RESUMEN
White adipose tissue (WAT) regulates energy balance through energy storage, adipokines secretion and the thermogenesis process. Beige adipocytes are responsible for WAT thermogenesis. They are generated by adipogenesis or transdifferentiation during cold or ß3-adrenergic agonist stimulus through a process called browning. Browning has gained significant interest for to its preventive effect on obesity. Glucocorticoids (GCs) have several functions in WAT biology; however, their role in beige adipocyte generation and WAT browning is not fully understood. The aim of our study was to determine the effect of dexamethasone (DXM) on WAT thermogenesis. For this purpose, rats were treated with DXM at room temperature (RT) or cold conditions to determine different thermogenic markers. Furthermore, the effects of DXM on the adipogenic potential of beige precursors and on mature beige adipocytes were evaluated in vitro. Our results showed that DXM decreased UCP-1 mRNA and protein levels, mainly after cold exposure. In vitro studies showed that DXM decreased the expression of a beige precursor marker (Ebf2), affecting their ability to differentiate into beige adipocytes, and inhibited the thermogenic response of mature beige adipocytes (Ucp-1, Dio2 and Pgc1α gene expressions and mitochondrial respiration). Overall, our data strongly suggest that DXM can inhibit the thermogenic program of both retroperitoneal and inguinal WAT depots, an effect that could be exerted, at least partially, by inhibiting de novo cell generation and the thermogenic response in beige adipocytes.
Asunto(s)
Tejido Adiposo Pardo , Tejido Adiposo Blanco , Ratas , Animales , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Obesidad/metabolismo , Adipogénesis , Dexametasona/farmacología , TermogénesisRESUMEN
Spexin (SPX) is a novel adipokine that plays an emerging role in metabolic diseases due to its involvement in carbohydrate homeostasis, weight loss, appetite control, and gastrointestinal movement, among others. In obese patients, SPX plasma levels are reduced. Little is known about the relationship between SPX and white adipose tissue (WAT) thermogenesis. Therefore, the aim of the present study was to evaluate the role of SPX in this process. C57BL/6J male mice were treated or not with SPX for ten days. On day 3, mice were randomly divided into two groups: one kept at room temperature and the other kept at cold temperature (4 °C). Caloric intake and body weight were recorded daily. At the end of the protocol, plasma, abdominal (epididymal), subcutaneous (inguinal), and brown AT (EAT, IAT, and BAT, respectively) depots were collected for measurements. We found that SPX treatment reduced Uncoupling protein 1 levels in WAT under both basal and cold conditions. SPX also reduced cox8b and pgc1α mRNA levels and mitochondrial DNA, principally in IAT. SPX did not modulate the number of beige precursors. SPX decreased spx levels in IAT depots and galr2 in WAT depots. No differences were observed in the BAT depots. In conclusion, we showed, for the first time, that SPX treatment in vivo reduced the thermogenic process in subcutaneous and abdominal AT, being more evident under cold stimulation.
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Tejido Adiposo Pardo , Frío , Hormonas Peptídicas , Termogénesis , Animales , Humanos , Masculino , Ratones , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/fisiología , Tejido Adiposo Blanco/metabolismo , Ratones Endogámicos C57BL , Termogénesis/efectos de los fármacos , Termogénesis/fisiología , Proteína Desacopladora 1/metabolismo , Hormonas Peptídicas/farmacología , Hormonas Peptídicas/fisiologíaRESUMEN
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.
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Adipocitos Beige , Andrógenos , Adipocitos Beige/metabolismo , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Andrógenos/metabolismo , Andrógenos/farmacología , Animales , Frío , Ratas , Termogénesis/fisiología , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMEN
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 7â¯days with either DXM (30⯵g/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⯵M) alone or combined with a mineralocorticoid receptor (MR) antagonist (Spironolactone 10⯵M) and/or a glucocorticoid receptor (GR) antagonist (RU486 1⯵M) to assess APCs competency and adipocyte differentiation. KEY FINDINGS: APCs from 2â¯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.
Asunto(s)
Adipocitos/citología , Adipogénesis , Dexametasona/farmacología , Células Madre/citología , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Adipogénesis/efectos de los fármacos , Adipogénesis/genética , Tejido Adiposo/citología , Animales , Biomarcadores/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Ratones , PPAR gamma/genética , PPAR gamma/metabolismo , Ratas Sprague-Dawley , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/metabolismo , Espacio Retroperitoneal , Células Madre/efectos de los fármacos , Células Madre/metabolismo , Factores de Transcripción/metabolismoRESUMEN
[This corrects the article DOI: 10.1155/2016/7838290.].
RESUMEN
BACKGROUND: Insulin-like Growth Factor1 (IGF1) is a powerful neuroprotective molecule. We have previously shown that short-term hypothalamic IGF1 gene therapy restores tuberoinfundibular 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.
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Terapia Genética , Vectores Genéticos/administración & dosificación , Factor I del Crecimiento Similar a la Insulina/genética , Prolactinoma/terapia , Animales , Femenino , Hipotálamo/metabolismo , Hipotálamo/patología , Prolactinoma/genética , Prolactinoma/patología , Ratas , Ratas Sprague-DawleyRESUMEN
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.
RESUMEN
AIM: Hypothalamic obese rats are characterized by pre-diabetes, dyslipidemia, hyperadiposity, inflammation and, liver dysmetabolism with oxidative stress (OS), among others. We studied endocrine-metabolic dysfunctions and, liver OS and inflammation in both monosodium l-glutamate (MSG)-neonatally damaged and control litter-mate (C) adult male rats, either chronically treated with N-Acetyl-l-Cysteine since weaned (C-NAC and MSG-NAC) or not. METHODOLOGY: We evaluated circulating TBARS, glucose, insulin, triglycerides, uric acid (UA) and, aspartate and alanine amino-transferase; insulin sensitivity markers (HOMA indexes, Liver Index of Insulin Sensitivity -LISI-) were calculated and liver steps of the insulin-signaling pathway were investigated. Additionally, we monitored liver OS (protein carbonyl groups, GSH and iNOS level) and inflammation-related markers (COX-2 and TNFα protein content; gene expression level of Il1b, Tnfα and Pai-1); and carbohydrate and lipid metabolic functions (glucokinase/fructokinase activities and, mRNA levels of Srebp1c, Fas and Gpat). KEY FINDINGS: Chronic NAC treatment in MSG rats efficiently decreased the high circulating levels of triglycerides, UA, transaminases and TBARS, as well as peripheral (high insulinemia and HOMA indexes) and liver (LISI and the P-AKT:AKT and P-eNOS:eNOS protein ratio values) insulin-resistance. Moreover, NAC therapy in MSG rats prevented liver dysmetabolism by decreasing local levels of OS and inflammation markers. Finally, NAC-treated MSG rats retained normal liver glucokinase and fructokinase activities, and Srebp1c, Fas and Gpat (lipogenic genes) expression levels. SIGNIFICANCE: Our study strongly supports that chronic oral antioxidant therapy (NAC administration) prevented the development of pre-diabetes, dyslipidemia, and inflamed-dysmetabolic liver in hypothalamic obese rats by efficiently decreasing high endogenous OS.
Asunto(s)
Acetilcisteína/uso terapéutico , Hipotálamo/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Obesidad/tratamiento farmacológico , Estado Prediabético/prevención & control , Acetilcisteína/farmacología , Animales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Hipotálamo/metabolismo , Resistencia a la Insulina/fisiología , Masculino , Obesidad/sangre , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Estado Prediabético/sangre , Ratas , Ratas Wistar , Resultado del TratamientoRESUMEN
Las mujeres embarazadas con insulino-sensibilidad disminuida están en riesgo de desarrollar trastornos hipertensivos. Utilizando el corte HOMA-IR en 2,64 la población en estudio fue dividida en dos grupos: (n=154 mujeres embarazadas), las que arrojaron un HOMA-IR basal (HOMA-0) <2,64 (no-insulinorresistentes; n=113) y aquellas con HOMA-0>2,64 (insulinorresistentes, n=41). Se analizaron: a) las concentraciones circulantes de glucosa e insulina durante una prueba de tolerancia oral a 75 g de glucosa (PTOG), y b) las relaciones entre varios parámetros de insulino-sensibilidad y la predicción del desarrollo de trastornos hipertensivos. A las mujeres embarazadas (semana 24-28) se les cuantificaron las concentraciones plasmáticas de glucosa e insulina a ambos tiempos de la PTOG. Se calcularon los valores de HOMA-IR y las relaciones glucosa a insulina (G:I) y se registraron parámetros antropométricos y resultados del embarazo. Las mujeres con HOMA-0 >2,64, aunque con glucemias en ayunas normales, mostraron mayores niveles de insulinemia y de HOMA-IR, y menores valores G:I en ambos tiempos de la PTOG. Estas mujeres embarazadas fueron las que tuvieron un mayor riesgo de desarrollar trastornos hipertensivos y mayores parámetros de morbilidad durante el período estudiado al compararlas con aquellas cuyo HOMA-0 fue <2,64.
Pregnant women with impaired insulin sensitivity are at risk for developing hypertensive disorders. By using a cut-off at 2.64 of the homeostasis model assessment (HOMA-IR) in basal condition (HOMA-0), the population under study (n=154 pregnant women) was split into two groups: 1) with basal HOMA- 0 <2.64 (non-insulin resistant; n=113) and 2) with basal HOMA-0 >2.64 (insulin resistant; n=41). Glucose and insulin circulating levels were analyzed throughout a 2-h oral 75 g glucose tolerance test (OGTT). The relationship between several parameters related to insulin resistance and the prevalence of pregnancy-induced hypertensive disorders was analyzed. Pregnant women (on week 24-28) were submitted to an OGTT, and glucose and insulin plasma concentrations were measured throughout the test. These peripheral metabolites levels and the values of the HOMA-IR and the glucose to insulin ratio (G:I) were analyzed. Anthropometric parameters and pregnancy outcome were recorded. Women with HOMA-0 >2.64 but normal fasting glycemia showed higher insulinemias, G:I values and HOMA-IR values at both times of the OGTT. The latter were at greater risk for developing late pregnancy-induced hypertension compared to women with HOMA-0 ≤2.64.
As mulheres grávidas com diminuição da sensibilidade à insulina correm o risco de desenvolver distúrbios hipertensivos. Usando o corte HOMA-IR 2,64, a população em estudo foi dividida em dois grupos: (n=154 mulheres grávidas), que deram um HOMA-IR basal (HOMA-0) ≤2,64 (não resistentes à insulina; n=113) e aquelas com HOMA-0 >2,64 (resistentes à insulina, n=41). Foram analisadas: a) as concentrações circulantes de glicose e insulina durante uma prova de tolerância oral a 75 g. de glicose (PTOG), e b) as relações entre diversos parâmetros de sensibilidade à insulina e a predição de desenvolver distúrbios de hipertensão. Foram quantificadas nas mulheres grávidas (24-28 semanas) as concentrações plasmáticas de glicose e insulina a ambos os tempos da PTOG. Valores de HOMA-IR foram calculados e as relações glicose a insulina (G:I) e se registraram parâmetros antropométricos e os resultados da gravidez. Mulheres com HOMA-0 >2,64, mas com glicemias em jejuns normais, mostraram níveis mais elevados de insulinemia e de HOMA-IR, e menores valores G:I em ambos os tempos da PTOG. Essas mulheres grávidas foram aquelas que tiveram maior risco de desenvolver distúrbios de hipertensão e maiores parâmetros de morbidade durante o período estudado em comparação com as mulheres cujo HOMA-0 foi ≤2,64.
Asunto(s)
Humanos , Femenino , Embarazo , Adulto , Glucemia , Resistencia a la Insulina , Embarazo , Hipertensión Inducida en el Embarazo , Argentina , Prevención Primaria , Antropometría , Salud Pública , Encuestas y Cuestionarios , Diabetes Gestacional , Embarazo de Alto Riesgo , Diabetes Mellitus Tipo 2 , Factor de Crecimiento Placentario , InsulinaRESUMEN
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.
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Dopamina/metabolismo , Terapia Genética/métodos , Vectores Genéticos/administración & dosificación , Hiperprolactinemia/terapia , Factor I del Crecimiento Similar a la Insulina/genética , Rejuvenecimiento , Adenoviridae/genética , Animales , Femenino , Hiperprolactinemia/genética , Hiperprolactinemia/patología , Hipotálamo/citología , Hipotálamo/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
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.
Asunto(s)
Biomarcadores/análisis , Diabetes Mellitus Tipo 2/prevención & control , Intolerancia a la Glucosa/prevención & control , Tamizaje Masivo/métodos , Estado Prediabético/prevención & control , Argentina/epidemiología , Glucemia/análisis , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Estudios de Seguimiento , Intolerancia a la Glucosa/diagnóstico , Intolerancia a la Glucosa/epidemiología , Prueba de Tolerancia a la Glucosa , Hemoglobina Glucada/análisis , Humanos , Resistencia a la Insulina , Masculino , Persona de Mediana Edad , Estado Prediabético/diagnóstico , Estado Prediabético/epidemiología , Prevención Primaria , Pronóstico , Estudios Prospectivos , Encuestas y CuestionariosRESUMEN
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.
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Tejido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Adipogénesis , Metabolismo de los Lípidos/fisiología , Adipoquinas/metabolismoRESUMEN
Se describe la relación funcional del metabolismo de las grasas y los hidratos de carbono y su interdependencia, desde los tradicionales conceptos del ciclo glucosa-ácidos grasos (Randle) y la hipótesis portal de la insulinorresistencia hasta los nuevos sobre los adipocitos marrones y beiges, con énfasis en el normal funcionamiento de un patrón endocrino cuya disfunción es clave en la fisiopatología: el eje adipoinsular, vinculado funcionalmente incluso con el hipotálamo, la hipófisis y las adrenales, que involucra 2 hormonas adipogénicas (insulina y glucocorticoide) que facilitarían el desarrollo de la grasa omental perivisceral, con fuertes consecuencias metabólicas. Se discute la ectopia o asiento de grasa en tejido magro por incapacidad del tejido adiposo para seguir atesorando grasas y la actividad endocrina del adipocito, con la producción de moléculas que influyen sobre los mecanismos productores de insulinorresistencia (leptina, adiponectina, TNF-α, resistina, etc.) y disfunción insular. Se describe la disminución de la capacidad oxidativa en la cadena respiratoria mitocondrial y el renacer del concepto de lipogénesis de novo, ambas favorecedoras del atesoramiento de grasas intracelular. En tejidos magros existen pequeñas reservas intracelulares de grasas que mantienen una regulación de funciones esenciales, aunque si aparece una sobrecarga lipídica, el fenómeno conduciría a disfunción (lipotoxicidad) y muerte celular (lipoapoptosis). La tormentosa relación entre las grasas 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 sus derivados sobre la función del islote pancreático. Sin déficit de insulina no hay diabetes.
A review is presented on a functional relationship between fat and carbohydrate metabolism and inter-dependence from the traditional concepts of glucose-fatty acids cycle (Randle), and from the insulin resistance portal hypothesis up to the new aspects on brown and beige adipocytes. Emphasis is placed on the normal function of an endocrine pattern, in which its malfunction is the key in the pathophysiology of these conditions: the adipoinsular axis, with a functional link with the hypothalamic-pituitary-adrenal axis, which involves 2 adipogenic hormones (insulin and glucocorticoid). This has an influence on the development of omental peri-visceral fat, with severe metabolic consequences. A discussion is also presented on the concept of ectopic fat on non-adipose tissues that results in the incapacity of fatty tissue for storing lipids and the considerations about the endocrine activity of adipocyte producing substances that influence several mechanisms that could result in insulin resistance (leptin, adiponectin, TNF-α, resistin, etc.). New aspects are considered regarding the decrease in the oxidative capacity in the mitochondrial respiratory chain, and the rebirth of the concept of de novo lipogenesis that increases the storing of intra-cellular fat. In non-adipose tissues there are small intra-cellular fat quantities for essential functions, but lipid overloading leads to cell dysfunction (lipo-toxicity) and death (lipo-apoptosis). The stormy relationship between fat and Langerhans' Islets goes beyond the functional effort as consequence of peripheral insulin-resistance and the pancreatic beta cell suffers a direct lipid (or derivatives) functional effect. Without insulin deficiency diabetes does not appear.
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Humanos , Diabetes Mellitus Tipo 2/fisiopatología , Metabolismo Energético/fisiología , Tejido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Adipogénesis/fisiología , Metabolismo de los Lípidos , Adipoquinas/metabolismoRESUMEN
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.
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Tejido Adiposo Blanco/fisiopatología , Trastornos Cronobiológicos/fisiopatología , Trastornos Cronobiológicos/terapia , Cronoterapia , Obesidad/fisiopatología , Obesidad/terapia , Animales , Trastornos Cronobiológicos/complicaciones , Relojes Circadianos/genética , Relojes Circadianos/fisiología , Homeostasis , Humanos , Hipotálamo/fisiopatología , Enfermedades Metabólicas/genética , Obesidad/complicaciones , Obesidad/genéticaRESUMEN
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 años. 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.
RESUMEN
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.
RESUMEN
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.
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Glucocorticoides/sangre , Grasa Intraabdominal/metabolismo , Obesidad/sangre , Adipocitos/metabolismo , Adipogénesis/fisiología , Adiposidad/fisiología , Animales , Diferenciación Celular/fisiología , Proliferación Celular/fisiología , Células Cultivadas , Corticosterona/sangre , Modelos Animales de Enfermedad , Hiperplasia/sangre , Hiperplasia/complicaciones , Hipertrofia/sangre , Hipertrofia/complicaciones , Insulina/sangre , Leptina/sangre , Masculino , Malonatos/efectos adversos , Ratas , Ratas Sprague-DawleyRESUMEN
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.
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Adipocitos/efectos de los fármacos , Fructosa/farmacología , Adipogénesis/efectos de los fármacos , Animales , Peso Corporal , Esquema de Medicación , Ingestión de Energía , Fructosa/administración & dosificación , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
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.
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Tejido Adiposo/metabolismo , Fenómenos Fisiológicos Nutricionales de los Animales , Carbohidratos de la Dieta/toxicidad , Fructosa/toxicidad , Desnutrición/etiología , Fenómenos Fisiologicos Nutricionales Maternos , Síndrome Metabólico/etiología , Efectos Tardíos de la Exposición Prenatal , Tejido Adiposo/fisiopatología , Adiposidad , Factores de Edad , Animales , Biomarcadores/sangre , Glucemia/metabolismo , Ingestión de Energía , Femenino , Leptina/sangre , Masculino , Desnutrición/sangre , Desnutrición/fisiopatología , Síndrome Metabólico/sangre , Síndrome Metabólico/fisiopatología , Fenotipo , Embarazo , Ratas Sprague-Dawley , Factores Sexuales , Aumento de PesoRESUMEN
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 (5day-old) testosterone propionate (TP; s.c. 1.25mg/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.