RESUMEN
The renin-angiotensin system (RAS) is an endocrine system composed of two main axes: the classical and the counterregulatory, very often displaying opposing effects. The classical axis, primarily mediated by angiotensin receptors type 1 (AT1R), is linked to obesity-associated metabolic effects. On the other hand, the counterregulatory axis appears to exert antiobesity effects through the activation of two receptors, the G protein-coupled receptor (MasR) and Mas-related receptor type D (MrgD). The local RAS in adipose organ has prompted extensive research into white adipose tissue and brown adipose tissue (BAT), with a key role in regulating the cellular and metabolic plasticity of these tissues. The MasR activation favors the brown plasticity signature in the adipose organ by improve the thermogenesis, adipogenesis, and lipolysis, decrease the inflammatory state, and overall energy homeostasis. The MrgD metabolic effects are related to the maintenance of BAT functionality, but the signaling remains unexplored. This review provides a summary of RAS counterregulatory actions triggered by Mas and MrgD receptors on adipose tissue plasticity. Focus on the effects related to the morphology and function of adipose tissue, especially from animal studies, will be given targeting new avenues for treatment of obesity-associated metabolic effects.
Asunto(s)
Tejido Adiposo , Proto-Oncogenes Mas , Receptores Acoplados a Proteínas G , Sistema Renina-Angiotensina , Animales , Humanos , Tejido Adiposo/metabolismo , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Metabolismo Energético , Obesidad/metabolismo , Obesidad/patología , Receptores Acoplados a Proteínas G/metabolismo , Sistema Renina-Angiotensina/fisiología , Transducción de SeñalRESUMEN
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.
Asunto(s)
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
Obesity is a chronic condition of multifactorial etiology characterized by excessive body fat due to a calorie intake higher than energy expenditure. Given the intrinsic limitations of surgical interventions and the difficulties associated with lifestyle changes, pharmacological manipulation is currently one of the main therapies for metabolic diseases. Approaches aiming to promote energy expenditure through induction of thermogenesis have been explored and, in this context, brown adipose tissue (BAT) activation and browning have been shown to be promising strategies. Although such processes are physiologically stimulated by the sympathetic nervous system, not all situations that are known to increase adrenergic signaling promote a concomitant increase in BAT activation or browning in humans. Thus, a better understanding of factors involved in the thermogenesis attributed to these tissues is needed to enable the development of future therapies against obesity. Herein we carry out a critical review of original articles in humans under conditions previously known to trigger adrenergic responses-namely, cold, catecholamine-secreting tumor (pheochromocytoma and paraganglioma), burn injury, and adrenergic agonists-and discuss which of them are associated with increased BAT activation and browning. BAT is clearly stimulated in individuals exposed to cold or treated with high doses of the ß3-adrenergic agonist mirabegron, whereas browning is certainly induced in patients after burn injury or with pheochromocytoma, as well as in individuals treated with ß3-adrenergic agonist mirabegron for at least 10 weeks. Given the potential effect of increasing energy expenditure, adrenergic stimuli are promising strategies in the treatment of metabolic diseases.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales , Feocromocitoma , Tejido Adiposo Pardo/metabolismo , Neoplasias de las Glándulas Suprarrenales/patología , Adrenérgicos/metabolismo , Agonistas Adrenérgicos/metabolismo , Metabolismo Energético , Humanos , Sistema Nervioso/metabolismo , Sistema Nervioso/patología , Obesidad/metabolismo , Feocromocitoma/patologíaRESUMEN
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 SD 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.
Asunto(s)
Tejido Adiposo Blanco/metabolismo , Frío/efectos adversos , Azúcares de la Dieta/toxicidad , Fructosa/toxicidad , Efectos Tardíos de la Exposición Prenatal/metabolismo , Termogénesis/fisiología , Adipogénesis/efectos de los fármacos , Adipogénesis/fisiología , Tejido Adiposo Blanco/efectos de los fármacos , Animales , Azúcares de la Dieta/administración & dosificación , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/fisiología , Femenino , Fructosa/administración & dosificación , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Ratas , Ratas Sprague-Dawley , Termogénesis/efectos de los fármacosRESUMEN
The increasing impact of obesity on global human health intensifies the importance of studies focusing on agents interfering with the metabolism and remodeling not only of the white adipose tissue (WAT) but also of the liver. In the present study, we have addressed the impact of n-3 PUFA in adipose cells' proliferation and adipogenesis, as well as in the hepatic lipid profile and morphology. Mice were induced to obesity by the consumption of a high-fat diet (HFD) for 16 weeks. At the 9th week, the treatment with fish oil (FO) was initiated and maintained until the end of the period. The FO treatment reduced the animals' body mass, plasma lipids, glucose, plasma transaminases, liver mass, triacylglycerol, and cholesterol liver content when compared to animals consuming only HFD. FO also decreased the inguinal (ing) WAT mass, reduced adipocyte volume, increased adipose cellularity (hyperplasia), and increased the proliferation of adipose-derived stromal cells (AdSCs) which corroborates the increment in the proliferation of 3T3-L1 pre-adipocytes or AdSCs treated in vitro with n-3 PUFA. After submitting the in vitro treated (n-3 PUFA) cells, 3T3-L1 and AdSCs, to an adipogenic cocktail, there was an increase in the mRNA expression of adipogenic transcriptional factors and other late adipocyte markers, as well as an increase in lipid accumulation when compared to not treated cells. Finally, the expression of browning-related genes was also higher in the n-3 PUFA treated group. We conclude that n-3 PUFA exerts an attenuating effect on body mass, dyslipidemia, and hepatic steatosis induced by HFD. FO treatment led to decreasing adiposity and adipocyte hypertrophy in ingWAT while increasing hyperplasia. Data suggest that FO treatment might induce recruitment (by increased proliferation and differentiation) of new adipocytes (white and/or beige) to the ingWAT, which is fundamental for the healthy expansion of WAT.
Asunto(s)
Adipogénesis/efectos de los fármacos , Ácidos Grasos Omega-3/farmacología , Aceites de Pescado/farmacología , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Obesidad/terapia , Células 3T3-L1 , Adipocitos/efectos de los fármacos , Tejido Adiposo Blanco/efectos de los fármacos , Adiposidad/efectos de los fármacos , Animales , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Dieta Alta en Grasa , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/etiología , Obesidad/complicacionesRESUMEN
Adipocytes are the main stromal cells in the mammary microenvironment, and crosstalk between adipocytes and breast cancer cells may play a critical and important role in cancer maintenance and progression. Tumorinduced differentiation to beige/brown adipose tissue is an important contribution to the hypermetabolic state of breast cancer. However, the effect of epithelial cellbeige adipocyte communication on tumor progression remains unclear. To contribute to the understanding of this phenomenon, we characterized components present in conditioned media (CM) from beige adipocytes (BAs) or white adipocytes (WAs), and evaluated the effects of BA and WACM on both adhesion and migration of tumor (LM3, 4T1 and MC4L1) and nontumor (NMuMG) mouse mammary epithelial cell lines. Additionally, we analyzed the expression of ObR, CD44, vimentin, MMP9, MCT1 and LDH in tumor and nontumor mouse mammary epithelial cell lines incubated with BACM, WACM or CtrolCM (control conditioned media). 3T3L1 preadipocytes differentiated into beige adipocytes upon PPARγ activation (rosiglitazone) displaying characteristics that morphologically resembled brown/beige adipocytes. Levels of UCP1, CIDEA, GLUT4, leptin, MCT4 and FABP4 were increased, while adiponectin, caveolin 1 and perilipin 1 levels were decreased in BAs with respect to WAs. Tumor cell lines revealed lower cell adhesion and increased cell migration after incubation with BA and WACM vs. CtrolCM. ObR and MMP9 in MC4L1 cells were significantly increased after incubation with BACM vs. WA and CtrolCM. In addition, MC4L1 and LM3 cells significantly increased their migration in the presence of BAs, suggesting that new signals originating from the crosstalk between BAs and tumor cells, could be responsible for this change. Our results indicate that beige adipocytes are able to regulate the behavior of both tumor and nontumor mouse mammary epithelial cells, favoring tumor progression.
Asunto(s)
Adipocitos Beige/metabolismo , Neoplasias de la Mama/patología , Neoplasias Mamarias Experimentales/patología , Células 3T3-L1 , Adipocitos Beige/efectos de los fármacos , Adipocitos Blancos/efectos de los fármacos , Adipocitos Blancos/metabolismo , Animales , Adhesión Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Medios de Cultivo Condicionados/metabolismo , Progresión de la Enfermedad , Femenino , Humanos , Glándulas Mamarias Animales , Ratones , PPAR gamma/agonistas , PPAR gamma/metabolismo , Rosiglitazona/farmacología , Microambiente Tumoral/efectos de los fármacosRESUMEN
Adipocytes exhibit different morphological and functional characteristics, depending on their anatomical location, developmental origin, and stimulus. While white adipocytes tend to accumulate energy as triglycerides, brown and beige adipocytes tend to direct carbon sources to fuel thermogenesis. White and beige adipocytes originate from common progenitor cells, which are distinct from brown adipocyte precursors. Having a method to study white vs. beige vs. brown adipocyte differentiation may help to unveil the mechanisms driving distinct adipogenic programs. Preadipocytes can be cultured and differentiated in vitro using a combination of compounds to stimulate adipogenesis. Here, we describe and compare protocols designed to stimulate adipocyte differentiation and induce brown/beige-like or white-like characteristics in differentiating adipocytes. The protocols consist in exposing murine preadipocytes to pharmacological stimuli aimed at triggering adipogenesis and inducing (or not) a thermogenic gene expression program. After 8 days of differentiation with a pro-browning cocktail, immortalized preadipocytes isolated from interscapular brown fat (9B cells) or inguinal white fat (9W cells) from the same mouse expressed higher levels of brown/beige adipocyte markers (e.g., Ucp1) and pan-adipocyte differentiation markers (e.g., Pparg, Cebpa and aP2) when compared to the same cells differentiated with a cocktail that lacked brown/beige adipogenic inducers (i.e., rosiglitazone, T3, and indomethacin). Consistent with a higher thermogenic potential of brown vs. beige adipocytes, differentiated 9B cells expressed higher Ucp1 levels than differentiated 9W cells. This simple protocol may help researchers to understand mechanisms of adipogenesis and how adipocytes become thermogenic.
RESUMEN
OBJECTIVE: Angiotensin-(1-7) [Ang-(1-7)], a component of the renin angiotensin system, is a vasodilator that exerts its effects primarily through the Mas receptor. The discovery of the Mas receptor in white adipose tissue (WAT) suggests an additional role for this peptide. The aim of the present study was to assess whether Ang-(1-7) can induce the expression of thermogenic genes in white adipose tissue and increase mitochondrial respiration in adipocytes. MATERIALS/METHODS: Stromal Vascular fraction (SVF)-derived from mice adipose tissue was stimulated for one week with Ang-(1-7), then expression of beige markers and mitochondrial respiration were assessed. Mas+/+ and Mas-/- mice fed a control diet or a high fat-sucrose diet (HFSD) were exposed to a short or long term infusion of Ang-(1-7) and body weight, body fat, energy expenditure, cold resistance and expression of beige markers were assessed. Also, transgenic rats overexpressing Ang-(1-7) were fed with a control diet or a high fat-sucrose diet and the same parameters were assessed. Ang-(1-7) circulating levels from human subjects with different body mass index (BMI) or age were measured. RESULTS: Incubation of adipocytes derived from SVF with Ang-(1-7) increased the expression of beige markers. Infusion of Ang-(1-7) into lean and obese Mas+/+mice also induced the expression of Ucp1 and some beige markers, an effect not observed in Mas-/- mice. Mas-/- mice had increased body weight gain and decreased cold resistance, whereas rats overexpressing Ang-(1-7) showed the opposite effects. Overexpressing rats exposed to cold developed new thermogenic WAT in the anterior interscapular area. Finally, in human subjects the higher the BMI, low circulating concentration of Ang-(1-7) levels were detected. Similarly, the circulating levels of Ang-(1-7) peptide were reduced with age. CONCLUSION: These data indicate that Ang-(1-7) stimulates beige markers and thermogenesis via the Mas receptor, and this evidence suggests a potential therapeutic use to induce thermogenesis of WAT, particularly in obese subjects that have reduced circulating concentration of Ang-(1-7).
Asunto(s)
Tejido Adiposo Beige/efectos de los fármacos , Angiotensina I/farmacología , Fragmentos de Péptidos/farmacología , Proteínas Proto-Oncogénicas/fisiología , Receptores Acoplados a Proteínas G/fisiología , Termogénesis/efectos de los fármacos , Tejido Adiposo Beige/metabolismo , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/metabolismo , Adulto , Animales , Respiración de la Célula/efectos de los fármacos , Respiración de la Célula/genética , Células Cultivadas , Metabolismo Energético/genética , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Obesidad/genética , Obesidad/metabolismo , Obesidad/patología , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/genética , Ratas , Ratas Transgénicas , Receptores Acoplados a Proteínas G/genética , Termogénesis/genética , Adulto JovenRESUMEN
BACKGROUND: Recruiting thermogenic adipocytes in white adipose tissue represents a potential therapeutic strategy for obesity. Interestingly, PPARγ, a major regulator of lipogenesis, is also a key factor in inducing thermogenic genes in adipose tissue. SCOPE OF THE REVIEW: We summarize some of the recent findings regarding the biology of beige adipocytes and their potential significance for metabolic health. We also discuss the role of PPARγ in development of beige adipocyte phenotype and in inducing two apparently divergent processes, namely, lipogenesis and thermogenesis. MAJOR CONCLUSIONS: PPARγ post-translation modifications and differential coregulator recruitment may be key factors in defining adipocyte commitment with lipogenesis or thermogenesis. GENERAL SIGNIFICANCE: Dissecting the mechanisms underlying its thermogenic effects may prompt the development of a new generation of PPARγ-based therapies.