Impact of Neonatal Manipulation of Androgen Receptor Function on Endocrine-Metabolic Programming in the Juvenile Female Rat

The impact of neonatal androgen receptor (AR) stimulation/blockage, due to testosterone propionate (TP)/AR antagonist treatment, on individual anthropometry and neuroendocrine-metabolic function was evaluated in the juvenile female rat. Pups (age 5 days) were s.c. injected with TP (1.25 mg), flutamide (F; 1.75 mg), and TP + F or vehicle (control, CT) and studied on day 30 of age. Body weight (BW), parametrial adipose tissue (PMAT) mass, food intake, adipoinsular axis, and steroidogenic functions were examined. Opposite to TP-rats, F-treated rats developed hypophagia, grew slowly (BW and PMAT), and displayed heightened peripheral insulin sensitivity. These F effects were abrogated in TP + F animals. Accordingly, TP rats displayed hyperleptinemia, an effect fully prevented by F cotreatment. Finally, androgen-treated animals bore an irreversible ovarian dysfunction (reduced circulating levels of 17HOP4 and ovary 17HOP4 content and P450c17 mRNA abundance). These data indicate that early stimulation of AR enhanced energy store, blockage of AR activity resulted in some beneficial metabolic effects, and neonatally androgenized rats developed a severe ovarian dysfunction. Our study highlights the important role of AR in the early organizational programming of metabolic and neuroendocrine functions.Fil: Ongaro, Luisina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; ArgentinaFil: Giovambattista, Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; ArgentinaFil: Spinedi, Eduardo Julio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Endocrinología Experimental y Aplicada. Universidad Nacional de la Plata. Facultad de Cs.médicas. Centro de Endocrinología Experimental y Aplicada; Argentin

The Polycystic Ovary Syndrome and the Metabolic Syndrome: A Possible Chronobiotic-Cytoprotective Adjuvant Therapy

Polycystic ovary syndrome is a highly frequent reproductive-endocrine disorder affecting up to 8–10% of women worldwide at reproductive age. Although its etiology is not fully understood, evidence suggests that insulin resistance, with or without compensatory hyperinsulinemia, and hyperandrogenism are very common features of the polycystic ovary syndrome phenotype. Dysfunctional white adipose tissue has been identified as a major contributing factor for insulin resistance in polycystic ovary syndrome. Environmental (e.g., chronodisruption) and genetic/epigenetic factors may also play relevant roles in syndrome development. Overweight and/or obesity are very common in women with polycystic ovary syndrome, thus suggesting that some polycystic ovary syndrome and metabolic syndrome female phenotypes share common characteristics. Sleep disturbances have been reported to double in women with PCOS and obstructive sleep apnea is a common feature in polycystic ovary syndrome patients. Maturation of the luteinizing hormone-releasing hormone secretion pattern in girls in puberty is closely related to changes in the sleep-wake cycle and could have relevance in the pathogenesis of polycystic ovary syndrome. This review article focuses on two main issues in the polycystic ovary syndrome-metabolic syndrome phenotype development: (a) the impact of androgen excess on white adipose tissue function and (b) the possible efficacy of adjuvant melatonin therapy to improve the chronobiologic profile in polycystic ovary syndrome-metabolic syndrome individuals. Genetic variants in melatonin receptor have been linked to increased risk of developing polycystic ovary syndrome, to impairments in insulin secretion, and to increased fasting glucose levels. Melatonin therapy may protect against several metabolic syndrome comorbidities in polycystic ovary syndrome and could be applied from the initial phases of patients’ treatment.Fil: Spinedi, Eduardo Julio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico La Plata. Centro de Endocrinología Experimental y Aplicada (i); ArgentinaFil: Cardinali, Daniel Pedro. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentin

The stormy relationship between fats and the development of type 2 diabetes mellitus: Updated. Part 2

En esta parte de la revisión se describe la relación funcional entre el metabolismo de los lípidos y los hidratos de carbono y su interdependencia, desde el ciclo glucosa-ácido grasos y la hipótesis portal de la insulinorresistencia a los nuevos conocimientos sobre los adipocitos marrones y beiges, con énfasis en el normal funcionamiento de un patrón endocrino cuya disfunción es clave en la fisiopatología de la DMT2 y la obesidad. Se discute la ectopia o el asiento de grasa en el tejido magro por incapacidad del tejido adiposo para seguir acopiando lípidos y la actividad endocrina del adipocito, con la producción de moléculas (adipoquinas) que influyen sobre los mecanismos inductores de insulinorresistencia (leptina, adiponectina, TNF-α, resistina, etc.) y disfunción de la célula beta. Se describen la disminución de la capacidad oxidativa en la cadena respiratoria mitocondrial y el renacer del concepto de lipogénesis de novo, ambas favoreciendo el acopie de lípido intracelular. En tejidos magros existen pequeñas reservas intracelulares de lípidos que mantienen la regulación de funciones esenciales, aunque si aparece una sobrecarga lipídica el fenómeno conduciría a una disfunción (lipotoxicidad) y a la muerte celular (lipoapoptosis). La tormentosa relación entre los lípidos y el islote de Langerhans va más allá del esfuerzo funcional que impone la insulinorresistencia periférica sobre la célula β, por efectos directos de los lípidos o de sus derivados sobre la función del islote pancreático. Sin déficit de insulina no se desarrolla diabetes.In this part of the review, the functional relationship between lipid and carbohydrate metabolisms and their interdependence is described, from the glucose-fatty acid cycle and the portal hypothesis of insulin resistance to the new knowledge on brown and beige adipocytes, with emphasis on the normal functioning of an endocrine pattern in which its dysfunction is a key factor in the pathophysiology of T2DM and obesity. Ectopic fat deposition in lean tissues due to the inability of the adipose tissue to continuously collect lipids and the endocrine activity of adipocytes is discussed. The production of molecules (adipokines) influencing some of the mechanisms involved in the development of insulin resistance (leptin, adiponectin, TNF-α, resistin, etc.) and beta cell dysfunction is also revisited. The decrease in the oxidative capacity in the mitochondrial respiratory chain and the rebirth of the concept of de novo lipogenesis are described, both effects favouring intracellular lipid accumulation. In lean tissues there are small intracellular lipid reserves that help to maintain the regulation of essential functions; however, when a lipid overload occurs the phenomenon could lead to severe cell dysfunction (lipotoxicity), and death (lipo-apoptosis). The stormy relationship between lipids and the Langerhans’ islets goes beyond the functional effort imposed by peripheral insulin-resistance on the β cells, either by the direct effect of lipids or by their derivatives on overall pancreatic islet function. Within a scenario of no insulin deficit, diabetes does not develop.Fil: Costa Gil, José Esteban. Universidad Favaloro. Facultad de Medicina; ArgentinaFil: Spinedi, Eduardo Julio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Endocrinología Experimental y Aplicada. Universidad Nacional de la Plata. Facultad de Cs.médicas. Centro de Endocrinología Experimental y Aplicada; Argentin

La tormentosa relación entre las grasas y el desarrollo de la diabetes mellitus de tipo 2: actualizado: parte 1

En esta parte de la revisión se describe la relación funcional entre el metabolismo de los lípidos y los hidratos de carbono y su interdependencia, desde el ciclo glucosa-ácido grasos y la hipótesis portal de la insulinorresistencia a los nuevos conocimientos sobre los adipocitos marrones y beiges, con énfasis en el normal funcionamiento de un patrón endocrino cuya disfunción es clave en la fisiopatología de la DMT2 y la obesidad. Se discute la ectopia o el asiento de grasa en el tejido magro por incapacidad del tejido adiposo para seguir acopiando lípidos y la actividad endocrina del adipocito, con la producción de moléculas (adipoquinas) que influyen sobre los mecanismos inductores de insulinorresistencia (leptina, adiponectina, TNF-α, resistina, etc.) y disfunción de la célula beta. Se describen la disminución de la capacidad oxidativa en la cadena respiratoria mitocondrial y el renacer del concepto de lipogénesis de novo, ambas favoreciendo el acopie de lípido intracelular. En tejidos magros existen pequeñas reservas intracelulares de lípidos que mantienen la regulación de funciones esenciales, aunque si aparece una sobrecarga lipídica el fenómeno conduciría a una disfunción (lipotoxicidad) y a la muerte celular (lipoapoptosis). La tormentosa relación entre los lípidos y el islote de Langerhans va más allá del esfuerzo funcional que impone la insulinorresistencia periférica sobre la célula β, por efectos directos de los lípidos o de sus derivados sobre la función del islote pancreático. Sin déficit de insulina no se desarrolla diabetes.Fil: Costa Gil, José Esteban. Universidad Favaloro. Facultad de Medicina; ArgentinaFil: Spinedi, Eduardo Julio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Endocrinología Experimental y Aplicada. Universidad Nacional de la Plata. Facultad de Cs.médicas. Centro de Endocrinología Experimental y Aplicada; Argentin

Impact of Neonatal Manipulation of Androgen Receptor Function on Endocrine-Metabolic Programming in the Juvenile Female Rat

The impact of neonatal androgen receptor (AR) stimulation/blockage, due to testosterone propionate (TP)/AR antagonist treatment, on individual anthropometry and neuroendocrine-metabolic function was evaluated in the juvenile female rat. Pups (age 5 days) were s.c. injected with TP (1.25 mg), flutamide (F; 1.75 mg), and TP + F or vehicle (control, CT) and studied on day 30 of age. Body weight (BW), parametrial adipose tissue (PMAT) mass, food intake, adipoinsular axis, and steroidogenic functions were examined. Opposite to TP-rats, F-treated rats developed hypophagia, grew slowly (BW and PMAT), and displayed heightened peripheral insulin sensitivity. These F effects were abrogated in TP + F animals. Accordingly, TP rats displayed hyperleptinemia, an effect fully prevented by F cotreatment. Finally, androgen-treated animals bore an irreversible ovarian dysfunction (reduced circulating levels of 17HOP4 and ovary 17HOP4 content and P450c17 mRNA abundance). These data indicate that early stimulation of AR enhanced energy store, blockage of AR activity resulted in some beneficial metabolic effects, and neonatally androgenized rats developed a severe ovarian dysfunction. Our study highlights the important role of AR in the early organizational programming of metabolic and neuroendocrine functions.Instituto Multidisciplinario de Biología CelularCentro de Endocrinología Experimental y Aplicad

White adipose tissue and circadian rhythm dysfunctions in obesity : Pathogenesis and available therapies

A combined neuroendocrine, metabolic, and chronobiological view can help to better understand the multiple and complex mechanisms involved in obesity development and maintenance, as well as to provide new effective approaches for its control and treatment. Indeed, we have currently updated data on the whole adipogenic process involved in white adipose tissue (WAT) mass expansion, namely due to a mechanism whereby WAT cells become hypertrophic, thus inducing a serious local (WAT) inflammatory condition that in turn, will impair not only the cross-talk between the hypothalamus and the WAT, but also favoring the development of deep and widespread neuroendocrine-metabolic dysfunction. Moreover, we also have revisited the circadian clock genes involved in dysfunctional WAT mass expansion and the mechanisms that may lead to obesity development, including early metabolic dysfunctions, enhanced oxidative stress and distorted energy homeostasis. The epigenetic changes of clock genes driving metabolic disease and obesity development have also been included in this review. Finally, we have also underlined the relevance of metabolic homeostasis regulation by central and peripheral organ clocks, sleep disturbances, nutrients, and feeding time, as key factors in obesity development as well as both, classical and chronotherapeutic approaches for its prevention and treatment.Centro de Endocrinología Experimental y Aplicad

Chronic glucocorticoid-rich milieu and liver dysfunction

We investigated the impact of chronic hypercorticosteronemia (due to neonatal monosodium L-glutamate, MSG, and treatment) on liver oxidative stress (OS), inflammation, and carbohydrate/lipid metabolism in adult male rats. We evaluated the peripheral concentrations of several metabolic and OS markers and insulin resistance indexes. In liver we assessed (a) OS (GSH and protein carbonyl groups) and inflammatory (IL-1b, TNFa, and PAI-1) biomarkers and (b) carbohydrate and lipid metabolisms. MSG rats displayed degenerated optic nerves, hypophagia, low body and liver weights, and enlarged adipose tissue mass; higher peripheral levels of glucose, triglycerides, insulin, uric acid, leptin, corticosterone, transaminases and TBARS, and peripheral and liver insulin resistance; elevated liver OS, inflammation markers, and glucokinase (mRNA/activity) and fructokinase (mRNA). Additionally, MSG liver phosphofructokinase-2, glucose-6-phosphatase (mRNA and activity) and glucose-6-phosphate dehydrogenase, Chrebp, Srebp1c, fatty acid synthase, and glycerol-3-phosphate (mRNAs) were increased. In conclusion adult MSG rats developed an insulin-resistant state and increased OS and serious hepatic dysfunction characterized by inflammation and metabolic signs suggesting increased lipogenesis. These features, shared by both metabolic and Cushing?s syndrome human phenotypes, support that a chronic glucocorticoid-rich endogenous environment mainly impacts on hepatic glucose cycle, displacing local metabolism to lipogenesis. Whether correcting the glucocorticoid-rich environment ameliorates such dysfunctions requires further investigation.Fil: Villagarcía, Hernán Gonzalo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Endocrinología Experimental y Aplicada. Universidad Nacional de la Plata. Facultad de Cs.médicas. Centro de Endocrinología Experimental y Aplicada; ArgentinaFil: Sabugo, Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Endocrinología Experimental y Aplicada. Universidad Nacional de la Plata. Facultad de Cs.médicas. Centro de Endocrinología Experimental y Aplicada; ArgentinaFil: Castro, María Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Endocrinología Experimental y Aplicada. Universidad Nacional de la Plata. Facultad de Cs.médicas. Centro de Endocrinología Experimental y Aplicada; ArgentinaFil: Schinella, Guillermo Raúl. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas; ArgentinaFil: Castrogiovanni, Daniel Cayetano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; ArgentinaFil: Spinedi, Eduardo Julio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Endocrinología Experimental y Aplicada. Universidad Nacional de la Plata. Facultad de Cs.médicas. Centro de Endocrinología Experimental y Aplicada; ArgentinaFil: Massa, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Endocrinología Experimental y Aplicada. Universidad Nacional de la Plata. Facultad de Cs.médicas. Centro de Endocrinología Experimental y Aplicada; ArgentinaFil: Francini, Flavio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Endocrinología Experimental y Aplicada. Universidad Nacional de la Plata. Facultad de Cs.médicas. Centro de Endocrinología Experimental y Aplicada; Argentin

Hijos de Malvinas: una historia que aún queda por contar

En este artículo me propongo presentar un recorte y reflexión sobre un trabajo más amplio -tesina de Licenciatura en Sociología de quien suscribe- en el cual busco indagar acerca de la relación entre la transmisión de memoria y las configuraciones identitarias de hijxs de excombatientes pertenecientes a la Casa del Soldado Excombatiente de Malvinas (CEMA). Por ello en los siguientes apartados presentaré los avances en relación al estado de la cuestión y el marco teórico del mismo, y concluiré con unas breves palabras finales acerca de las oportunidades que esta mirada nos abre.Eje temático: Representaciones, sentidos e identidades en disputa: b- Representaciones, sentidos y debates en las voces de los combatientes y sus hijosFacultad de Humanidades y Ciencias de la Educació

Relationship between impaired adipogenesis of retroperitoneal adipose tissue and hypertrophic obesity: role of endogenous glucocorticoid excess

Although the pro-adipogenic effect of glucocorticoid (GC) on adipose tissue (AT) precursor cell differentiation is openly accepted, the effect of chronically high peripheral levels of GC on AT mass expansion is not fully understood. In the present study, we aim to assess the in vitro adipogenic capacity of AT precursor cells isolated from retroperitoneal (RP) AT pads of the hypercorticosteronaemic, adult neonatally treated monosodium L-glutamate (MSG) male rat. To ascertain this issue, we explored the in vitro adipogenic process of stromal-vascular fraction (SVF) cells isolated from RPAT pads of 60-day-old MSG rats. The data recorded indicated that RPAT-SVF cells from hypercorticosteronaemic MSG rats, although displaying an enhanced proliferation capacity, differentiated slower than normal cells. This dysfunction was associated with a reduction in key parameters indicative of precursor cell commitment, differentiation capacity and the percentage of fully differentiated adipocytes, with a retarded maturation process. The distorted adipogenic capacity was highly conditioned by RPAT-SVF cells displaying a low committed population and both excessive and reduced expression of anti- (Pref-1 and Wnt-10b) and pro-adipogenic (mineralocorticoid receptor) signals respectively. Notably, the normalization of peripheral corticosterone levels in MSG rats, as a result of bilateral adrenalectomy combined with GC replacement therapy, fully prevented reduced RPAT precursor cell commitment and overall impaired adipogenesis. Our study strongly supports that the impaired adipogenic process observed in the adult hypertrophic obese MSG male rat is a GC-dependent mechanism, thus explaining the unhealthy RPAT expansion observed in human hypertrophic obese phenotypes, such as in the Cushing's syndrome.Facultad de Ciencias ExactasInstituto Multidisciplinario de Biología CelularCentro de Endocrinología Experimental y Aplicad