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White adipose tissue (WAT) browning has gained interest due to its impact in obesity. Here, we evaluated the effect of androgens on the Ucp1-dependent thermogenic process from inguinal (IAT) and retroperitoneal (RPAT) WAT. Surgically androgens depleted rats (ODX) showed basal thermogenic activation (room temperature) in both WAT depots, which expressed higher levels of Ucp1, Prdm16 and Pgc1a. WAT pads from ODX cold-exposed rats (ODX-C) expressed increased levels of Ucp1 and Pgc1a and showed high UCP1 protein content. In primary beige adipocyte cultures, testosterone decreased the mitochondrial marker Cox8b and mitochondrial content. Finally, testosterone and dihydrotestosterone (DHT) decreased the expression of Ucp1, Pcg1a and Prdm16 in forskolin-stimulated beige adipocytes, an effect that was prevented by the antiandrogen flutamide. In conclusion, androgen deficient rats developed WAT depots with enhanced basal and cold-stimulated thermogenic activity. Additionally, in vitro androgen treatments inhibited the thermogenic program, effect which was mediated by the androgen receptor pathway.

Alzheimer’s disease (AD) is associated with altered eating behavior and metabolic disruption. Amyloid plaques and neurofilament tangles are observed in many hypothalamic nuclei from AD brains. Some of these areas (suprachiasmatic nuclei, lateral hypothalamic area) also play a role in the regulation of the sleep/wake cycle and may explain the comorbidity of eating and sleep disorders observed in AD patients. Inadequate sleep increases the neurodegenerative process, for example, the decrease of slow-wave sleep impairs clearance of β-amyloid peptide (Aβ) and tau protein from cerebral interstitial fluid. Cerebrospinal fluid (CSF) melatonin levels decrease even in preclinical stages (Braak-1 stage) when patients manifest no cognitive impairment, suggesting that reduction of melatonin in CSF may be an early marker (the cause for which is still unknown) of oncoming AD. Melatonin administration augments glymphatic clearance of Aβ and reduces generation and deposition of Aβ in transgenic animal models of AD. It may also set up a new equilibrium among hypothalamic feeding signals. While melatonin trials performed in the clinical phase of AD have failed to show or showed only modest positive effects on cognition, in the preclinical stage of dementia (minimal cognitive impairment) the effect of melatonin is demonstrable with significant improvement of sleep and quality of life. In this review, we discuss the main aspects of hypothalamic alterations in AD, the association between interrupted sleep and neurodegeneration, and the possible therapeutic effect of melatonin on these processes., Facultad de Ciencias Médicas, Centro de Endocrinología Experimental y Aplicada

Background: Insulin-like Growth Factor1 (IGF1) is a powerful neuroprotective molecule. We have previously shown that short-term hypothalamic IGF1 gene therapy restores tuberoinfundibu-lar dopaminergic neuron function in aging female rats. Objective: Our aim was to implement long-term IGF-I gene therapy in pituitary prolactinomas in senile female rats. Methods: Here, we assessed the long-term effect of IGF1 gene therapy in the hypothalamus of young (4 mo.) and aging (24 mo.) female rats carrying spontaneous pituitary prolactinomas. We constructed and injected a Helper-Dependent (HD) adenovector expressing the gene for rat IGF1 or the reporter red fluorescent protein DsRed. Ninety-one days post vector injection, all rats were sacrificed and their brains and pituitaries fixed. Serum prolactin (PRL), Estrogen (E2) and progesterone (P4), as well as hypothalamic IGF1 content, were measured by RIA. Anterior pituitaries were immunostained with an anti-rat PRL antibody and submitted to morphometric analysis. Results: DsRed expression in the Mediobasal Hypothalamus (MBH) was strong after the treatment in the DsRed group while IGF1 content in the MBH was higher in the IGF1 group. The IGF1 treatment affected neither pituitary weight nor PRL, E2 or P4 serum levels in the young rats. In the old rats, IGF1 gene therapy reduced gland weight as compared with intact counterparts and tended to reduce PRL levels as compared with intact counterparts. The treatment significantly rescued the phenotype of the lactotropic cell population in the senile adenomas. Conclusion: We conclude that long-term hypothalamic IGF1 gene therapy is effective to rescue spontaneous prolactinomas in aging female rats. Fil: Brown, Oscar Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentina Fil: Canatelli Mallat, Martina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentina Fil: Console de Avegliano, Gloria Miriam. Universidad Nacional de La Plata. Facultad de Ciencias Médicas; Argentina Fil: Camihort, Gisela. Universidad Nacional de La Plata. Facultad de Ciencias Médicas; Argentina Fil: Luna, Georgina. Universidad Nacional de La Plata. Facultad de Ciencias Médicas; Argentina Fil: 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; Argentina Fil: Goya, Rodolfo Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentina

The aging female rat constitutes an interesting model of spontaneous and progressive age-related dopaminergic dysfunction as it allows assessing new therapeutic strategies for Parkinson's disease. Insulin-like growth factor I (IGF-I) is emerging as a powerful neuroprotective molecule, strongly induced in the central nervous system after different insults. We constructed a helper-dependent recombinant adenoviral vector (HDRAd-IGFI) harboring the gene for rat IGF-I. This was used to implement long-term IGF-I gene therapy in the hypothalamus of aged female rats, which display hypothalamic dopaminergic (DA) dysfunction and, as a consequence, chronic hyperprolactinemia. Rejuvenating long-term IGF-I gene therapy was implemented in young (3 months) and aged (24 months) female rats, which received a single intrahypothalamic injection of 4 × 109 viral particles of either HD-RAd-IGFI or HD-RAd-DsRed (control vector) and were sacrificed 119 days postinjection. In the young animals, neither vector modified serum prolactin (PRL) levels, but in the RAd-IGFI-injected aged rats a nearly full reversion of their hyperprolactinemic status was recorded. Morphometric analysis revealed a significant increase in the total number of tyrosine hydroxylase (TH)-positive cells in the hypothalamus of experimental compared with control aged animals (5874 ± 486 and 3390 ± 498, respectively). Our results indicate that IGF-I gene therapy in aged female rats is highly effective in rejuvenating the hypothalamic DA neuron groups. Fil: Schwerdt, José Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentina Fil: López León, Micaela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentina Fil: Cónsole, Gloria M. Universidad Nacional de La Plata. Facultad de Ciencias Médicas; Argentina Fil: Brown, Oscar Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentina Fil: Morel, Gustavo Ramón. Universidad Nacional de La Plata. Facultad de Ciencias Exactas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentina Fil: Spinedi, Eduardo Julio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico La Plata. Centro de Endocrinología Experimental y Aplicada (i); Argentina Fil: Goya, Rodolfo Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentina

Aim An adverse endogenous environment during early life predisposes to metabolic disorder development. We previously reported adverse metabolic and adipose tissue effects in adult male rats born to dams fed with a fructose-rich diet (FRD). The aim of this work was to determine the effect of a FRD consumed by the pregnant mother on the white adipose tissue (WAT) browning capacity of male offspring at adulthood. Main methods Adult S D male offspring from control (C) and FRD-fed mothers were exposed during one week to a cold stimulus. WAT browning capacity was studied through in vivo and in vitro approaches. Key findings After cold exposure, WAT browning was higher in fructose-programmed animals as evidenced by an increase in ucp-1 gene expression, protein levels, and higher UCP-1 positive foci. Moreover, pgc1-α gene expression was increased. In vitro studies showed a lower adipogenic capacity in cells of prenatally fructose-exposed animals differentiated with a white differentiation cocktail, while a higher ucp-1 expression was noted when their cells were treated with a pro-beige differentiation cocktail. Significance For the first time we demonstrate that pre-natal fructose exposure predisposes programmed male rats to a higher WAT browning-induced response, under stimulated conditions, despite an apparent lower basal thermogenic capacity. These results should be considered in future studies to generate new therapeutic approaches to deal with adverse programming malnutrition effects.

Aim Dexamethasone (DXM) is a synthetic glucocorticoid whose effects in early and terminal adipogenesis have been addressed. In this study, we evaluated if DXM affects adipocyte precursor cells (APCs), priming them for further adipogenic differentiation. For this purpose, we analyzed APCs number and competency after DXM treatment. Materials and methods Adult male rats were injected for 2 or 7 days with either DXM (30 μg/kg of weight, sc.) or vehicle. Stromal vascular fraction (SVF) cells from retroperitoneal adipose tissue (RPAT) were isolated to quantify APCs by flow cytometry (CD34+/CD45−/CD31−). Also, expression of competency markers (PPARγ2 and Zfp423) was assessed. Additionally, SVF cells from control rats were incubated with DXM (0.25 μM) alone or combined with a mineralocorticoid receptor (MR) antagonist (Spironolactone 10 μM) and/or a glucocorticoid receptor (GR) antagonist (RU486 1 μM) to assess APCs competency and adipocyte differentiation. Key findings APCs from 2 days DXM-treated rats showed increased expression of PPARγ2 and Zfp423 (competency markers), but did not affect APCs percentage by FACS analysis (CD34+/CD45−/CD31−). Additionally, we found that DXM treatment in SVF also increased APCs competency in vitro, predisposing APCs to further adipocyte differentiation. These effects on APCs were abrogated only when both, MR and GR, were blocked. Significance Overall, our results suggest that DXM primes APCs for differentiation mainly by enhancing Zfp423 and PPARγ2 expressions. Also, we showed that the inhibition of MR and GR was necessary for the complete abolishment of DXM effects.

Polycystic ovary syndrome is a highly frequent reproductive-endocrine disorder affecting up to 8?10% of women worldwide atreproductive age. Although its etiology is not fully understood, evidence suggests that insulin resistance, with or withoutcompensatory 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 ovarysyndrome. Environmental (e.g., chronodisruption) and genetic/epigenetic factors may also play relevant roles in syndromedevelopment. Overweight and/or obesity are very common in women with polycystic ovary syndrome, thus suggesting thatsome polycystic ovary syndrome and metabolic syndrome female phenotypes share common characteristics. Sleep disturbanceshave been reported to double in women with PCOS and obstructive sleep apnea is a common feature in polycystic ovarysyndrome patients. Maturation of the luteinizing hormone-releasing hormone secretion pattern in girls in puberty is closelyrelated to changes in the sleep-wake cycle and could have relevance in the pathogenesis of polycystic ovary syndrome. Thisreview article focuses on two main issues in the polycystic ovary syndrome-metabolic syndrome phenotype development: (a) theimpact of androgen excess on white adipose tissue function and (b) the possible efficacy of adjuvant melatonin therapy toimprove the chronobiologic profile in polycystic ovary syndrome-metabolic syndrome individuals. Genetic variants in melatoninreceptor have been linked to increased risk of developing polycystic ovary syndrome, to impairments in insulin secretion, and toincreased fasting glucose levels. Melatonin therapy may protect against several metabolic syndrome comorbidities in polycysticovary syndrome and could be applied from the initial phases of patients? treatment., Centro de Endocrinología Experimental y Aplicada

Background Primary Prevention of Diabetes Program in Buenos Aires Province evaluates the effectiveness of adopting healthy lifestyle to prevent type 2 diabetes (T2D) in people at high risk of developing it. We aimed to present preliminary data analysis of FINDRISC and laboratory measurements taken during recruitment of people for the Primary Prevention of Diabetes Program in Buenos Aires Province in the cities of La Plata, Berisso, and Ensenada, Argentina. Methods People were recruited through population approach (house-to-house survey by FINDRISC in randomized areas) and opportunistic approach (FINDRISC completed by participants during consultations for nonrelated prediabetes/diabetes symptoms in public and private primary care centres of cities involved). In people with FINDRISC score ≥ 13 points, we evaluated blood concentrations of HbA1c , creatinine, lipids, and an oral glucose tolerance test (OGTT). Results Approximately 3415 individuals completed the FINDRISC populational survey and 344 the opportunistic survey; 43% of the 2 groups scored over 13 points; 2.8 and 75.4% of them, respectively, took the prescribed OGTT. Approximately 53.7% of the OGTT showed normal values and 5.2% unknown T2D. The remaining cases showed 69.5% impaired fasting glucose, 13.6% impaired glucose tolerance, and 16.9% both impairments. HbA1c values showed significant differences compared with normal glucose tolerance (4.96 ± 0.43%), prediabetes (5.28 ± 0.51%), and T2D (5.60 ± 0.51%). Participants with prediabetes and T2D showed a predominant increase in low-density lipoprotein-cholesterol values. In prediabetes, >50% showed insulin resistance. Conclusions People with prediabetes/T2D had dyslipidemia associated with insulin resistance, which promotes the development of T2D and cardiovascular disease. Thus, it merits its appropriate treatment., Centro de Endocrinología Experimental y Aplicada, Instituto de Investigaciones en Humanidades y Ciencias Sociales

Rats neonatally treated withmonosodiumL-glutamate (MSG) are deeply dysfunctional in adulthood. We explored the effect of an oral low dose of metformin treatment in male MSG rats on adipoinsular axis and visceral adipose tissue (VAT) dysfunctions, in both basal (nonfasting) and endotoxemia conditions. MSG rats, treated or not treated with metformin (30 days prior to experimentation), and control litter-mates (CTR) were studied at 90 days of age. Peripheral concentrations of glucose, lipids, and hormones were determined in basal and post-lipopolysaccharide (LPS) treatment conditions. Food intake and body weight (BW) were recorded and VAT mass and leptin mRNA levels were evaluated. Data indicated that MSG rats were lighter and displayed hypercorticosteronemia, hypophagia, adipoinsular axis hyperactivity, and enhanced VAT mass associated with an increased leptin gene expression. Interestingly,metformin-treatedMSG rats corrected BWcatch-up and counteracted VAT (mass and leptinmRNA level) and adipoinsular axis (basal and post-LPS) dysfunctions. Thus metformin treatment in MSG rats is able to correct several VAT and metabolic-endocrine dysfunctions. Our study suggests that a low-dose metformin therapy is effective to correct, at least in part, adipoinsular axis dysfunction in hypertrophic obese phenotypes, such as that of the human Cushing syndrome., Facultad de Ciencias Médicas

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., Centro de Endocrinología Experimental y Aplicada, Consejo Nacional de Investigaciones Científicas y Técnicas

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., Centro de Endocrinología Experimental y Aplicada, Consejo Nacional de Investigaciones Científicas y Técnicas

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 Aplicada

In spite of the increased attention devoted to the literature and by health ministries, overweight and obesity prevalence continues to increase worldwide [1] . A systematic analysis performed in 2013 referred to the global burden of these conditions, and showed that more than 50% of the world’s 671 million obese people live in 10 countries: the United States, China, India, Russia, Brazil, Mexico, Egypt, Germany, Pakistan, and Indonesia [2] . Additionally, overweight/obesity has unhealthy outcomes such as diabetes, hypertension, and cancer [3] . Fil: 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 Ciencias Médicas. Centro de Endocrinología Experimental y Aplicada; Argentina Fil: Cardinali, Daniel Pedro. 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 Ciencias Médicas. Centro de Endocrinología Experimental y Aplicada; Argentina Fil: Gagliardino, Juan Jose. 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 Ciencias Médicas. Centro de Endocrinología Experimental y Aplicada; Argentina

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 Celular, Centro de Endocrinología Experimental y Aplicada

Pregnant women with impaired insulin sensitivity are at risk for developing pregnancy-induced hypertensive disorders (PIHD). We analyzed glucose and insulin circulating levels throughout a 2-h oral 75 g glucose tolerance test in pregnant women, and related the 2-h insulinemias to PIHD prevalence.Pregnant women (gestational week 24-28) were submitted to a glucose overload, and glucose and insulin plasma concentrations were measured throughout the test. These peripheral metabolite levels, the homeostasis model assessment (HOMA) values and the glucose to insulin ratio (G:Ir) were analyzed. Anthropometric parameters and pregnancy outcome were recorded.Women with normal fasting glycemia, insulinemia and HOMA values, G:Ir and 2 h-glycemia but whose 2 h-insulinemia was higher than 215.25 pM were at greater risk for developing late pregnancy hypertension and preeclampsia compared to women of similar characteristics but whose 2 h-insulinemias were lower than 215.25 pM.2-h insulinemias higher than 215.25 pM after a 75 g glucose overload could be highly indicative of women at increased risk of developing PIHD.

Adipose tissue (AT) expansion is the result of two processes: hyperplasia and hypertrophy; and both, directly or indirectly, depend on the adipogenic potential of adipocyte precursor cells (APCs). Glucocorticoids (GCs) have a potent stimulatory effect on terminal adipogenesis; while their effects on early stages of adipogenesis are largely unknown. In the present work, we study, in a model of high GC levels, the adipogenic potential of APCs from retroperitoneal AT (RPAT) and its relationship with RPAT mass expansion. We employed a model of hyper-adiposity (30- and 60-day-old rats) due to high endogenous GC levels induced by neonatal treatment with L-monosodium glutamate (MSG).We found that the RPAT APCs from 30-day-old MSG rats showed an increased adipogenic capacity, depending on the APCs’ competency, but not in their number. Analyses of RPAT adipocyte diameter revealed an increase in cell size, regardless of the rat age, indicating the prevalence of a hypertrophic process. Moreover, functional RPAT alterations worsened in 60-day-old rats, suggesting that the hyperplastic AT expansion found in 30-day-old animals might have a protective role. We conclude that GCs chronic excess affects APCs’ adipogenic capacity, modifying their competency. This change would modulate the hyperplastic/hypertrophic balance determining healthy or unhealthy RPAT expansion and, therefore, its functionality., Facultad de Ciencias Médicas

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 adultMSGrats developed an insulinresistant 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., Facultad de Ciencias Médicas

The aim of this work was to determine the effect of a fructose rich diet (FRD) consumed by the pregnant mother on the endocrine-metabolic and in vivo and in vitro adipose tissue (AT) functions of the male offspring in adulthood. At 60 days of age, rats born to FRD-fed mothers (F) showed impaired glucose tolerance after glucose overload and high circulating levels of leptin (LEP). Despite the diminished mass of retroperitoneal AT, this tissue was characterized by enhanced LEP gene expression, and hypertrophic adipocytes secreting in vitro larger amounts of LEP. Analyses of stromal vascular fraction composition by flow cytometry revealed a reduced number of adipocyte precursor cells. Additionally, 60 day-old control (C) and F male rats were subjected to control diet (CC and FC animals) or FRD (CF and FF rats) for three weeks. FF animals were heavier and consumed more calories. Their metabolic-endocrine parameters were aggravated; they developed severe hyperglycemia, hypertriglyceridemia, hyperleptinemia and augmented AT mass with hypertrophic adipocytes. Our study highlights that manipulation of maternal diet induced an offspring phenotype mainly imprinted with a severely unhealthy adipogenic process with undesirable endocrine-metabolic consequences, putting them at high risk for developing a diabetic state., Facultad de Ciencias Médicas

Intervenciones: Sobre estilo de vida, previenen el desarrollo de diabetes tipo 2 (DMT2) en personas con tolerancia a la glucosa o glucemia de ayunas alterada (TGA y GAA, respectivamente), aisladas o combinadas. Objetivo: Evaluar la efectividad de adoptar estilo de vida saludable sobre la manifestación clínica de DMT2 en personas con riesgo de desarrollarla. Metodología: Estudio prospectivo en participantes de 3 municipios de provincia de Buenos Aires (La Plata, Berisso y Ensenada), mediante cuestionario FINDRISC; quienes superen su puntaje de riesgo (≥ 13), realizarán prueba de tolerancia oral a la glucosa. El estudio incluirá a todas las personas con TGA/GAA que deseen participar y firmen un consentimiento informado, distribuidas en 2 grupos: a) intervención autoadministrada, y b) intervención intensificada (talleres de modalidad grupal mensuales sobre plan de alimentación saludable y práctica regular de actividad física 3 veces por semana). Ambos grupos tendrán un seguimiento de 2 an˜ os. Se utilizarán cuestionarios para evaluar bienestar, hábitos alimentarios y actividad física de cada participante al inicio del estudio y cada 6 meses durante el seguimiento. En ambos grupos se realizarán individualmente mediciones antropométricas y análisis de laboratorio a los 0, 12 y 24 meses. Igualmente, se evaluará la coste-efectividad de las estrategias implementadas. Resultados y conclusiones: Los resultados del estudio permitirán: a) demostrar la factibilidad y el costo de este tipo de programas: b) identificar genotipos de personas en riesgo facilitando intervenir en ellas precoz y eficientemente; c) definir si estas intervenciones también mejoran otros FRCV presentes; d) cuantificar las lesiones de microangiopatía (microaneurismas retinianos) en población con TGA/GAA, y e) identificar barreras y alianzas estratégicas interdisciplinarias e intersectoriales para la implementación efectiva de este tipo de programas., Lifestyle interventions: Prevent/delay the development of type 2 diabetes (T2DM) in people with impaired glucose tolerance or impaired fasting blood glucose (IGT and IFG, respectively), alone or combined. Objective: To evaluate the effectiveness of adopting a healthy lifestyle on the clinical manifestation of T2DM in people at risk of its development. Methodology: A prospective study will be conducted, using the FINDRISC questionnaire, on participants selected from three municipalities of the Province of Buenos Aires (La Plata, Berisso and Ensenada). An oral glucose tolerance test will be performed on those participants who exceed their risk score (≥ 13). The study will include all people with IGT/ IFG who wish to participate and sign an informed consent form. They will be randomly divided into two groups: a) self-administered intervention and b) Intensified Intervention (monthly group sessions on healthy meal plan and weekly sessions of physical activity). Both groups will be followed-up for two years. Questionnaires will be used to assess welfare (WHO-5), eating habits, and physical activity of each participant at baseline and every six months of followup. Individual anthropometric measurements and laboratory analysis will be performed in both groups at 0, 12 and 24 months. The cost-effectiveness of the strategies implemented will also be assessed. Results and conclusions: The results of the study will allow to: a) demonstrate the feasibility and cost of such programs, b) identify genotypes of people at risk that would facilitate early implementation of effective prevention strategies; c) define whether these interventions would also improve other associated cardiovascular risk factors, d) Identify and quantify microangiopathy lesions (retinal micro-aneurysms) in a population with IGT/IFG, and e) identify barriers and interdisciplinary strategic alliances for effective implementation of such programs., Facultad de Ciencias Médicas

A sex steroid-dependent modulation of the immune function in mammals is accepted, and evidence suggests that while estrogens enhance, androgens inhibit the immune response. The aim of this study was to explore in the adult male rat the effect of either neonatal flutamide (FTM) treatment or prepubertal orchidectomy (ODX) on endocrine markers in the basal condition and peripheral tumor necrosis factor alpha (TNFα) levels during inflammatory stress. For these purposes, (1) 5-day-old male rats were subcutaneously injected with either sterile vehicle alone or containing 1.75 mg FTM, and (2) 25-day-old male rats were sham operated or had ODX. Rats were sacrificed (at 100 days of age) in the basal condition for determination of peripheral metabolite levels. Additional rats were intravenously injected with bacterial lipopolysaccharide (LPS; 25 μg/kg body weight, i.v.) and bled for up to 4 h. Data indicate that (1) ODX increased peripheral glucocorticoid levels and reduced those of testosterone, whereas FTM-treated rats displayed low circulating leptin concentrations, and (2) LPS-induced TNFα secretion in plasma was significantly enhanced in the FTM and ODX groups. Our study supports that neonatal FTM treatment affected adiposity function, and adds data maintaining that androgens have a suppressive role in proinflammatory cytokine release in plasma during inflammation. Fil: Ongaro Gambino, 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; Argentina Fil: 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; Argentina Fil: 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; Argentina Fil: Gaillard, Rolf C.. Lausanne University Hospital; Suiza Fil: 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

There are only a few studies on the ontogeny and differentiation process of the hypothalamic supraoptic-paraventriculo-neurohypophysial neurosecretory system. In vitro neuron survival improves if cells are of embryonic origin; however, surviving hypothalamic neurons in culture were found to express small and minimal amounts of arginine-vasopressin (AVP) and oxytocin (OT), respectively. The aim of this study was to develop a primary neuronal culture design applicable to the study of magnocellular hypothalamic system functionality. For this purpose, a primary neuronal culture was set up after mechanical dissociation of sterile hypothalamic blocks from 17-day-old Sprague–Dawley rat embryos (E17) of both sexes. Isolated hypothalamic cells were cultured with supplemented (B27)-NeuroBasal medium containing an agent inhibiting non-neuron cell proliferation. The neurosecretory process was characterized by detecting AVP and OT secreted into the medium on different days of culture. Data indicate that spontaneous AVP and OT release occurred in a culture day-dependent fashion, being maximal on day 13 for AVP, and on day 10 for OT. Interestingly, brain-derived neurotrophic factor (BDNF) and Angiotensin II (A II) were able to positively modulate neuropeptide output. Furthermore, on day 17 of culture, non-specific (high-KCl) and specific (Angiotensin II) stimuli were able to significantly (P < 0.05) enhance the secretion of both neuropeptides over respective baselines. This study suggests that our experimental design is useful for the study of AVP- and OT-ergic neuron functionality and that BDNF and A II are positive modulators of embryonic hypothalamic cell development.

An adverse endogenous environment during early life predisposes the organism to develop metabolic disorders. We evaluated the impact of intake of an iso-caloric fructose rich diet (FRD) by lactating mothers (LM) on several metabolic functions of their male offspring. On postnatal d 1, ad libitum eating, lactating Sprague-Dawley rats received either 10% F (wt/vol; FRD-LM) or tap water (controls, CTR-LM) to drink throughout lactation. Weaned male offspring were fed ad libitum a normal diet, and body weight (BW) and food intake were registered until experimentation (60 d of age). Basal circulating levels of metabolic markers were evaluated. Both iv glucose tolerance and hypothalamic leptin sensitivity tests were performed. The hypothalamus was dissected for isolation of total RNA and Western blot analysis. Retroperitoneal (RP) adipose tissue was dissected and either kept frozen for gene analysis or digested to isolate adipocytes or for histological studies. FRD rats showed increased BW and decreased hypothalamic sensitivity to exogenous leptin, enhanced food intake (between 49-60 d), and decreased hypothalamic expression of several anorexigenic signals. FRD rats developed increased insulin and leptin peripheral levels and decreased adiponectinemia; although FRD rats normally tolerated glucose excess, it was associated with enhanced insulin secretion. FRD RP adipocytes were enlarged and spontaneously released high leptin, although they were less sensitive to insulin-induced leptin release. Accordingly, RP fat leptin gene expression was high in FRD rats. Excessive fructose consumption by lactating mothers resulted in deep neuroendocrine-metabolic disorders of their male offspring, probably enhancing the susceptibility to develop overweight/obesity during adult life., Facultad de Ciencias Exactas, Facultad de Ciencias Médicas

The aim of this study was to evaluate the effect of ovariectomy on the acute-phase response of inflammatory stress. Ex vivo adrenocortical, peripheral mononuclear cell (PMNC) and adipocyte activities were studied in intact and ovariectomized mice. Endotoxemia was mimicked by intraperitoneal administration of bacterial lipopolysaccharide (LPS; 25 mg per mouse) to sham-operated and 21-day ovariectomized mice. Circulating corticosterone, tumor necrosis factor-α (TNFα) and leptin concentrations were monitored before and 30–120 min after the administration of LPS. Additionally, in vitro experiments were performed with isolated corticoadrenal cells, PMNCs and omental adipocytes from sham-operated and ovariectomized mice incubated with specific secretagogues. The results indicate that while ovariectomy enhanced TNFα secretion after in vivo administration of LPS, it reduced corticoadrenal response and abrogated LPS-elicited leptin secretion into the circulation. While the corticoadrenal sensitivity to ACTH stimulation was reduced by ovariectomy, the LPS-induced PMNC response was not affected. Exogenous leptin enhanced baseline PMNC function regardless of surgery. Finally, ovariectomy drastically reduced in vitro adipocyte functionality. Our data support the notion that ovariectomy modified neuroendocrine-immune-adipocyte axis function and strongly suggest that ovarian activity could play a pivotal role in the development of an adequate immune defense mechanism after injury.

It has been proposed that ghrelin induces food intake by a mechanism due to the stimulation of hypothalamic NPY-ergic activity. It is recognized that bilateral adrenalectomy (ADX) enhances hypothalamic CRH-ergic function and reduces appetite. Thus, the aim of the present study was to test whether, icv-administered, ghrelin modulates NPY- and CRH-ergic functions after food restriction (FR) and glucocorticoid deprivation. For this purpose, 1 microg ghrelin was administered icv to ad libitum (AL) eating and to corticosterone (B)-depleted (ADX) and -replete (sham and ADX+B) male animals habituated, for 15 d, to FR. Food intake, hypothalamic function, and peripheral ghrelin, ACTH, and B concentrations were evaluated 2 h after ghrelin administration. Results indicate that while icv ghrelin treatment stimulated 2-h food intake in AL rats, it failed to do so in sham- and ADX+B-FR animals; moreover, 2-h food intake was inhibited by icv ghrelin treatment in ADX-FR rats. Regarding peripheral hormone levels: (a) basal circulating ghrelin levels, already enhanced (vs AL rats) by FR, significantly increased 2 h after icv ghrelin treatment in AL and sham-FR rats; (b) central ghrelin treatment stimulated ACTH secretion in circulation of AL and glucocorticoid-replete-FR rats; and (c) B circulating levels remained unchanged after ghrelin treatment, although they were in relation to the food intake condition of rats. Finally, hypothalamic NPY mRNA expression was enhanced by FR and, in response to icv ghrelin treatment, it decreased in ADX-FR rats only. ADX-enhanced hypothalamic CRH mRNA levels were reduced by ghrelin icv administration only when animals received B replacement therapy. Our data indicate an inhibitory effect of hypothalamic ghrelin on NPY-ergic activity in FR rats lacking endogenous glucocorticoid.

Neonatal administration of monosodium glutamate (MSG) to rats produces severe lesions in certain hypothalamic nuclei, with repercussions in different neuroendocrine axes, and serves as a model for their study. In addition, adipose tissue, as a target organ, is known to be directly related to several neurondocrine axes. We used 21-day-old female Sprague-Dawley rats that had received a neonatal treatment with MSG (4 mg/g body weight, i.p., from day 2 up to day 10 of age) in addition to control rats (injected with 10% NaCl solution, on a similar schedule). We performed a specific immunohistochemical study on each anterior-pituitary cell population, along with the morphometry of these cells and of the parietal and visceral adipose tissue, and measured the levels of serum leptin and triglycerides. The MSG animals evinced significant changes in volume density (VD), cell density (CD), and cell size (CS) in the corticotropes, thyrotropes, and LH gonadotropes, but not in the somatotropes, lactotropes, and FSH gonadotropes. The modification common to the three cell types was a hyperplasia, but with different results depending on cell size. Furthermore, in the MSG rats significant changes were also observed in the VD, CD, and CS of the adipose tissue, consisting of adipogenesis and decrease of adipocyte size in visceral fat, together with probable lipogenesis as judged by an increase in adipocyte size in the parietal fat. The serum levels of leptin and triglycerides appeared significantly higher in MSG animals. For the first time in this animal model, and at the level of three neuroendocrine axes, our results suggest changes that correlate hypothalamic damage, cellular pituitary alterations, and the response of the adipose tissue as a target organ for MSG insult.

En la fisiopatología de la obesidad intervienen factores genéticos, sociales, metabólicos, endocrinos y neurológicos. Esta multifactoriedad junto al hecho que estos factores se interrelacionan a través de mecanismos muy complejos, que son sólo parcialmente conocidos, ha llevado a que la comprensión íntima de este trastorno resulte una tarea sumamente ardua. Por estos motivos, el conocimiento integral de esta afección plantea un desafío al que actualmente están abocados numerosos grupos de investigadores. El análisis de la obesidad como un trastorno neuroendocrino, propone el estudio de este fenómeno desde una visión particular que implica disfunciones en casi todos los órganos endocrinos y en el sistema nervioso central, fundamentalmente en la actividad hipotalámica. Estas alteraciones afectan principalmente a los ejes neuroendocrinos hipotálamo-hipofiso-adrenal, adipo-insular y al control hipotalámico, tanto de la ingesta de alimento como del almacenamiento y gasto energético. Este artículo plantea una actualización en este campo; en primer lugar, se realiza una breve descripción, en forma independiente, de los principales sistemas antes mencionados y luego una descripción de su funcionamiento normal integrado. Finalmente, se describen desregulaciones de estos mecanismos y se discute como ellas contribuirían al desarrollo y/o mantenimiento de la obesidad.Genetic, social, metabolic, endocrine and neural events participate in the physiopathological development of obesity. Because of the multifactorial background of obesity, up to now, it has been very difficult to fully understand the whole disease. In fact, the relationship between several signals, through very complex mechanisms, is only partially known. Obesity, from a neuroendocrine point of view, implies taking into account abnormalities in both hypothalamic and endocrine functions. Among altered functions in obesity, namely those involving the hypothalamo-pituitary-adrenal and adipo-insular axes activities and the neural circuitry controlling food intake and energy expenditure have been subjects of major research. This review attempts to update information about this disorder by, firstly, analyzing each of the already mentioned systems and, secondly, focusing on the normal function of integrated processes. Finally, the discussion of some altered mechanisms and the role played by each of them in the development/maintenance of the obesity phenotype are also revisited.

Estradiol has been implicated in the regulation of food intake; however, its effect seems to be exerted in a bimodal fashion. We examined whether a single im injection of estradiol valerate (E2V), lastingly effective, could induce changes in parametrial fat function that further induce a new set point of leptin sensitivity in the female rat. E2V induced severe anorexia and loss of body weight between d 4 and 12 posttreatment. E2V rats recovered normal food intake and departing body weights on wk 2 and 3 posttreatment, respectively; however, they did not reach body weights of control rats. On d 61 posttreatment, we found that unfasting E2V, vs control, rats displayed increased E2 and leptin circulating levels; reduced plasma tumor necrosis factor-alpha(TNF-alpha) concentrations; similar circulating levels of glucose, insulin, and triglyceride; and lower parametrial fat mass containing a higher number of adipocytes that, although normal in size, in vitro released more leptin. Metabolic responses to fasting indicated that unlike control animals, E2V rats did not decrease triglyceride circulating levels, and that both groups decreased plasma glucose, leptin, and insulin, but not TNF-alpha, levels. High glucose load experiments indicated that E2V animals displayed a better insulin sensitivity than control rats; did not significantly increase circulating leptin concentrations as control rats did; and, unlike control, significantly decreased plasma triglyceride levels. Our data strongly support a potent acute anorectic effect of E2 and that, after several weeks, E2 modified parametrial fat function and insulin sensitivity, protecting the organism against future unfavorable metabolic conditions., Instituto Multidisciplinario de Biología Celular

We explored whether testosterone influences circulating leptin turnover in rats. Sham-operated male and female rats and 21-d gonadectomized rats treated or not treated with testosterone propionate were used. Anesthetized rats were implanted with an iv catheter, and then blood samples were drawn before and throughout a 60-min period following systemic leptin administration. Plasma testosterone, estradiol, and leptin concentrations were monitored. The results indicated that while gonadectomy blunted circulating concentrations of the homologous sex steroid, testosterone therapy, in gonadectomized rats, restored plasma testosterone concentrations to values found in normal male rats. Pharmacokinetic parameters evaluated during the test indicated the following: First, in the overall pharmacokinetic analyses, testosterone therapy in gonadectomized rats induced a more rapid disappearance of leptin from the circulation. Second, orchidectomy significantly enhanced the area under the curve (AUC) of circulating leptin, an effect fully reversed by testosterone treatment. Third, testosterone treatment in ovariectomized rats significantly decreased the AUC of leptin concentrations. Fourth, while gonadectomy alone did not modify circulating leptin half-life, conversely, testosterone therapy in gonadectomized rats decreased leptin half-life in the circulation. Finally, while orchidectomy reduced leptin body clearance, this parameter was increased by androgen therapy in gonadectomized rats. Our results strongly support that testosterone could play a main role in plasma leptin turnover by increasing leptin clearance rate and shortening plasma leptin half-life.

Aim: Androgen excess predisposes the organism to develop metabolic–endocrine and reproductive dysfunctions, among them the development of a phenotype resembling that of human Polycystic Ovary Syndrome (PCOS). Methods: We analyzed the impact of a single neonatal (5 day-old) testosterone propionate (TP; s.c. 1.25 mg/female pup) dose on: a) several metabolic–endocrine activities and b) ovarian steroidogenic and granulosa cell (GC) functions and also follicular population in juvenile and adult TP and control (CT) rats. Key findings: Compared to CT rats, TP animals were characterized by: a) accelerated growth, hyperadiposity and hyperleptinemia, b) very early (pre-weaning age) vaginal opening, c) hyperinsulinemia in adult life, d) dysfunctional ovarian steroidogenesis, e) conserved GC functionality in both juveniles (in vitro) and adults (in vivo), and f) estrous cycles arrested at estrus. Finally, histological studies of the ovaries indicated that in TP (vs. CT) rats: i) primary and antral follicle frequencies were 3- and 15-fold higher and lower, respectively, in juveniles and ii) secondary and atretic follicle frequencies were 3- and 5-fold lower and higher, respectively, in adults. Large cystic images without corpus luteum were observed in the ovaries from adult TP rats only. Significance: Our results strongly suggest that transient neonatal hyperandrogenemia induced early misprogramming of metabolic–endocrine and ovarian (steroidogenesis/folliculogenesis) functions. Conversely, TP rats preserved their ovary GC endocrine function. Our results further support the high risk of developing ovarian hyperstimulation syndrome for infertile women with transient/chronic hyperandrogenemia (PCOS) subjected to assisted reproductive technologies. Fil: Ongaro Gambino, Luisina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico La Plata. Instituto Multidisciplinario de Biología Celular (i); Argentina. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas; Argentina Fil: Salvetti, Natalia Raquel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Santa Fe. Instituto de Ciencias Veterinarias del Litoral; Argentina Fil: Giovambattista, Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico la Plata. Instituto Multidisciplinario de Biología Celular (i); Argentina. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas; Argentina Fil: Spinedi, Eduardo Julio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Cientifico Tecnológico la Plata. Centro de Endocrinologia Experimental y Aplicada (i); Argentina. Universidad Nacional de La Plata; Argentina Fil: Ortega, Hugo Hector. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Santa Fe. Instituto de Ciencias Veterinarias del Litoral; Argentina. Universidad Nacional del Litoral; Argentina

The present study was designed to assess the effect of maternal undernutrition, during gestation and lactation, on the neuroendocrine [hypothalamo-pituitary-adrenal (HPA)]-immune axis response to endotoxin (LPS) administration. For this purpose, 21-day-old male rats from both well-nourished (WN) and undernourished (UN) mothers were examined 2 h after injection (i.p.) of vehicle alone (VEH) or containing LPS (130 µg/kg BW). Circulating levels of glucose (GLU), ACTH, corticosterone (B), tumor necrosis factor-alpha (TNFα) and leptin were explored. The results indicate that: (a) mother body weight was significantly (p < 0.05) reduced, as a consequence of UN, at the second and third weeks of pregnancy; (b) no differences in basal glycemia were found in the two groups of pups, and LPS treatment did not induce hypoglycemia, in either group; (c) basal plasma ACTH, B and TNFα levels were similar in the two groups, and LPS-induced ACTH, B and TNFα secretions, although severalfold higher than respective VEH values (p < 0.05) in pups from WN mothers, were fully (ACTH and B) and partially (TNFα) abolished in products from UN mothers; (d) both mean body weights and basal plasma leptin levels were significantly (p < 0.05) lower in pups from UN than from WN mothers, and LPS administration did not modify plasma leptin values in products from both groups. In addition, results of dispersed total adrenal cells incubated in vitro indicate that: (a) both basal and ACTH (22 pM)-induced B secretion were significantly (p < 0.05) lower in cells from UN than WN pups, and (b) leptin (100 nM) was able to inhibit partially ACTH-stimulated B output by adrenal gland (AG) cells from WN pups; however, it failed to inhibit ACTH-stimulated glucocorticoid release by AG cells from UN pups. The present results indicate that undernutrition in mothers, during the very critical periods of gestation and lactation, induces in their male pups at weaning: (a) reduced circulating leptin levels and body weight values; (b) metabolic adaptation to normal carbohydrate metabolism; (c) hyporesponsiveness of the HPA and immune (TNFα) axes during endotoxemia, and (d) leptin resistance at the adrenocortical level. This study strongly supports that undernutrition of mothers results in neuroendocrine immune dysfunction of their pups; however, adrenal resistance to the inhibitory effect of leptin on glucocorticoid output is developed, probably as an adaptive mechanism to counteract unfavorable metabolic conditions.

The present study was designed to determine whether the glucocorticoid inhibitory feedback mechanism plays a role in the well-known tolerance of the neuroendocrine-immune axis response to repeated endotoxemia. Adult male rats underwent adrenalectomy (ADX) and were implanted with a subcutaneous corticosterone (compound B, CB, 75 mg) pellet, or sham operated and implanted with a placebo pellet. On the morning of day 8 after surgery (experimental day, D1), all rats received an intravenous injection of lipopolysaccharide (LPS) (25 µg/kg body weight) which was repeated daily until D5. Blood was drawn via intravenous indwelling catheters before (sample time zero) as well as 1, 2, 3 and 4 h after LPS treatment on D1, 3 and 5 for measurements of corticotropin (ACTH), CB, tumor necrosis factor-α (TNF-α) and leptin. In sham animals, tolerance to repeated LPS administration was complete by D5 for the corticotrope axis and the immune response. In addition, LPS was found to stimulate leptin secretion on day 1 in intact rats, an effect that also disappeared thereafter. ADX + CB rats showed only a partial tolerance of the corticotrope axis on D5, whereas tolerance of the immune response was similar to that found in sham animals. Interestingly, the acute stimulation of leptin secretion by LPS in ADX + CB rats was qualitatively similar to that of intact controls on D1, but plasma leptin levels were significantly reduced on D3 and 5 compared to controls. Our results demonstrate that the adrenal response tolerance of the hypothalamo-pituitary-adrenal axis to repeated endotoxemia. In addition, our finding that TNF-α secretion follows the same pattern in sham-operated and in adrenalectomized animals suggests that unlike the corticotrope axis, tolerance of the immune response does not depend upon stimulated CB levels. The decrease in circulating levels of leptin following ADX is consistent with the stimulatory effects of glucocorticoids on leptin secretion. However, our finding of an acute stimulation of leptin secretion by LPS in ADX + CB animals demonstrates that this effect of endotoxemia is at least partially glucocorticoid independent.

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 Exactas, Instituto Multidisciplinario de Biología Celular, Centro de Endocrinología Experimental y Aplicada

We studied the effect of feeding normal adult male rats with a commercial diet (CD) supplemented with fructose added to the drinking water (10% wt/vol; fructose-rich diet, FRD) on the adipogenic capacity of stromal-vascular fraction (SVF) cells isolated from visceral adipose tissue (VAT) pads. Animals received either the CD or FRD ad libitum for 3 weeks; thereafter, we evaluated the in vitro proliferative and adipogenic capacities of their VAT SVF cells. FRD significantly increased plasma insulin, triglyceride and leptin levels, VAT mass/cell size, and the in vitro adipogenic capacity of SVF cells. Flow cytometry studies indicated that VAT precursor cell population number did not differ between groups; however, the accelerated adipogenic process could result from an imbalance between endogenous pro- and anti-adipogenic SVF cell signals, clearly shifted towards the former. The increased insulin milieu and its intracellular mediator (insulin receptor substrate-1) in VAT pads, and the enhanced SVF cell expression of Zpf423 and PPAR-γ2 (all pro-adipogenic modulators), together with a decreased SVF cell concentration of anti-adipogenic factors (preadipocyte factor-1 and wingless-type MMTV-10b) strongly support this assumption. We hypothesize that the VAT mass expansion recorded in FRD rats results from the combination of initial accelerated adipogenesis and final cell hypertrophy. It remains to be determined whether FRD administration over longer periods of time could perpetuate both processes, or whether cell hypertrophy itself remains responsible for a further VAT mass expansion, as observed in advanced/morbid obesity. This article is protected by copyright. All rights reserved. Fil: Zubiría, María Guillermina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico La Plata. Instituto Multidisciplinario de Biología Celular (i); Argentina Fil: Fariña, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Cientifico Tecnológico La Plata. Centro de Endocrinologia Experimental y Aplicada (i); Argentina Fil: Moreno, Griselda Noemí. Universidad Nacional de la Plata. Facultad de Cs.exactas. Departamento de Cs.biologicas. Laboratorio de Invest.del Sistema Inmune; Argentina Fil: Gagliardino, Juan Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Cientifico Tecnológico La Plata. Centro de Endocrinologia Experimental y Aplicada (i); Argentina Fil: Spinedi, Eduardo Julio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Cientifico Tecnológico La Plata. Centro de Endocrinologia Experimental y Aplicada (i); Argentina Fil: Giovambattista, Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico La Plata. Instituto Multidisciplinario de Biología Celular (i); Argentina

In the present study, we tested the effect of OS (oxidative stress) inhibition in rats fed on an FRD [fructose-rich diet; 10% (w/v) in drinking water] for 3 weeks. Normal adult male rats received a standard CD (commercial diet) or an FRD without or with an inhibitor of NADPH oxidase, APO (apocynin; 5 mM in drinking water; CD-APO and FRD-APO). We thereafter measured plasma OS and metabolic-endocrine markers, AAT (abdominal adipose tissue) mass and cell size, FA (fatty acid) composition (content and release), OS status, LEP (leptin) and IRS (insulin receptor substrate)-1/IRS-2 mRNAs, ROS (reactive oxygen species) production, NADPH oxidase activity and LEP release by isolated AAT adipocytes. FRD-fed rats had larger AAT mass without changes in body weight, and higher plasma levels of TAG (triacylglycerol), FAs, TBARS (thiobarbituric acid-reactive substance) and LEP. Although no significant changes in glucose and insulin plasma levels were observed in these animals, their HOMA-IR (homoeostasis model assessment of insulin resistance) values were significantly higher than those of CD. The AAT from FRD-fed rats had larger adipocytes, higher saturated FA content, higher NADPH oxidase activity, greater ROS production, a distorted FA content/release pattern, lower insulin sensitivity together with higher and lower mRNA content of LEP and IRS-1-/2 respectively, and released a larger amount of LEP. The development of all the clinical, OS, metabolic, endocrine and molecular changes induced by the FRD were significantly prevented by APO co-administration. The fact that APO treatment prevented both changes in NADPH oxidase activity and the development of all the FRD-induced AAT dysfunctions in normal rats strongly suggests that OS plays an important role in the FRD-induced MS (metabolic syndrome) phenotype. Fil: Fariña, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Cientifico Tecnológico La Plata. Centro de Endocrinologia Experimental y Aplicada (i); Argentina Fil: Garcia, Maria Elisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Cientifico Tecnológico La Plata. Centro de Endocrinologia Experimental y Aplicada (i); Argentina Fil: Alzamendi, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico La Plata. Instituto Multidisciplinario de Biología Celular (i); Argentina Fil: Giovambattista, Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico La Plata. Instituto Multidisciplinario de Biología Celular (i); Argentina Fil: Marra, Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico La Plata. Instituto de Investigaciones Bioquímicas de La Plata; Argentina Fil: Spinedi, Eduardo Julio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico La Plata. Instituto Multidisciplinario de Biología Celular (i); Argentina Fil: Gagliardino, Juan Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Cientifico Tecnológico La Plata. Centro de Endocrinologia Experimental y Aplicada (i); Argentina

We have previously addressed that fructose rich diet (FRD) intake for three weeks increases the adipogenic potential of stromal vascular fraction cells from the retroperitoneal adipose tissue (RPAT). We have now evaluated the effect of prolonged FRD intake (eight weeks) on metabolic parameters, number of adipocyte precursor cells (APCs) and in vitro adipogenic potential from control (CTR) and FRD adult male rats. Additionally, we have examined the direct fructose effects on the adipogenic capacity of normal APCs. FRD fed rats had increased plasma levels of insulin, triglyceride and leptin, and RPAT mass and adipocyte size. FACS studies showed higher APCs number and adipogenic potential in FRD RPAT pads; data is supported by high mRNA levels of competency markers: PPARγ2 and Zfp423. Complementary in vitro experiments indicate that fructose-exposed normal APCs displayed an overall increased adipogenic capacity. We conclude that the RPAT mass expansion observed in eight week-FRD fed rats depends on combined accelerated adipogenesis and adipocyte hypertrophy, partially due to a direct effect of fructose on APCs., Facultad de Ciencias Médicas

Aim. To test the potential role of PPARγ in the endocrine abdominal tissue dysfunction induced by feeding normal rats with a fructose rich diet (FRD) during three weeks. Methodology. Adult normal male rats received a standard commercial diet (CD) or FRD, (10% in drinking water) without or with pioglitazone (PIO) (i.p. 0.25mg/Kg BW/day; CD-PIO and FRD-PIO). Thereafter, we measured circulating metabolic, endocrine, and oxidative stress (OS) markers, abdominal adipose tissue (AAT) mass, leptin (LEP) and plasminogen activator inhibitor-1 (PAI-1) tissue content/expression, and leptin release by isolated adipocytes incubated with different concentrations of insulin. Results. Plasma glucose, insulin, triglyceride, TBARS, LEP, and PAI-1 levels were higher in FRD rats; PIO coadministration fully prevented all these increments. AAT adipocytes from FRD rats were larger, secreted a higher amount of LEP, and displayed decreased sensitivity to insulin stimulation; these effects were significantly ameliorated by PIO. Whereas AAT LEP and PAI-1 (mRNA) concentrations increased significantly in FRD rats, those of insulin-receptor-substrate- (IRS-) 1 and IRS-2 were reduced. PIO coadministration prevented FRD effects on LEP, PAI-1, and IRS-2 (fully) and IRS-1 (partially) mRNAs in AAT. Conclusion. PPARγ would play a relevant role in the development of the FRD-induced metabolicendocrine dysfunction., Facultad de Ciencias Médicas

The effect of progesterone (P4) on fructose rich diet (FRD) intake-induced metabolic, endocrine and parametrial adipose tissue (PMAT) dysfunctions was studied in the adult female rat. Sixty day-old rats were i.m. treated with oil alone (control, CT) or containing P4 (12 mg/kg). Rats ate Purina chow-diet ad libitum throughout the entire experiment and, between 100 and 120 days of age drank ad libitum tap water alone (normal diet; CT-ND and P4-ND) or containing fructose (10% w/v; CT-FRD and P4-FRD). At age 120 days, animals were subjected to a glucose tolerance test or decapitated. Plasma concentrations of various biomarkers and PMAT gene abundance were monitored. P4-ND (vs. CT-ND) rats showed elevated circulating levels of lipids. CT-FRD rats displayed high (vs. CT-ND) plasma concentrations of lipids, leptin, adiponectin and plasminogen activator inhibitor-1 (PAI-1). Lipidemia and adiponectinemia were high (vs. P4-ND) in P4-FRD rats. Although P4 failed to prevent FRD-induced hyperleptinemia, it was fully protective on FRD-enhanced plasma PAI-1 levels. PMAT leptin and adiponectin mRNAs were high in CT-FRD and P4-FRD rats. While FRD enhanced PMAT PAI-1 mRNA abundance in CT rats, this effect was absent in P4 rats. Our study supports that a preceding P4-enriched milieu prevented the enhanced prothrombotic risk induced by FRD-elicited high PAI-1 production., Instituto Multidisciplinario de Biología Celular, Facultad de Ciencias Médicas, Facultad de Ciencias Exactas

The intake of a fructose-rich diet (FRD) in the normal female rat induces features similar to those observed in the human metabolic syndrome phenotype. We studied the impact of FRD administration to mothers on pregnancy outcome. On gestational day (Gd) zero rats were assigned to either group: ad libitum drinking tap water alone (normal diet, ND) or containing fructose (10% w/vol; FRD) through pregnancy; all rats were fed a Purina chow diet ad libitum ND and FRD rats were daily cotreated or not with metformin (60 mg/Kg/day oral; ND + MF and FRD + MF) and submitted to a high glucose load test on Gd 14. Additionally, placentas from different groups were studied on Gd 20. Data indicated that: (1) although FRD rats well tolerated glucose overload, their circulating levels of insulin were significantly higher than in ND rats; (2) the mesometrial triangle blood vessel area was significantly lower in placentas from FRD than ND dams; (3) the detrimental effects of FRD administration to mothers were ameliorated by metformin cotreatment. Our study suggests that excessive intake of fructose during pregnancy enhanced the risk for developing gestational diabetes and subsequent preeclampsia, and that metformin prevented the poor pregnancy outcome induced by FRD., Instituto Multidisciplinario de Biología Celular, Centro de Endocrinología Experimental y Aplicada

Many studies have documented the presence of a sexually dimorphic response of neuroendocrine functions in response to immune signals. The aims of the present study were to evaluate the hypothalamopituitary-adrenal (HPA) axis response to inflammatory stress stimulus in 15-month-old mice, and to determine whether such a response depends on circulating sex steroids. Our results indicate that in the 15-month-old mice: (1) there is a sexual dimorphism in the HPA axis activity in basal condition and after endotoxin treatment with generally higher levels of several parameters of this axis in female than in male mice, (2) gonadectomy alone, followed by sex steroid therapy, modulates HPA axis function in both basal and stress conditions, and (3) whereas estradiol plays a stimulatory role on adrenal function, testosterone inhibits adrenal glucocorticoid production. This study further suggests a clear sexual dimorphism in middle-aged mice injected with endotoxin. These results may be relevant for the treatment of sepsis in aged patients.

Susceptibility to inflammatory disease in infantile Lewis (LEW/N) female rats seems to be related to their impaired hypothalamo-pituitary-adrenal (HPA) axis response to different inflammatory stimuli, while the relative resistance to this type of disease in Fischer (F344/N) female rats is apparently due to their potent HPA axis response to the same stimuli. In the present study, we attempted to elucidate whether there is an impairment in the HPA axis response in the juvenile female LEW/N rat to inflammatory and noninflammatory stimuli, and also to determine whether the endogenous sex-steroid environment influences the HPA axis function in both strains of rats. For these purposes, juvenile F344/N and LEW/N rats of both sexes were submitted to different treatments: (a) inhalation of normal atmosphere or ether vapors for 1 min (Ether); (b) i.p. injection of vehicle alone or containing CRH (0.5 microgram/rat), arginine vasopressin (AVP; 5 micrograms/rat, angiotensin II (AII; 5 micrograms/rat), insulin (INS; 0.3 IU/rat), bacterial lipopolysaccharide (LPS; 100 micrograms/rat) or snake venom (SV; 100 micrograms/rat). Rats were then killed at different time intervals (in min) after treatments: 20 for Ether, AVP and CRH, 30 for AII, 45 for INS, 60 for SV and 120 for LPS.(ABSTRACT TRUNCATED AT 250 WORDS)

The hypothalamic damage induced by neonatal treatment with monosodium l-glutamate (MSG) induces several metabolic abnormalities, resulting in a rat hyperleptinemic–hyperadipose phenotype. This study was conducted to explore the impact of the neonatal MSG treatment, in the adult (120 days old) female rat on: (a) the in vivo and in vitro mineralocorticoid responses to ACTH and angiotensin II (AII); (b) the effect of leptin on ACTH- and AII-stimulated mineralocorticoid secretions by isolated corticoadrenal cells; and (c) abdominal adiposity characteristics. Our data indicate that, compared with age-matched controls, MSG rats displayed: (1) enhanced and reduced mineralocorticoid responses to ACTH and AII treatments, respectively, effects observed in both in vivo and in vitro conditions; (2) adrenal refractoriness to the inhibitory effect of exogenous leptin on ACTH-stimulated aldosterone output by isolated adrenocortical cells; and (3) distorted omental adiposity morphology and function. This study supports that the adult hyperleptinemic MSG female rat is characterized by enhanced ACTH-driven mineralocorticoid function, impaired adrenal leptin sensitivity, and disrupted abdominal adiposity function. MSG rats could counteract undesirable effects of glucocorticoid excess, by developing a reduced AII-driven mineralocorticoid function. Thus, chronic hyperleptinemia could play a protective role against ACTH-mediated allostatic loads in the adrenal leptin resistant, MSG female rat phenotype., Facultad de Ciencias Médicas, Comisión de Investigaciones Científicas de la provincia de Buenos Aires

Hyperandrogenemia predisposes an organism toward developing impaired insulin sensitivity. The aim of our study was to evaluate endocrine and metabolic effects during early allostasis induced by a fructose-rich diet (FRD) in normal (control; CT) and neonatal-androgenized (testosterone propionate; TP) female adult rats. CT and TP rats were fed either a normal diet (ND) or an FRD for 3 weeks immediately before the day of study, which was at age 100 days. Energy intake, body weight (BW), parametrial (PM) fat characteristics, and endocrine/metabolic biomarkers were then evaluated. Daily energy intake was similar in CT and TP rats regardless of the differences in diet. When compared with CT-ND rats, the TP-ND rats were heavier, had larger PM fat, and were characterized by basal hypoadiponectinemia and enhanced plasma levels of non-esterified fatty acid (NEFA), plasminogen activator inhibitor-1 (PAI-1), and leptin. FRD-fed CT rats, when compared with CT-ND rats, had high plasma levels of NEFA, triglyceride (TG), PAI-1, leptin, and adiponectin. The TP-FRD rats, when compared with TP-ND rats, displayed enhanced leptinemia and triglyceridemia, and were hyperinsulinemic, with glucose intolerance. The PM fat taken from TP rats displayed increase in the size of adipocytes, decrease in adiponectin (protein/gene), and a greater abundance of the leptin gene. PM adipocyte response to insulin was impaired in CT-FRD, TP-ND, and TP-FRD rats. A very short duration of isocaloric FRD intake in TP rats induced severe metabolic dysfunction at the reproductive age. Our study supports the hypothesis that the early-androgenized female rat phenotype is highly susceptible to developing endocrine/metabolic dysfunction. In turn, these abnormalities enhance the risk of metabolic syndrome, obesity, type 2 diabetes, and cardiovascular disease.