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With the increased prevalence of obesity and related co-morbidities, such as type 2 diabetes (T2D), worldwide, improvements in pharmacological treatments are necessary. The brain- and peripheral-cannabinoid receptor 1 (CB1R) antagonist rimonabant (RIM) has been shown to induce weight loss and improve glucose homeostasis. We have previously demonstrated that RIM promotes adipose tissue beiging and decreased adipocyte cell size, even during maintenance on a high-fat diet. Given the adverse side-effects of brain-penetrance with RIM, in this study we aimed to determine the site of action for a non-brain-penetrating CB1R antagonist AM6545. By using in vitro assays, we demonstrated the direct effects of this non-brain-penetrating CB1R antagonist on cultured adipocytes. Specifically, we showed, for the first time, that AM6545 significantly increases markers of adipose tissue beiging, mitochondrial biogenesis, and lipolysis in 3T3-L1 adipocytes. In addition, the oxygen consumption rate (OCR), consisting of baseline respiratory rate, proton leak, maximal respiratory capacity, and ATP synthase activity, was greater for cells exposed to AM6545, demonstrating greater mitochondrial uncoupling. Using a lipolysis inhibitor during real-time OCR measurements, we determined that the impact of CB1R antagonism on adipocytes is driven by increased lipolysis. Thus, our data suggest the direct role of CB1R antagonism on adipocytes does not require brain penetrance, supporting the importance of focus on peripheral CB1R antagonism pharmacology for reducing the incidence of obesity and T2D.
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Adipocitos/efectos de los fármacos , Lipólisis/efectos de los fármacos , Morfolinas/farmacología , Consumo de Oxígeno/efectos de los fármacos , Pirazoles/farmacología , Receptor Cannabinoide CB1/antagonistas & inhibidores , Células 3T3 , Animales , Evaluación Preclínica de Medicamentos , Ratones , Mitocondrias/efectos de los fármacos , Morfolinas/uso terapéutico , Obesidad/tratamiento farmacológico , Pirazoles/uso terapéuticoRESUMEN
Obesity increases the risks of developing cardiovascular and metabolic diseases and degrades quality of life, ultimately increasing the risk of death. However, not all forms of obesity are equally dangerous: some individuals, despite higher percentages of body fat, are at less risk for certain chronic obesity-related complications. Many open questions remain about why this occurs. Data suggest that the physical location of fat and the overall health of fat dramatically influence disease risk; for example, higher concentrations of visceral relative to subcutaneous adipose tissue are associated with greater metabolic risks. As such, understanding the determinants of the location and health of adipose tissue can provide insight about the pathological consequences of obesity and can begin to outline targets for novel therapeutic approaches to combat the obesity epidemic. Although age and sex hormones clearly play roles in fat distribution and location, much remains unknown about gene regulation at the level of adipose tissue or how genetic variants regulate fat distribution. In this review, we discuss what is known about the determinants of body fat distribution, and we highlight the important roles of sex hormones, aging, and genetic variation in the determination of body fat distribution and its contribution to obesity-related comorbidities.
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Tejido Adiposo/patología , Salud , Obesidad/patología , Variación Genética , Hormonas Esteroides Gonadales/metabolismo , Humanos , Obesidad/epidemiología , Obesidad/genética , Obesidad/metabolismo , RiesgoRESUMEN
Most preclinical and clinical, animal, and human research has been biased with respect to sex and even more so with respect to gender. In fact, little is known about the impact of sex and even less about the influence of gender on overall metabolic processes. The National Institutes of Health has recognized this gap in scientific knowledge and now mandates that studies be conducted in both sexes and to include gender as variables influencing physiological processes such as metabolism. It is therefore critical to understand and appreciate how to incorporate sex and gender in preclinical and clinical research in order to enhance our understanding of the mechanisms by which metabolic processes differ by sex and gender. In this chapter, we define sex and gender and discuss when sex and gender are not aligned, such as that which occurs in transgender individuals, and how this impacts metabolic processes. We discuss the importance of understanding the influence and interactions between sex hormones and sex chromosomes rather than focusing on their relative contributions to metabolism in isolation. This knowledge will optimize therapies specific for individuals which need to encompass sex and gender.
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Metabolismo Energético/efectos de los fármacos , Terapia de Reemplazo de Hormonas/métodos , Personas Transgénero , Transexualidad/tratamiento farmacológico , Femenino , Identidad de Género , Disparidades en el Estado de Salud , Terapia de Reemplazo de Hormonas/efectos adversos , Humanos , Masculino , Factores de Riesgo , Caracteres Sexuales , Cromosomas Sexuales , Factores Sexuales , Personas Transgénero/psicología , Transexualidad/metabolismo , Transexualidad/fisiopatología , Transexualidad/psicología , Resultado del TratamientoRESUMEN
Maternal nutrition has a profound long-term impact on infant health. Poor maternal nutrition influences placental development and fetal growth, resulting in low birth weight, which is strongly associated with the risk of developing chronic diseases, including heart disease, hypertension, asthma, and type 2 diabetes, later in life. Few studies have delineated the mechanisms by which maternal nutrition affects fetal lung development. Here, we report that maternal exposure to a diet high in fat (HFD) causes placental inflammation, resulting in placental insufficiency, fetal growth restriction (FGR), and inhibition of fetal lung development. Notably, pre- and postnatal exposure to maternal HFD also results in persistent alveolar simplification in the postnatal period. Our novel findings provide a strong association between maternal diet and fetal lung development.
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Dieta Alta en Grasa/efectos adversos , Retardo del Crecimiento Fetal/etiología , Pulmón/embriología , Animales , Glucemia , Femenino , Retardo del Crecimiento Fetal/sangre , Inflamación/metabolismo , Insulina/sangre , Pulmón/crecimiento & desarrollo , Pulmón/patología , Masculino , Ratones Endogámicos C57BL , Placenta/inmunología , Embarazo , Aumento de PesoRESUMEN
Obesity and its associated co-morbidities are worldwide public health concerns. Obesity is characterized by excessive adipose tissue accumulation; however, it is important to recognize that human and rodent adipose tissues are made up of several distinct adipose tissue sub-types. White adipose tissue (WAT) is considered the prototypical fat cell, due to its capacity and capability to store large amounts of lipid. In contrast, brown adipose tissue (BAT) oxidizes substrates to generate heat. BAT contains more mitochondria than WAT and express uncoupling protein-1 (UCP1), which mediates BAT thermogenesis. A third sub-type of adipose tissue, Brown-in-white (BRITE)/beige adipocytes arise from WAT upon adrenergic stimulation and resembles BAT functionally. The energy burning feature of BAT/beige cells, combined with evidence of an inverse-correlation between BAT/beige adipose tissue and obesity have given rise to the hypothesis that obesity may be linked to BAT/beige 'malfunction'. Females have more BAT and perhaps an enhanced capacity to beige their adipose tissue when compared to males. Multiple signal pathways are capable of activating BAT thermogenesis and beiging of WAT; here, we discuss the potential role of estrogens in enhancing and mediating these factors to enhance adipose tissue thermogenesis.
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Tejido Adiposo Pardo/fisiología , Tejido Adiposo Blanco/efectos de los fármacos , Estrógenos/metabolismo , Estrógenos/farmacología , Tejido Adiposo Pardo/diagnóstico por imagen , Tejido Adiposo Blanco/diagnóstico por imagen , Animales , Proteínas Morfogenéticas Óseas/metabolismo , Frío , Humanos , Leptina/metabolismo , Neuroimagen , Termogénesis/fisiologíaRESUMEN
Cell culture has enhanced our understanding of cellular physiology and constitutes an important tool in advancing mechanistic insight. Researchers should be reminded, however, that there are limitations in extrapolating data derived from cultured cells to questions focusing on the impact of sex. In this Opinion, we highlight two underappreciated aspects of cell culture systems regarding sex: how cell culture media alters the sex hormone environment, and how the innate sex of the cell is often not factored into the overall analysis. By paying careful attention to these areas, researchers can facilitate reproducibility of their cell culture models, which is consistent with the mandate from the National Institutes of Health to improve scientific rigor and reproducibility in research.
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Células Cultivadas/fisiología , Medios de Cultivo/química , Hormonas Esteroides Gonadales/síntesis química , Animales , Investigación Biomédica/métodos , Técnicas de Cultivo , Humanos , Factores SexualesRESUMEN
OBJECTIVES: Brown adipose tissue (BAT) and BAT-like adipose tissues, referred to as 'beige' adipose tissues uncouple respiration from ATP synthesis via uncoupling protein one (UCP-1). There is a sexual dimorphism with respect to beige and BAT tissues; pre-menopausal women have more BAT and are more sensitive to BAT activation than men or postmenopausal women. We hypothesized selective activation of adipose tissue estrogen receptor alpha (ERα) induces beiging of WAT through induction of lipolysis mediated by adipose tissue triglyceride lipase (ATGL). METHODS: 3T3-L1 and primary adipocytes were treated with the selective ERα agonist pyrazole triol (PPT), and selection deletion of ERα (using siRNA) was used to determine if selective ERα activation, or inhibition, influences the adipose tissue expression of genes associated with beiging. In a second series of experiments, ERα was selectively added back to adipose tissue of mice lacking total body ERα (ERKO) to determine if add back of ERα changed the morphology of adipose tissue to resemble beige tissues. Additionally, WT and ERKO mice were exposed to cold and FDG labeled glucose uptake was measured to determine the ability of cold to induce UCP-1 in ERKO mice. To begin to mechanistically probe how activation of ERα facilitates beiging, we tested the influence of PPT to activate the lipolytic pathway through ATGL. Finally, since ERα exerts its effects both at the genomic and non-genomic level depending on its cellular location, we determined in vivo if beiging occurs in mice expressing ERα only at the plasma membrane (MOER mice) or only at nucleus (NOER mice). RESULTS: Selective ERα activation by PPT increased markers of beiging in vitro in 3T3-L1 and primary adipocytes, whereas, knockdown of ERα with siRNA reduced the ability of PPT to induce beiging in vitro. ERα add back to the adipose tissue of ERKO mice resulted in multilocular adipose tissue resembling a beige phenotype. Following cold exposure, FDG labeled glucose in BAT tissues of ERKO mice was reduced when compared to weight-matched controls. Glycerol release and ATGL expression were increased after PPT treatment, while pre-treatment with the ATGL inhibitor prevented PPT's ability to increase UCP-1 expression. Finally, MOER mice were more sensitive to beiging of adipose tissues when compared to NOER mice. CONCLUSION: Our results demonstrate for the first time that selective-activation of ERα in adipocytes increases markers of beiging and this is likely through induction of AMPK and ATGL-mediated lipolysis providing FFAs as a fuel to activate UCP-1.
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Adipocitos Beige/metabolismo , Adipocitos Blancos/metabolismo , Receptor alfa de Estrógeno/agonistas , Células 3T3 , Quinasas de la Proteína-Quinasa Activada por el AMP , Adipocitos Beige/efectos de los fármacos , Adipocitos Blancos/efectos de los fármacos , Animales , Células Cultivadas , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Femenino , Glucosa/metabolismo , Lipasa/metabolismo , Lipólisis , Ratones , Ratones Endogámicos C57BL , Fenoles/farmacología , Proteínas Quinasas/metabolismo , Pirazoles/farmacología , Proteína Desacopladora 1/metabolismoRESUMEN
The influence of sex on cellular function and metabolism is often ill defined in many human and animal studies. The National Institute of Health (NIH) recognized this gap in scientific knowledge and mandated that sex be factored into the design and data analysis of all cell culture and animal studies. Therefore, it is critical to understand how to incorporate sex in pre-clinical and clinical research. Here, we discuss how the sexual identify of cells influences experimental responses in cell culture and we highlight the importance of the culture media and its constituents to the function of cells. We further discuss the importance of understanding the influence and interactions between sex hormones and sex chromosomes. A deeper understanding of how sex chromosomes and sex hormones function as variables in complex biological systems may lead to better, more personalized medical therapies.
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Hormonas Esteroides Gonadales/metabolismo , Caracteres Sexuales , Cromosomas Sexuales/genética , Factores Sexuales , Animales , Investigación Biomédica/tendencias , Hormonas Esteroides Gonadales/genética , Humanos , National Institutes of Health (U.S.) , Factores de Riesgo , Estados UnidosRESUMEN
BACKGROUND: 17 Alpha-estradiol (17 α-E2) is a natural, non-feminizing stereoisomer of 17 beta-estradiol (17 ß-E2). Whereas much is known about the physiological effects of 17 ß-E2, much less is known about 17 α-E2. For example, 17 ß-E2 exerts anti-inflammatory effects in neurons and adipocytes through binding and activation of estrogen receptor alpha (ERα); however, if 17 α-E2 has similar effects on inflammation is currently unknown. METHODS: To begin to address this, we analyzed the ability of 17 α-E2 and 17 ß-E2 to suppress lipopolysaccharide (LPS)-induced inflammation in vitro using embryonic fibroblast cells (MEF) from wild type and total body ERα (ERKO) male and female mice. Additionally, we further probed if there were sex differences with respect to the effects of E2s using primary pre-adipocyte cells from C57BL/6J male and female mice. Also, we probed mechanistically the effects of E2s in fully differentiated 3T3-L1 cells. RESULTS: Both E2s decreased LPS-induced markers of inflammation Tnf-α and Il-6, and increased the anti-inflammatory markers Il-4 and IL-6 receptor (Il-6ra) in MEF cells. To begin to understand the mechanisms by which both E2's mediate their anti-inflammatory effects, we probed the role of ERα using two methods. First, we used MEF cells from ERKO mice and found reductions in ERα diminished the ability of 17 α-E2 to suppress Tnf-α in female but not in male cells, demonstrating a sexual dimorphism in regard to the role of ERα to mediate 17 α-E2's effects. Second, we selectively reduced the expression of ERα in 3T3-L1 cells using siRNA and found reductions in ERα diminished the ability of both E2s to suppress Tnf-α and Il-6 expression. Lastly, to determine the mechanisms by which E2s reduce inflammation, we explored the role of NFκB-p65 and found both E2s decreased NFκB-p65 expression. CONCLUSIONS: In conclusion, we demonstrate for the first time that 17 α-E2, as well as 17 ß-E2, suppresses inflammation through their effects on ERα and NFκB-p65.
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Antiinflamatorios no Esteroideos/farmacología , Estradiol/farmacología , Inflamación/tratamiento farmacológico , Células 3T3-L1 , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Animales , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Inflamación/metabolismo , Lipopolisacáridos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Caracteres Sexuales , Factor de Transcripción ReIA/metabolismoRESUMEN
Aging is associated with visceral adiposity, metabolic disorders, and chronic low-grade inflammation. 17α-estradiol (17α-E2), a naturally occurring enantiomer of 17ß-estradiol (17ß-E2), extends life span in male mice through unresolved mechanisms. We tested whether 17α-E2 could alleviate age-related metabolic dysfunction and inflammation. 17α-E2 reduced body mass, visceral adiposity, and ectopic lipid deposition without decreasing lean mass. These declines were associated with reductions in energy intake due to the activation of hypothalamic anorexigenic pathways and direct effects of 17α-E2 on nutrient-sensing pathways in visceral adipose tissue. 17α-E2 did not alter energy expenditure or excretion. Fasting glucose, insulin, and glycosylated hemoglobin were also reduced by 17α-E2, and hyperinsulinemic-euglycemic clamps revealed improvements in peripheral glucose disposal and hepatic glucose production. Inflammatory mediators in visceral adipose tissue and the circulation were reduced by 17α-E2. 17α-E2 increased AMPKα and reduced mTOR complex 1 activity in visceral adipose tissue but not in liver or quadriceps muscle, which is in contrast to the generalized systemic effects of caloric restriction. These beneficial phenotypic changes occurred in the absence of feminization or cardiac dysfunction, two commonly observed deleterious effects of exogenous estrogen administration. Thus, 17α-E2 holds potential as a novel therapeutic for alleviating age-related metabolic dysfunction through tissue-specific effects.
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Adiposidad/efectos de los fármacos , Envejecimiento/fisiología , Estradiol/farmacología , Estrógenos/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Animales , Índice de Masa Corporal , Feminización , Grasa Intraabdominal/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
In women, obesity is associated with decrements in reproductive health that are improved with weight loss. Due to the difficulty of maintaining weight loss through lifestyle interventions, surgical interventions have become popular treatments for obesity. We examined how weight loss induced by Roux-en Y gastric bypass surgery (RYGB) or calorie restriction impacted expression of hypothalamic genes related to energy intake and reproduction. RYGB and calorie restriction induced equivalent weight loss; however, expression of the anorexigenic melanocortin pathway decreased only in calorie restricted mice. Serum estradiol concentrations were lower in calorie restricted mice relative to RYGB during proestrous, suggesting that RYGB maintained normal estrous cycling. Thus, the effects of RYGB for female mice, and possibly humans, extend beyond weight loss to include enhanced reproductive health.
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Restricción Calórica , Derivación Gástrica , Obesidad/terapia , Animales , Modelos Animales de Enfermedad , Estradiol/sangre , Femenino , Ratones , Ratones Endogámicos , Ratones Obesos , Obesidad/sangre , Obesidad/complicaciones , Obesidad/cirugía , Embarazo/fisiología , Fenómenos Fisiológicos Reproductivos , Pérdida de Peso/fisiologíaRESUMEN
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.
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Caracteres Sexuales , Evolución Biológica , Enfermedad , Femenino , Hormonas , Humanos , Masculino , Factores de Riesgo , Factores SexualesRESUMEN
OBJECTIVE: Roux-en-Y gastric bypass (RYGB) is an effective method of weight loss and remediation of type-2 diabetes; however, the mechanisms leading to these improvements are unclear. Additionally, adipocytes within white adipose tissue (WAT) depots can manifest characteristics of brown adipocytes. These 'BRITE/beige' adipocytes express uncoupling protein 1 (UCP1) and are associated with improvements in glucose homeostasis and protection from obesity. Interestingly, atrial and B-type natriuretic peptides (NPs) promote BRITE/beige adipocyte enrichment of WAT depots, an effect known as "browning." Here, we investigate the effect of RYGB surgery on NP, NP receptors, and browning in the gonadal adipose tissues of female mice. We propose that such changes may lead to improvements in metabolic homeostasis commonly observed following RYGB. METHODS: Wild type, female, C57/Bl6 mice were fed a 60% fat diet ad libitum for six months. Mice were divided into three groups: Sham operated (SO), Roux-en-Y gastric bypass (RYGB), and Weight matched, sham operated (WM-SO). Mice were sacrificed six weeks following surgery and evaluated for differences in body weight, glucose homeostasis, adipocyte morphology, and adipose tissue gene expression. RESULTS: RYGB and calorie restriction induced similar weight loss and improved glucose metabolism without decreasing food intake. ß3-adrenergic receptor expression increased in gonadal adipose tissue, in addition to Nppb (BNP), and NP receptors, Npr1, and Npr2. The ratio of Npr1:Npr3 and Npr2:Npr3 increased in RYGB, but not WM-SO groups. Ucp1 protein and mRNA, as well as additional markers of BRITE/beige adipose tissue and lipolytic genes increased in RYGB mice to a greater extent than calorie-restricted mice. CONCLUSIONS: Upregulation of Nppb, Npr1, Npr2, and ß3-adrenergic receptors in gonadal adipose tissue following RYGB was associated with increased markers of browning. This browning of gonadal adipose tissue may underpin the positive effect of RYGB on metabolic parameters and may in part be mediated through upregulation of natriuretic peptides.
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Hypoxia Inducible Factor 1 (HIF-1) promotes fibrosis and inflammation in adipose tissues, while estrogens and Estrogen Receptor α (ERα) have the opposite effect. Here we identify an Estrogen Response Element (ERE) in the promoter of Phd3, which is a negative regulatory enzyme of HIF-1, and we demonstrate HIF-1α is ubiquitinated following 17-ß estradiol (E2)/ERα mediated Phd3 transcription. Manipulating ERα in vivo increases Phd3 transcription and reduces HIF-1 activity, while addition of PHD3 ameliorates adipose tissue fibrosis and inflammation. Our findings outline a novel regulatory relationship between E2/ERα, PHD3 and HIF-1 in adipose tissues, providing a mechanistic explanation for the protective effect of E2/ERα in adipose tissue.