high prolactin levels impact on gene expression at discrete hypothalamic nuclei involved in food intake

Author

David R. Grattan, Penelope J. Knowles, Ana Maria Ornstein, Guillermina Maria Luque, Felicitas Lopez-Vicchi, Damasia Becu-Villalobos, Papillon Gustafson, and Sharon R Ladyman

Subjects
0301 basic medicine, Blood Glucose, medicine.medical_specialty, Enzyme-Linked Immunosorbent Assay, NPY, Biology, Real-Time Polymerase Chain Reaction, Biochemistry, Ciencias Biológicas, 03 medical and health sciences, Eating, Mice, LEPTIN, 0302 clinical medicine, Biología Celular, Microbiología, Internal medicine, Dopamine receptor D2, Orexigenic, Brown adipose tissue, Genetics, medicine, STAT5 Transcription Factor, Animals, Insulin, Receptor, AGRP, Molecular Biology, Mice, Knockout, STAT, Leptin, ARCUATE NUCLEUS, digestive, oral, and skin physiology, Arcuate Nucleus of Hypothalamus, Neuropeptide Y receptor, Immunohistochemistry, Prolactin, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, medicine.symptom, Weight gain, CIENCIAS NATURALES Y EXACTAS, 030217 neurology & neurosurgery, Biotechnology, medicine.drug
Abstract

To study the pathological effects of continuous hyperprolactinemia on food intake mechanisms we used female mice that lack dopamine D2 receptors in lactotropes (lacDrd2KO). These mice had lifelong hyperprolactinemia, increased food intake, and gradual development of obesity from 5 to 10 months of age. Ongoing endogenous prolactin signaling in lacDrd2KO mice was evidenced by increased basal phosphorylation of STAT5b in hypothalamic areas related to food intake, such as the arcuate (ARN), dorsomedial (DMN), and ventromedial nuclei. In the ARN of young lacDrd2KO mice there were higher Prlr mRNA levels and in obese 10‐month‐old lacDrd2KO mice increased expression of the orexigenic genes Neuropeptide Y (Npy ) and Agouti‐related peptide, compared to controls. Furthermore, Npy expression was increased in the DMN, probably contributing to increased food intake and decreased expression of Uncoupling protein‐1 in brown adipose tissue, both events favoring weight gain. Leptin resistance in obese lacD2RKO mice was evidenced by its failure to lower food intake and a dampened response of STAT3 phosphorylation, specifically in the mediobasal hypothalamus. Our results suggest that pathological chronically high prolactin levels, as found in psychiatric treatments or patients with prolactinomas, may impact on specific hypothalamic nuclei altering gene expression, leptin response, and food intake. Fil: López Vicchi, María Felicitas. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Ladyman, Sharon R.. Maurice Wilkins Centre; Nueva Zelanda. University of Otago; Nueva Zelanda Fil: Ornstein, Ana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Gustafson, Papillon. University of Otago; Nueva Zelanda Fil: Knowles, Penelope. University of Otago; Nueva Zelanda Fil: Luque, Guillermina Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Grattan, David R.. Maurice Wilkins Centre; Nueva Zelanda. University of Otago; Nueva Zelanda Fil: Becu Villalobos, Damasia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina

Published
2019

8. Corrigendum to 'Angiogenesis in Pituitary Adenomas: Human Studies and New Mutant Mouse Models'

Author

Guillermina Maria Luque, Lautaro Zubeldia-Brenner, I.M. Lacau-Mengido, Sofia Perrone, Maria Ines Perez Millan, Silvia Inés Berner, Carolina Cristina, Gianina Demarchi, Felicitas Lopez Vicchi, Ana Maria Ornstein, and Damasia Becu-Villalobos

Subjects
Endocrinology, Human studies, Endocrine and Autonomic Systems, Angiogenesis, business.industry, Endocrinology, Diabetes and Metabolism, Mutant, Cancer research, Medicine, Corrigendum, RC648-665, business, Diseases of the endocrine glands. Clinical endocrinology
Abstract

The role of angiogenesis in pituitary tumor development has been questioned, as pituitary tumors have been usually found to be less vascularized than the normal pituitary tissue. Nevertheless, a significantly higher degree of vasculature has been shown in invasive or macropituitary prolactinomas when compared to noninvasive and microprolactinomas. Many growth factors and their receptors are involved in pituitary tumor development. For example, VEGF, FGF-2, FGFR1, and PTTG, which give a particular vascular phenotype, are modified in human and experimental pituitary adenomas of different histotypes. In particular, vascular endothelial growth factor, VEGF, the central mediator of angiogenesis in endocrine glands, was encountered in experimental and human pituitary tumors at different levels of expression and, in particular, was higher in dopamine agonist resistant prolactinomas. Furthermore, several anti-VEGF techniques lowered tumor burden in human and experimental pituitary adenomas. Therefore, even though the role of angiogenesis in pituitary adenomas is contentious, VEGF, making permeable pituitary endothelia, might contribute to adequate temporal vascular supply and mechanisms other than endothelial cell proliferation. The study of angiogenic factor expression in aggressive prolactinomas with resistance to dopamine agonists will yield important data in the search of therapeutical alternatives.

Published
2020
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9. Brain Control of Sexually Dimorphic Liver Function and Disease: The Endocrine Connection

Author

Ana Maria Ornstein, Catalina De Winne, Damasia Becu-Villalobos, Felicitas Lopez Vicchi, Maria Cecilia Ramirez, Eleonora Sorianello, Luis Abelardo Villarruel, Belen Brie, and Paolo N. Catalano

Subjects
0301 basic medicine, Male, medicine.medical_specialty, LIVER, CIENCIAS MÉDICAS Y DE LA SALUD, XENOESTROGENS, Endocrine System, Biology, Fisiología, Epigenesis, Genetic, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, GHRH, Internal medicine, medicine, Endocrine system, Animals, Humans, Sex Characteristics, Sexual differentiation, Liver Diseases, DOPAMINE RECEPTOR, HYPOTHALAMUS, Brain, Cell Biology, General Medicine, Growth hormone secretion, GH, Sexual dimorphism, Medicina Básica, 030104 developmental biology, Somatostatin, Endocrinology, Liver, Hypothalamus, GROWTH HORMONE, Female, Liver function, GENE DIMORPHISM, 030217 neurology & neurosurgery, Hormone
Abstract

A multistep signaling cascade originates in brain centers that regulate hypothalamic growth hormone-releasing hormone (Ghrh) and somatostatin expression levels and release to control the pattern of GH secretion. This process is sexually fine-tuned, and relays important information to the liver where GH receptors can be found. The temporal pattern of pituitary GH secretion, which is sex-specific in many species (episodic in males and more stable in females), represents a major component in establishing and maintaining the sexual dimorphism of hepatic gene transcription. The liver is sexually dimorphic exhibiting major differences in the profile of more than 1000 liver genes related to steroid, lipid, and foreign compound metabolism. Approximately, 90% of these sex-specific liver genes were shown to be primarily dependent on sexually dimorphic GH secretory patterns. This proposes an interesting scenario in which the central nervous system, indirectly setting GH profiles through GHRH and somatostatin control, regulates sexual dimorphism of liver activity in accordance with the need for sex-specific steroid metabolism and performance. We describe the influence of the loss of sexual dimorphism in liver gene expression due to altered brain function. Among other many factors, abnormal brain sexual differentiation, xenoestrogen exposure and D2R ablation from neurons dysregulate the GHRH?GH axis, and ultimately modify the liver capacity for adaptive mechanisms. We, therefore, propose that an inefficient brain control of the endocrine growth axis may underlie alterations in several metabolic processes through an indirect influence of sexual dimorphism of liver genes. Fil: Brie, Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Ramirez, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: de Winne, Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: López Vicchi, María Felicitas. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Villarruel, Luis Abelardo. Comision Nacional de Energia Atomica. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Ciudad Universitaria. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia.; Argentina Fil: Sorianello, Eleonora Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Catalano, Paolo Nicolás. Comision Nacional de Energia Atomica. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Ciudad Universitaria. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia.; Argentina Fil: Ornstein, Ana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Becu Villalobos, Damasia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina

Published
2018

10. Inhibition of Notch signaling attenuates pituitary adenoma growth in Nude mice

Author

Carolina Cristina, Catalina De Winne, I.M. Lacau-Mengido, Lautaro Zubeldia-Brenner, Damasia Becu-Villalobos, Hugo Vankelecom, Christophe Willems, Sofia Perrone, Santiago A. Rodríguez-Seguí, and Ana Maria Ornstein

Subjects
0301 basic medicine, Cancer Research, POSTNATAL PITUITARY, Angiogenesis, Endocrinology, Diabetes and Metabolism, PROLACTIN, medicine.disease_cause, ANGIOGENESIS, ACTIVATION, 0302 clinical medicine, Endocrinology, TUMOR, BTG2, Mice, Inbred BALB C, DIFFERENTIAL GENE-EXPRESSION, Receptors, Notch, PROLIFERATION, Cell migration, Bioquímica y Biología Molecular, Tumor Burden, GH, Medicina Básica, Oncology, 030220 oncology & carcinogenesis, Female, DAPT, Life Sciences & Biomedicine, Signal Transduction, Adenoma, CIENCIAS MÉDICAS Y DE LA SALUD, Notch signaling pathway, Mice, Nude, Diamines, Biology, 03 medical and health sciences, Endocrinology & Metabolism, Pituitary adenoma, Cell Line, Tumor, PITUITARY, medicine, Animals, BREAST-CANCER, Pituitary Neoplasms, Tumor microenvironment, Science & Technology, RECEPTOR, Pituitary tumors, medicine.disease, Prolactin, Rats, Thiazoles, 030104 developmental biology, Cancer research, CELL-GROWTH, OVEREXPRESSION, Carcinogenesis
Abstract

Preclinical and clinical studies support that Notch signaling may play an important oncogenic role in cancer, but there is scarce information for pituitary tumors. We therefore undertook a functional study to evaluate Notch participation in pituitary adenoma growth. Tumors generated in nude mice by subcutaneous GH3 somatolactotrope cell injection were treated in vivo with DAPT, a γ-secretase inhibitor, thus inactivating Notch signaling. This treatment led to pituitary tumor reduction, lower prolactin and GH tumor content, and a decrease in angiogenesis. Furthermore, in silico transcriptomic and epigenomic analyses uncovered several tumor suppressor genes related to Notch signaling in pituitary tissue, namely Btg2, Nr4a1, Men1, Zfp36, and Cnot1. Gene evaluation suggested that Btg2, Nr4a1 and Cnot1 may be possible players in GH3 xenograft growth. Btg2 mRNA expression was lower in GH3 tumors compared to the parental line, and DAPT increased its expression levels in the tumor in parallel with the inhibition of its volume. Cnot1 mRNA levels were also increased in the pituitary xenografts by DAPT treatment. And the Nr4a1 gene was lower in tumors compared to the parental line, though not modified by DAPT. Finally, because DAPT in vivo may be also acting on tumor microenvironment, we determined the direct effect of DAPT on GH3 cells in vitro. We found that DAPT decreases the proliferative, secretory and migration potential of GH3 cells. These results position selective interruption of Notch signaling as a potential therapeutic tool in adjuvant treatments for aggressive or resistant pituitary tumors. Fil: Zubeldia Brenner, Lautaro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: de Winne, Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Perrone, Sofía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina Fil: Rodríguez Seguí, Santiago Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Willems, Christophe. Katholikie Universiteit Leuven; Bélgica Fil: Ornstein, Ana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Lacau Mengido, Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Vankelecom, Hugo. Katholikie Universiteit Leuven; Bélgica Fil: Cristina, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina Fil: Becu, Damasia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina

Published
2018

11. Angiogenesis in Pituitary Adenomas: Human Studies and New Mutant Mouse Models

Author

Felicitas Lopez Vicchi, Ana Maria Ornstein, I.M. Lacau-Mengido, Silvia Inés Berner, Guillermina Maria Luque, Maria Ines Perez Millan, Carolina Cristina, Damasia Becu-Villalobos, Sofia Perrone, Gianina Demarchi, and Lautaro Zubeldia-Brenner

Subjects
medicine.medical_specialty, CIENCIAS MÉDICAS Y DE LA SALUD, Angiogenesis, Endocrinology, Diabetes and Metabolism, Review Article, lcsh:Diseases of the endocrine glands. Clinical endocrinology, Dopamine agonist, ANGIOGENESIS, chemistry.chemical_compound, Endocrinology, PITUITARY, Internal medicine, ADENOMAS, medicine, Receptor, lcsh:RC648-665, Endocrine and Autonomic Systems, business.industry, Fibroblast growth factor receptor 1, Pituitary tumors, purl.org/becyt/ford/3.1 [https], Bioquímica y Biología Molecular, medicine.disease, VEGF, Endothelial stem cell, Vascular endothelial growth factor, Medicina Básica, chemistry, purl.org/becyt/ford/3 [https], business, medicine.drug, Endocrine gland
Abstract

The role of angiogenesis in pituitary tumor development has been questioned, as pituitary tumors have been usually found to be less vascularized than the normal pituitary tissue. Nevertheless, a significantly higher degree of vasculature has been shown in invasive or macropituitary prolactinomas when compared to noninvasive and microprolactinomas. Many growth factors and their receptors are involved in pituitary tumor development. For example, VEGF, FGF-2, FGFR1, and PTTG, which give a particular vascular phenotype, are modified in human and experimental pituitary adenomas of different histotypes. In particular, vascular endothelial growth factor, VEGF, the central mediator of angiogenesis in endocrine glands, was encountered in experimental and human pituitary tumors at different levels of expression and, in particular, was higher in dopamine agonist resistant prolactinomas. Furthermore, several anti-VEGF techniques lowered tumor burden in human and experimental pituitary adenomas. Therefore, even though the role of angiogenesis in pituitary adenomas is contentious, VEGF, making permeable pituitary endothelia, might contribute to adequate temporal vascular supply and mechanisms other than endothelial cell proliferation. The study of angiogenic factor expression in aggressive prolactinomas with resistance to dopamine agonists will yield important data in the search of therapeutical alternatives. Fil: Cristina, Silvia Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina Fil: Luque, Guillermina Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Demarchi, Gianina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina Fil: López Vicchi, María Felicitas. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Zubeldia Brenner, Lautaro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Pérez Millán, María Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Perrone, Sofía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina Fil: Ornstein, Ana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Lacau, Isabel Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Berner, Silvia Inés. Clínica Santa Isabel; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital Oftalmológico Santa Lucía; Argentina Fil: Becu, Damasia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina

Published
2014
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12. Chronic hyperprolactinemia evoked by disruption of lactotrope dopamine D2 receptors impacts on liver and adipocyte genes related to glucose and insulin balance

Author

Catalina De Winne, Esteban Fiore, Felicitas Lopez-Vicchi, Guillermo Mazzolini, Marcelo Rubinstein, Belen Brie, Damasia Becu-Villalobos, Maria Ines Perez-Millan, Guillermina Maria Luque, and Ana Maria Ornstein

Subjects
0301 basic medicine, DOPAMIN, Physiology, Lactotrophs, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Gene Expression, PROLACTIN, GLUCOSE, purl.org/becyt/ford/1 [https], chemistry.chemical_compound, Mice, 0302 clinical medicine, Adipocyte, Adipocytes, Homeostasis, Insulin, Receptor, Mice, Knockout, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Nuclear Proteins, Bioquímica y Biología Molecular, INSULIN, Immunohistochemistry, Up-Regulation, Liver, Lipogenesis, Female, Sterol Regulatory Element Binding Protein 1, CIENCIAS NATURALES Y EXACTAS, medicine.medical_specialty, Receptors, Prolactin, Radioimmunoassay, 030209 endocrinology & metabolism, Enzyme-Linked Immunosorbent Assay, Biology, Real-Time Polymerase Chain Reaction, Prolactin cell, Ciencias Biológicas, 03 medical and health sciences, Physiology (medical), Dopamine receptor D2, Internal medicine, medicine, Animals, Obesity, purl.org/becyt/ford/1.6 [https], Glucokinase, Receptors, Dopamine D2, Glucose Tolerance Test, Fatty Liver, Hyperprolactinemia, 030104 developmental biology, Endocrinology, Glucose, chemistry, Hepatocytes, Transcription Factors
Abstract

We studied the impact of high prolactin titers on liver and adipocyte gene expression related to glucose and insulin homeostasis in correlation with obesity onset. To that end we used mutant female mice that selectively lack dopamine type 2 receptors (D2Rs) from pituitary lactotropes (lacDrd2KO), which have chronic high prolactin levels associated with increased body weight, marked increments in fat depots, adipocyte size, and serum lipids, and a metabolic phenotype that intensifies with age. LacDrd2KO mice of two developmental ages, 5 and 10 mo, were used. In the first time point, obesity and increased body weight are marginal, although mice are hyperprolactinemic, whereas at 10 mo there is marked adiposity with a 136% increase in gonadal fat and a 36% increase in liver weight due to lipid accumulation. LacDrd2KO mice had glucose intolerance, hyperinsulinemia, and impaired insulin response to glucose already in the early stages of obesity, but changes in liver and adipose tissue transcription factors were time and tissue dependent. In chronic hyperprolactinemic mice liver Prlr were upregulated, there was liver steatosis, altered expression of the lipogenic transcription factor Chrebp, and blunted response of Srebp-1c to refeeding at 5 mo of age, whereas no effect was observed in the glycogenesis pathway. On the other hand, in adipose tissue a marked decrease in lipogenic transcription factor expression was observed when morbid obesity was already settled. These adaptive changes underscore the role of prolactin signaling in different tissues to promote energy storage. Fil: Luque, Guillermina Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: López Vicchi, María Felicitas. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Ornstein, Ana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Brie, Belen. Ministerio de Ciencia. Tecnología e Innovación Productiva. Agencia Nacional de Promoción Cientifíca y Tecnológica; Argentina Fil: De Winne, Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Fiore, Esteban Juan. Universidad Austral. Facultad de Cs.biomédicas. Instituto de Investigaciones En Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Pque. Centenario. Instituto de Investigaciones En Medicina Traslacional; Argentina Fil: Pérez Millán, María Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Cs.biomédicas. Instituto de Investigaciones En Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Pque. Centenario. Instituto de Investigaciones En Medicina Traslacional; Argentina Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina Fil: Becu, Damasia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina

Published
2016

13. Disruption of the Dopamine D2 Receptor Impairs Insulin Secretion and Causes Glucose Intolerance

Author

David J. Hill, Marcelo Rubinstein, Edith Arany, Astrid Chamson-Reig, Ana Maria Ornstein, Michael B. Wheeler, Isabel García-Tornadú, and Damasia Becu-Villalobos

Subjects
cell division, Blood Glucose, Male, Time Factors, insulin tolerance test, medicine.medical_treatment, animal cell, haloperidol, Impaired glucose tolerance, DOPAMINE, Mice, Endocrinology, pancreas islet cell, Insulin Secretion, Hyperinsulinemia, Insulin, Glucose homeostasis, DIABETES, insulin release, Insulin-Like Growth Factor I, pancreas function, Mice, Knockout, Otras Medicina Básica, article, Immunohistochemistry, Otras Ciencias Médicas, Insulin oscillation, Medicina Básica, D2, priority journal, Dopamine Agonists, cabergoline, Female, medicine.drug, medicine.medical_specialty, CIENCIAS MÉDICAS Y DE LA SALUD, in vitro study, pancreas islet beta cell, Cabergoline, animal experiment, Radioimmunoassay, Biology, Dopamine agonist, animal tissue, in vivo study, cell isolation, Insulin resistance, Internal medicine, Glucose Intolerance, drug mechanism, medicine, glucose homeostasis, Animals, Ergolines, Pancreas, mouse, Cell Proliferation, Analysis of Variance, nonhuman, Receptors, Dopamine D2, dopamine 2 receptor, animal model, Insulin tolerance test, medicine.disease, Prolactin, Glucose, Dopamine Antagonists, Haloperidol
Abstract

The relationship between antidopaminergic drugs and glucose has not been extensively studied, even though chronic neuroleptic treatment causes hyperinsulinemia in normal subjects or is associated with diabetes in psychiatric patients. We sought to evaluate dopamine D2 receptor (D2R) participation in pancreatic function. Glucose homeostasis was studied in D2R knockout mice (Drd2(-/-)) mice and in isolated islets from wild-type and Drd2(-/-) mice, using different pharmacological tools. Pancreas immunohistochemistry was performed. Drd2(-/-) male mice exhibited an impairment of insulin response to glucose and high fasting glucose levels and were glucose intolerant. Glucose intolerance resulted from a blunted insulin secretory response, rather than insulin resistance, as shown by glucose-stimulated insulin secretion tests (GSIS) in vivo and in vitro and by a conserved insulin tolerance test in vivo. On the other hand, short-term treatment with cabergoline, a dopamine agonist, resulted in glucose intolerance and decreased insulin response to glucose in wild-type but not in Drd2(-/-) mice; this effect was partially prevented by haloperidol, a D2R antagonist. In vitro results indicated that GSIS was impaired in islets from Drd2(-/-) mice and that only in wild-type islets did dopamine inhibit GSIS, an effect that was blocked by a D2R but not a D1R antagonist. Finally, immunohistochemistry showed a diminished pancreatic beta-cell mass in Drd2(-/-) mice and decreased beta-cell replication in 2-month-old Drd2(-/-) mice. Pancreatic D2Rs inhibit glucose-stimulated insulin release. Lack of dopaminergic inhibition throughout development may exert a gradual deteriorating effect on insulin homeostasis, so that eventually glucose intolerance develops Fil: Garcia Tornadu, Isabel Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Argentina Fil: Ornstein, Ana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Argentina Fil: Chamson Reig, Astrid. Lawson Health Research Institute; Canadá Fil: Wheeler, Michael B.. University of Toronto. Departments of Physiology and Medicine ; Canadá Fil: Hill, David J.. Lawson Health Research Institute; Canadá Fil: Arany, Edith. Lawson Health Research Institute; Canadá Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiologia, Biologia Molecular y Celular. Laboratorio de Fisiologia y Biologia Molecular; Argentina Fil: Becu, Damasia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Argentina

Published
2010
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14. New Insights into the Endocrine and Metabolic Roles of Dopamine D2 Receptors Gained from the Drd2–/– Mouse

Author

Gabriela Sofía Risso, Isabel García-Tornadú, Victoria Recouvreux, Guillermina Maria Luque, Maria Cecilia Ramirez, Damasia Becu-Villalobos, Ana Maria Ornstein, Carolina Cristina, Maria Ines Perez-Millan, and Graciela Díaz-Torga

Subjects
medicine.medical_specialty, Somatotropic cell, Endocrine and Autonomic Systems, Endocrinology, Diabetes and Metabolism, Dopaminergic, Biology, medicine.disease, Growth hormone–releasing hormone, Prolactin, Cellular and Molecular Neuroscience, Endocrinology, Hypothalamus, Internal medicine, medicine, Glucose homeostasis, Prolactinoma, Hormone
Abstract

Dopamine D2 receptor (D2R) participation in prolactin regulation is well documented, but the role of D2Rs in the control of other hormones involved in growth, food intake and glucose metabolism has not been extensively studied. The study of D2R knockout mice (Drd2–/–) puts forward new insights into the role of the D2R in growth hormone (GH)-releasing hormone-GH regulation, peptides involved in food intake, glucose homeostasis, as well as in prolactinoma development. The expected phenotype of chronic hyperprolactinemia and prolactinoma development was found in the Drd2–/– mouse, and this model constitutes a valuable tool in the study of dopamine-resistant prolactinomas. Unexpectedly, these mice were growth retarded, and the importance of functional hypothalamic D2Rs in the neonatal period was revealed. In the Drd2–/– mouse there was a failure of high neonatal GH levels and therefore the expansion of pituitary somatotropes was permanently altered. These mice also had increased food intake, and a sexually dimorphic participation of the D2R in food intake regulation is suggested. The effect described is probably secondary to D2R regulation of prolactin secretion. Furthermore, the negative modulation of D2Rs on α-melanocyte-stimulating hormone release and positive action on the hypothalamic expression of orexins reveals the complex D2R regulation of food intake. Finally, pancreatic D2Rs inhibit glucose-stimulated insulin release. Lack of dopaminergic inhibition throughout development in the Drd2–/– mouse may exert a gradual deteriorating effect on insulin homeostasis, so that eventually glucose intolerance develops. These results highlight the complex endocrine actions of the D2Rs at different levels, hypothalamus, pituitary or pancreas, which function to improve fitness, reproductive success and survival.

Published
2010
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15. Pituitary and Brain Dopamine D2 Receptors Regulate Liver Gene Sexual Dimorphism

Author

Marcelo Rubinstein, Isabel García-Tornadú, Ana Maria Ornstein, Guillermina Maria Luque, Damasia Becu-Villalobos, Maria Cecilia Ramirez, and Maria Ines Perez Millan

Subjects
Male, medicine.medical_specialty, LIVER, CIENCIAS MÉDICAS Y DE LA SALUD, SEXUAL DIMORPHISM, Growth Hormone-Somatostatin-GRH, Lactotrophs, Medicina Clínica, Biology, Fisiología, Prolactin cell, Mice, Endocrinology, Internal medicine, Endocrinología y Metabolismo, medicine, Animals, Regulation of gene expression, Mice, Knockout, Neurons, Sex Characteristics, Receptors, Dopamine D2, Dopaminergic, BRAIN METABOLISM, Brain, Proteins, Prolactin, DOPAMINE D2 RECEPTOR, Class II gene, Sexual dimorphism, Medicina Básica, medicine.anatomical_structure, Gene Expression Regulation, Liver, Dopaminergic pathways, Growth Hormone, Pituitary Gland, Knockout mouse, Female
Abstract

Liver sexual gene dimorphism, which depends mainly on specific patterns of GH secretion, may underlie differential susceptibility to some liver diseases. Because GH and prolactin secretion are regulated by dopaminergic pathways, we studied the participation of brain and lactotrope dopamine 2 receptors (D2Rs) on liver gene sexual dimorphism, to explore a link between the brain and liver gene expression. We used global D2R knockout mice (Drd2(-/-)) and conducted a functional dissection strategy based on cell-specific Drd2 inactivation in neurons (neuroDrd2KO) or pituitary lactotropes. Disruption of neuronal D2Rs (which impaired the GH axis) decreased most of male or female-predominant class I liver genes and increased female-predominant class II genes in males, consistent with the positive (class I) or negative (class II) regulation of these genes by GH. Notably, sexual dimorphism was lost for class I and II genes in neuroDrd2KO mice. Disruption of lactotrope D2Rs did not modify class I or II genes in either sex, because GH axis was preserved. But surprisingly, 1 class II gene (Prlr) and female-predominant class I genes were markedly up-regulated in lacDrd2KO females, pointing to direct or indirect effects of prolactin in the regulation of selected female-predominant liver genes. This suggestion was strengthened in the hyperprolactinemic Drd2(-/-) female mouse, in which increased expression of the same 4 liver genes was observed, despite a decreased GH axis. We hereby demonstrate endocrine-mediated D2R actions on sexual dimorphic liver gene expression, which may be relevant during chronic dopaminergic medications in psychiatric disease. Fil: Ramirez, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina Fil: Ornstein, Ana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina Fil: Luque, Guillermina Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina Fil: Pérez Millán, María Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina Fil: Garcia Tornadu, Isabel Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina Fil: Rubinstein, Marcelo. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina Fil: Becu, Damasia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina

Published
2014

16. Selective disruption of dopamine D2 receptors in pituitary lactotropes increases body weight and adiposity in female mice

Author

Maria Ines Perez Millan, Guillermina Maria Luque, Marcelo Rubinstein, Maria Cecilia Ramirez, Daniela Noain, Damasia Becu-Villalobos, and Ana Maria Ornstein

Subjects
Male, medicine.medical_specialty, Pituitary gland, Food intake, CIENCIAS MÉDICAS Y DE LA SALUD, Genotype, GLUCOSE INTOLERANCE, Estrous Cycle, Biology, Body weight, Prolactin cell, Eating, Mice, Endocrinology, Internal medicine, Dopamine receptor D2, Glucose Intolerance, medicine, Animals, Insulin, Receptor, Adiposity, Mice, Knockout, Receptors, Dopamine D2, Body Weight, FOOD INTAKE, purl.org/becyt/ford/3.1 [https], Bioquímica y Biología Molecular, Glucose Tolerance Test, Prolactin, HYPERPROLACTINEMIA, Mice, Inbred C57BL, Medicina Básica, medicine.anatomical_structure, Adipose Tissue, Pituitary Gland, purl.org/becyt/ford/3 [https], Female, LACDRD2KO, LACTOTROPE
Abstract

Prolactin, a pleiotropic hormone secreted by lactotropes, has reproductive and metabolic functions. Chronically elevated prolactin levels increase food intake, but in some hyperprolactinemic states such as in the global dopamine D2 receptor (D2R) knockout mouse, food intake is not increased. Here, we conduct a cell-specific genetic dissection study using conditional mutant mice that selectively lack D2Rs from pituitary lactotropes (lacDrd2KO) to evaluate the role of elevated prolactin levels without any confounding effect of central D2Rs on motor and reward mechanisms related to food intake. LacDrd2KO female mice exhibited chronic hyperprolactinemia, pituitary hyperplasia, and a preserved GH axis. In addition, lacDrd2KO female but not male mice evidenced increased food intake by three months of age and, from five months onwards their body weights were heavier. A marked increment in fat depots, adipocyte size, serum triglyceride and non-esterified fatty acid levels, and a decrease in lipolytic enzymes in adipose tissue were evidenced. Furthermore, lacDrd2KO female mice had glucose intolerance but a preserved response to insulin. In the hypothalamus Npy mRNA expression was increased, and Pomc and Ppo mRNA levels were unaltered (in contrast to results in global D2R knockout mouse). Thus, the orexigenic effect of prolactin, and its action on hypothalamic Npy expression were fully evidenced, leading to increased food intake and adiposity. Our results highlight the metabolic role of prolactin and illustrate the value of studying cell-specific mutant mice to disentangle patho-physiological mechanisms otherwise masked in null allele mutants or in animals treated with pervasive pharmacological agents. Fil: Pérez Millán, María Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Luque, Guillermina Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Ramirez, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Noain, Daniela Maria Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina Fil: Ornstein, Ana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina Fil: Becu, Damasia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina

Published
2014

17. Gastrointestinal parasite control during prepuberty improves mammary parenchyma development in Holstein heifers

Author

Néstor Formía, Damasia Becu-Villalobos, Ana Maria Ornstein, I.M. Lacau-Mengido, Adrián F. Perri, M E Mejía, Santiago S. Diab, and Nicolás Licoff

Subjects
medicine.medical_treatment, Mammary gland, Helminthiasis, Physiology, Mycology & Parasitology, Feces, Lactation, Trichostrongylus, Sexual Maturation, Insulin-Like Growth Factor I, Nematode Infections, Cancer, biology, Antiparasitic Agents, General Medicine, Gastrointestinal parasites, Mammary Glands, Fisheries Sciences, purl.org/becyt/ford/4.2 [https], medicine.anatomical_structure, IGF-1, Female, Helminthiasis, Animal, Otras Producción Animal y Lechería, Mammary development, medicine.medical_specialty, Dairy heifers, Cattle Diseases, Microbiology, Time, Mammary Glands, Animal, Internal medicine, Prepuberty, Parenchyma, Breast Cancer, medicine, Animals, Veterinary Sciences, Parasite Egg Count, General Veterinary, Animal, Growth factor, Ciencias Veterinarias, Puberty, Ostertagia, Producción Animal y Lechería, biology.organism_classification, Endocrinology, CIENCIAS AGRÍCOLAS, Parasitology, Cattle, purl.org/becyt/ford/4 [https], Hormone
Abstract

Parasitism during development impairs normal growth and delays the onset of puberty through altered hormone profiles, including insulin-like growth factor one (IGF-1). Asmammary gland development during prepuberty is strongly dependent on IGF-1, we determined if antiparasitic treatment during this stage of growth improved mammary gland development. One group of Holstein heifers was treated monthly, rotationally with antiparasitic drugs from birth to 70 weeks of age, a second group was untreated. Treated heifer calves had between 56% and 65% less EPG counts than untreated ones. Presence of Ostertagia, Cooperia, Haemonchus and Trichostrongylus was demonstrated. Treatment effectively advanced the onset of puberty and increased IGF-1 levels. At 20, 30, 40 and 70 weeks of age biopsies from the mammary gland were taken and histological sections were prepared and stained with hematoxylin–eosin. Pictures were analyzed to compare parenchyma area in relation to total mammary tissue between groups. Mammary samples from treated heifers had higher ratios of parenchyma/total area than untreated ones. As mammary development during prepuberty is crucial for mammary performance during lactation, these results add new evidence to the importance of gastrointestinal parasite control in heifers., Escuela de Agricultura y Ganadería "María Cruz y Manuel L. Inchausti", Facultad de Ciencias Veterinarias

Published
2013
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18. Sex Differences in the Pituitary Transforming Growth Factor-β1 System: Studies in a Model of Resistant Prolactinomas

Author

M. Andrea Camilletti, M. Clara Guida, Daniel B. Rifkin, Ana Maria Ornstein, M. Victoria Recouvreux, Lara Lapyckyj, Graciela Díaz-Torga, and Damasia Becu-Villalobos

Subjects
Male, Pituitary gland, medicine.medical_specialty, Integrins, Genotype, medicine.drug_class, Growth Factors-Cytokines, Biology, Pituitary neoplasm, Prolactin cell, Thrombospondin 1, Transforming Growth Factor beta1, Mice, Endocrinology, Sex Factors, Internal medicine, Dopamine receptor D2, medicine, Animals, Pituitary Neoplasms, Prolactinoma, Mice, Knockout, Receptors, Dopamine D2, Dopaminergic, medicine.disease, Prolactin, medicine.anatomical_structure, Gene Expression Regulation, Estrogen, Pituitary Gland, Female, Tissue Kallikreins
Abstract

Dopamine and estradiol interact in the regulation of lactotroph cell proliferation and prolactin secretion. Ablation of the dopamine D2 receptor gene (Drd2−/−) in mice leads to a sexually dimorphic phenotype of hyperprolactinemia and pituitary hyperplasia, which is stronger in females. TGF-β1 is a known inhibitor of lactotroph proliferation. TGF-β1 is regulated by dopamine and estradiol, and it is usually down-regulated in prolactinoma experimental models. To understand the role of TGF-β1 in the gender-specific development of prolactinomas in Drd2−/− mice, we compared the expression of different components of the pituitary TGF-β1 system, including active cytokine content, latent TGF-β–binding protein isoforms, and possible local TGF-β1 activators, in males and females in this model. Furthermore, we evaluated the effects of dopamine and estradiol administration to elucidate their role in TGF-β1 system regulation. The expression of active TGF-β1, latent TGF-β–binding protein isoforms, and several putative TGF-β1 activators evaluated was higher in male than in female mouse pituitary glands. However, Drd2−/− female mice were more sensitive to the decrease in active TGF-β1 content, as reflected by the down-regulation of TGF-β1 target genes. Estrogen and dopamine caused differential regulation of several components of the TGF-β1 system. In particular, we found sex- and genotype- dependent regulation of active TGF-β1 content and a similar expression pattern for 2 of the putative TGF-β1 activators, thrombospondin-1 and kallikrein-1, suggesting that these proteins could mediate TGF-β1 activation elicited by dopamine and estradiol. Our results indicate that (1) the loss of dopaminergic tone affects the pituitary TGF-β1 system more strongly in females than in males, (2) males express higher levels of pituitary TGF-β1 system components including active cytokine, and (3) estradiol negatively controls most of the components of the system. Because TGF-β1 inhibits lactotroph proliferation, we propose that the higher levels of the TGF-β1 system in males could protect or delay the development of prolactinomas in Drd2−/− male mice.

Published
2013

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