RESUMEN

High-fat diet (HFD)-induced obesity is associated with increased cancer risk. Long-term feeding with HFD increases the concentration of the saturated fatty acid palmitic acid (PA) in the hypothalamus. We previously showed that, in hypothalamic neuronal cells, exposure to PA inhibits the autophagic flux, which is the whole autophagic process from the synthesis of the autophagosomes, up to their lysosomal fusion and degradation. However, the mechanism by which PA impairs autophagy in hypothalamic neurons remains unknown. Here, we show that PA-mediated reduction of the autophagic flux is not caused by lysosomal dysfunction, as PA treatment does not impair lysosomal pH or the activity of cathepsin B.Instead, PA dysregulates autophagy by reducing autophagosome-lysosome fusion, which correlates with the swelling of endolysosomal compartments that show areduction in their dynamics. Finally, because lysosomes undergo constant dynamic regulation by the small Rab7 GTPase, we investigated the effect of PA treatment on its activity. Interestingly, we found PA treatment altered the activity of Rab7. Altogether, these results unveil the cellular process by which PA exposure impairs the autophagic flux. As impaired autophagy in hypothalamic neurons promotes obesity, and balanced autophagy is required to inhibit malignant transformation, this could affect tumor initiation, progression, and/or response to therapy of obesity-related cancers.

RESUMEN

In patients with advanced-stage chronic kidney disease (CKD), progressive kidney function decline leads to increased risk for hyperkalemia (serum potassium > 5.0 or >5.5 mEq/L). Medications such as renin-angiotensin-aldosterone system inhibitors pose an additional hyperkalemia risk, especially in patients with CKD. When hyperkalemia develops, clinicians often recommend a diet that is lower in potassium content. This review discusses the barriers to adherence to a low-potassium diet and the impact of dietary restrictions on adverse clinical outcomes. Accumulating evidence indicates that a diet that incorporates potassium-rich foods has multiple health benefits, which may also be attributable to the other vitamin, mineral, and fiber content of potassium-rich foods. These benefits include blood pressure reductions and reduced risks for cardiovascular disease and stroke. High-potassium foods may also prevent CKD progression and reduce mortality risk in patients with CKD. Adjunctive treatment with the newer potassium-binding agents, patiromer and sodium zirconium cyclosilicate, may allow for optimal renin-angiotensin-aldosterone system inhibitor therapy in patients with CKD and hyperkalemia, potentially making it possible for patients with CKD and hyperkalemia to liberalize their diet. This may allow them the health benefits of a high-potassium diet without the increased risk for hyperkalemia, although further studies are needed.

RESUMEN

The ability of adipose tissue to expand is dependent on adipocyte differentiation and adipose tissue glucose disposal. The CCAAT/enhancer-binding protein alpha (CEBPA) enhances the expression of the Slc2a4 gene and GLUT4 protein, which are markers of adipocyte differentiation/glucose disposal. We hypothesized estradiol (E2) facilitates adipocyte differentiation/glucose disposal by an estrogen receptor 1 (ESR1)-dependent and CEBPA-mediated mechanism. Our results suggest that E2 (10 nM) has a positive effect on 3T3-L1 adipocyte differentiation (days 2-8), lipid accumulation, Slc2a4 and Cebpa mRNA expression, total GLUT4 and nuclear CEBPA contents, and CEBP/Slc2a4-binding activity. Esr1 silencing (∼50%) in mature adipocytes abrogates the 24-h E2 effects on nuclear CEBPA content, Slc2a4/GLUT4 expression and GLUT4 translocation to the cell membrane. Thus, E2 stimulates adipocyte differentiation and Slc2a4/GLUT4 expression in an ESR1/CEBPA-mediated pathway. Our data provide mechanistic insight demonstrating E2 participates in adipose-tissue differentiation and glucose transporter expression which ultimately can improve adipose tissue expandability and glycemic control.

Asunto(s)

Adipocitos/citología , Adipogénesis/efectos de los fármacos , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Estradiol/farmacología , Receptor alfa de Estrógeno/fisiología , Regulación de la Expresión Génica/efectos de los fármacos , Transportador de Glucosa de Tipo 4/metabolismo , Células 3T3-L1 , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Animales , Proteínas Potenciadoras de Unión a CCAAT/genética , Diferenciación Celular , Estrógenos/farmacología , Femenino , Transportador de Glucosa de Tipo 4/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Regiones Promotoras Genéticas

RESUMEN

Estrogens and their receptors play key roles in regulating body weight, energy expenditure, and metabolic homeostasis. It is known that lack of estrogens promotes increased food intake and induces the expansion of adipose tissues, for which much is known. An area of estrogenic research that has received less attention is the role of estrogens and their receptors in influencing intermediary lipid metabolism in organs such as the brain. In this review, we highlight the actions of estrogens and their receptors in regulating their impact on modulating fatty acid content, utilization, and oxidation through their direct impact on intracellular signaling cascades within the central nervous system.

Asunto(s)

Química Encefálica/fisiología , Receptor alfa de Estrógeno/fisiología , Estrógenos/fisiología , Metabolismo de los Lípidos/fisiología , Animales , Química Encefálica/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/fisiología , Receptor alfa de Estrógeno/efectos de los fármacos , Receptor alfa de Estrógeno/metabolismo , Estrógenos/farmacología , Humanos , Metabolismo de los Lípidos/efectos de los fármacos

RESUMEN

Low levels of estrogens are associated with obesity-related comorbidities. Mice with lower levels of estrogens are thereby more sensitive to the effects of a high-fat-diet (HFD) for the development of glucose intolerance and insulin resistance. Studies in vivo have demonstrated that taurine (TAU) supplementation prevents glucose and insulin resistance. Thus, we aimed to investigate the potential beneficial effects of TAU supplementation on glucose homeostasis of mice with low levels of estrogens fed with a HFD. 3-month-old female C57BL/6J mice underwent bilateral ovariectomy (OVX). After 1 week of recovery, mice were divided into 4 groups and either received: a standard chow diet (OVXC), chow diet plus drinking water enriched with 3% of TAU (OVXCT), HFD (OVXH), and HFD plus supplementation of TAU (OVXHT) for 14 weeks. Exposure to the HFD increased adiposity and plasma levels of glucose and insulin. Contrary to our prediction, the addition of TAU enhanced the deleterious effects of the HFD. Glucose and insulin tolerance tests (ipGTT and ipITT) indicated that mice maintained on the HFD + TAU had worse glucose intolerance and insulin resistance that was linked to lower insulin signaling in skeletal muscle and liver. Insulin secretion of isolated pancreatic islets of OVXH mice was higher than OVXC, and the addition of TAU associated with a HFD did not modulate insulin secretion, suggesting a failure of pancreatic ß cells of OVXHT mice. These results suggest that despite the beneficial reports of TAU, it should be used cautiously in situations where the levels of estrogens are low.

Asunto(s)

Suplementos Dietéticos , Glucosa/metabolismo , Obesidad/tratamiento farmacológico , Taurina/administración & dosificación , Animales , Glucemia/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Estrógenos/metabolismo , Homeostasis , Humanos , Insulina/metabolismo , Resistencia a la Insulina/genética , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/patología , Ratones , Obesidad/genética , Obesidad/metabolismo , Obesidad/patología , Ovariectomía

RESUMEN

Cardiovascular disease (CVD) is one of the leading causes of mortality in developed countries. The incidence of CVD is sexually dimorphic, and research has focused on the contribution of sex steroids to the development and progression of the cardiometabolic syndrome, which is defined as a clustering of interrelated risk factors that promote the development of atherosclerosis (which can lead to CVD) and type 2 diabetes mellitus. Data are inconclusive as to how sex steroids and their respective receptors increase or suppress the risk of developing the cardiometabolic syndrome and thus CVD. In this Review, we discuss the potential role, or roles, of sex hormones in cardiometabolic health by first focusing on the influence of oestrogens and their receptors on the risk of developing cardiometabolic syndrome and CVD. We also highlight what is known about testosterone and its potential role in protecting against the development of the cardiometabolic syndrome and CVD. Given the inconclusive nature of the data regarding the direct effects of each sex hormone, we advocate and highlight the importance of studying the relative levels and the ratio of sex hormones to each other, as well as the use of cross sex hormone therapy and its effect on cardiometabolic health.

Asunto(s)

Enfermedades Cardiovasculares , Estrógenos/fisiología , Enfermedades Metabólicas , Receptores de Estrógenos/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/fisiopatología , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/fisiopatología , Estrógenos/análisis , Femenino , Hormonas Esteroides Gonadales/análisis , Hormonas Esteroides Gonadales/fisiología , Corazón/fisiopatología , Humanos , Masculino , Enfermedades Metabólicas/epidemiología , Enfermedades Metabólicas/fisiopatología , Persona de Mediana Edad , Polimorfismo Genético , Premenopausia , Receptores de Estrógenos/genética , Factores de Riesgo , Factores Sexuales , Testosterona/análisis , Testosterona/fisiología

RESUMEN

In this Essay, we discuss the critical need to incorporate sex and gender in pre-clinical and clinical research to enhance our understanding of the mechanisms by which metabolic processes differ by sex and gender. This knowledge will allow for development of personalized medicine which will optimize therapies specific for individuals.

Asunto(s)

Caracteres Sexuales , Evolución Biológica , Enfermedad , Femenino , Hormonas , Humanos , Masculino , Factores de Riesgo , Factores Sexuales

RESUMEN

Menopause-related withdrawal of ovarian estrogens is associated with reduced energy metabolism and overall impairment of substrate oxidation. Estradiol's withdrawal after menopause is associated with a reduction in energy metabolism and impaired substrate oxidation, which contributes to weight gain and visceral fat accumulation. Here we aimed to investigate the association between plasma estradiol concentrations and energy expenditure (EE)/substrate oxidation in a group of overweight postmenopausal women before and after a fatty meal challenge. Women were divided into three groups according to their plasma estradiol concentrations (E2): group 1 - E2 ≤ 39, group 2 - 40 ≤ E2 ≤ 59, and group 3 - E2 ≥ 60 pg/mL. VO2 and VCO2 volumes were collected following indirect calorimetry 5 h following a single lipid overload meal (1100 kcal, 72% of fat). For comparisons between groups and within the same group, a linear regression model with mixed effects was applied (P < 0.05). Forty-four women aged 55 ± 0.7 years-old, 8 ± 1.1 years following menopause, with a BMI of 30.5 ± 0.5 kg/m2, and 41.9 ± 0.7% of body fat were enrolled the study. Plasma E2 concentrations were: group 1 - 30.4 ± 1.9, group 2 - 46.9 ± 1.5, and group 3 - 91.3 ± 12.0 pg/mL (P < 0.0001). EE at baseline and in the resting state was 1320 ± 24.3 kcal/d, and increased to 1440 ± 27.0 kcal/d 30 min following ingestion of the fatty meal (P < 0.0001), and rose again to an average of 1475 ± 30.3 kcal/d at the completion of experiment (P < 0.0001). Carbohydrate oxidation (Chox) was 0.155 ± 0.01 g/min at resting, maintained as 0.133 ± 0.00 g/min 30 min after ingestion of the fatty meal, and was 0.123 ± 0.01 g/min at the end of the testing period. Lipid oxidation (Lipox) was 0.041 ± 0.003 g/min at resting, increasing to 0.054 ± 0.003 g/min at 30 min (P = 0.01), and reaching 0.063 ± 0.003 g/min at the end of the experiment (P < 0.0001). There was no difference between groups for EE, Chox or Lipox. Our data suggest that EE and substrate oxidation were modulated following a lipid-meal challenge equally in all groups and this did not differ with plasma E2 concentrations.

Asunto(s)

Metabolismo Energético/fisiología , Estradiol/sangre , Metabolismo de los Lípidos , Comidas , Obesidad/metabolismo , Posmenopausia , Composición Corporal , Índice de Masa Corporal , Calorimetría Indirecta/métodos , Metabolismo de los Hidratos de Carbono , Niño , Grasas de la Dieta/administración & dosificación , Grasas de la Dieta/metabolismo , Ingestión de Alimentos , Estrógenos , Femenino , Humanos , Grasa Intraabdominal/metabolismo , Menopausia , Persona de Mediana Edad , Oxidación-Reducción , Periodo Posprandial

RESUMEN

High-fat diets (HFDs) lead to obesity and inflammation in the central nervous system (CNS). Estrogens and estrogen receptor α (ERα) protect premenopausal females from the metabolic complications of inflammation and obesity-related disease. Here, we demonstrate that hypothalamic PGC-1α regulates ERα and inflammation in vivo. HFD significantly increased palmitic acid (PA) and sphingolipids in the CNS of male mice when compared to female mice. PA, in vitro, and HFD, in vivo, reduced PGC-1α and ERα in hypothalamic neurons and astrocytes of male mice and promoted inflammation. PGC-1α depletion with ERα overexpression significantly inhibited PA-induced inflammation, confirming that ERα is a critical determinant of the anti-inflammatory response. Physiologic relevance of ERα-regulated inflammation was demonstrated by reduced myocardial function in male, but not female, mice following chronic HFD exposure. Our findings show that HFD/PA reduces PGC-1α and ERα, promoting inflammation and decrements in myocardial function in a sex-specific way.

Asunto(s)

Dieta Alta en Grasa/efectos adversos , Receptor alfa de Estrógeno/metabolismo , Hipotálamo/metabolismo , Factores de Transcripción/metabolismo , Animales , Astrocitos/metabolismo , Línea Celular , Receptor alfa de Estrógeno/genética , Femenino , Hipotálamo/citología , Hipotálamo/efectos de los fármacos , Inflamación/etiología , Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/metabolismo , Ácido Palmítico/efectos adversos , Ácido Palmítico/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Factores Sexuales , Esfingolípidos/metabolismo , Factores de Transcripción/genética , Disfunción Ventricular/etiología , Disfunción Ventricular/metabolismo

RESUMEN

We show that chronic high fat diet (HFD) feeding affects the hypothalamus of male but not female mice. In our study we demonstrate that palmitic acid and sphingolipids accumulate in the central nervous system of HFD-fed males. Additionally, we show that HFD-feeding reduces proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) thus reducing estrogen receptor α (ERα) and driving hypothalamic inflammation in male but not female mice. Hypothalamic inflammation correlates with markers of metabolic dysregulation as indicated by dysregulation in glucose intolerance and myocardial function. Lastly, we demonstrate that there are blockages in mitophagy and lipophagy in hypothalamic tissues in males. Our data suggest there is a sexually dimorphic response to chronic HDF exposure, females; despite gaining the same amount of body weight following HFD-feeding, appear to be protected from the adverse metabolic effects of the HFD.