RESUMO
Notch3 promotes mammary luminal cell specification and forced Notch3 activation can induce mammary tumor formation. However, recent studies suggest a tumor-suppressive role for Notch3. Here, we report on Notch3 expression and functional analysis in the mouse mammary gland. Notch3 is expressed in the luminal compartment throughout mammary gland development, but switches to basal cells with initiation of post-lactational involution. Deletion of Notch3 caused a decrease of Notch activation in luminal cells and diminished luminal progenitors at puberty, as well as reduced alveolar progenitors during pregnancy. Parous Notch3-/- mammary glands developed hyperplasia with accumulation of CD24hiCD49flo cells, some of which progressed to invasive tumors with luminal features. Notch3 deletion abolished Notch activation in basal cells during involution, accompanied by altered apoptosis and reduced brown adipocytes, leading to expansion of parity-identified mammary epithelial cells (PI-MECs). Interestingly, the postpartum microenvironment is required for the stem cell activity of Notch3-/- PI-MECs. Finally, high expression of NOTCH3 is associated with prolonged survival in patients with luminal breast cancer. These results highlight an unexpected tumor-suppressive function for Notch3 in the parous mammary gland through restriction of PI-MEC expansion.
Assuntos
Células Epiteliais , Glândulas Mamárias Animais , Animais , Células Epiteliais/metabolismo , Feminino , Lactação , Camundongos , Camundongos Transgênicos , Gravidez , Células-TroncoRESUMO
The escalating incidence of metabolic pathologies such as obesity and diabetes mellitus underscores the imperative for innovative therapeutics targeting lipid metabolism modulation. Within this context, augmenting thermogenic processes in adipose cells emerges as a viable therapeutic approach. Given the limitations of previous ß3-adrenergic receptor (ß3-AR) agonist treatments in human diseases, there is an increasing focus on therapies targeting the ß2-adrenergic receptor (ß2-AR). Olodaterol (OLO) is a potent ß2-AR agonist that is a potential novel pharmacological candidate in this area. Our study explores the role and underlying mechanisms of OLO in enhancing brown adipose thermogenesis, providing robust evidence from in vitro and in vivo studies. OLO demonstrated a dose-dependent enhancement of lipolysis, notably increasing the expression of Uncoupling Protein 1 (UCP1) and raising the rate of oxygen consumption in primary brown adipocytes. This suggests a significant increase in thermogenic potential and energy expenditure. The administration of OLO to murine models noticeably enhanced cold-induced nonshivering thermogenesis. OLO elevated UCP1 expression in the brown adipose tissue of mice. Furthermore, it promoted brown adipocyte thermogenesis by activating the ß2-AR/cAMP/PKA signaling cascades according to RNA sequencing, western blotting, and molecular docking analysis. This investigation underscores the therapeutic potential of OLO for metabolic ailments and sheds light on the intricate molecular dynamics of adipocyte thermogenesis, laying the groundwork for future targeted therapeutic interventions in human metabolic disorders.
Assuntos
Adipócitos Marrons , Benzoxazinas , Termogênese , Camundongos , Humanos , Animais , Adipócitos Marrons/metabolismo , Simulação de Acoplamento Molecular , Termogênese/genética , Tecido Adiposo Marrom/metabolismo , Transdução de Sinais , Obesidade/metabolismo , Agonistas Adrenérgicos beta , Receptores Adrenérgicos , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMO
Three types of adipocytes, white, brown, and beige, regulate the systemic energy balance through the storage and expenditure of chemical energy. In addition, adipocytes produce various bioactive molecules known as adipokines. In contrast to white adipocyte-derived molecules, less information is available on the adipokines produced by brown adipocytes (batokine). This study explored the regulatory expression of interleukin (IL)-6 in cell culture studies. Norepinephrine or a nonselective ß-adrenergic receptor agonist increased the expression of IL-6 in primary brown adipocytes and HB2 brown adipocytes. Treatment with forskolin (Fsk), an activator of the cAMP-dependent protein kinase (PKA) pathway (downstream signaling of the ß-adrenergic receptor), efficiently stimulated IL-6 expression in brown adipocytes and myotubes. Phosphorylated CREB and phosphorylated p38 MAP kinase levels were increased in Fsk-treated brown adipocytes within 5 min. In contrast, a long-term (â¼60 min and â¼4 h) treatment with Fsk was required for increase in STAT3 phosphorylation and C/EBPß expression, respectively. The PKA, p38 MAP kinase, STAT3, and C/EBPß pathways are required for the maximal IL-6 expression induced by Fsk, which were verified by use of various inhibitors of these signal pathways. Vitamin C enhanced Fsk-induced IL-6 expression through the extracellular signal-regulated kinase activity. The present study provides basic information on the regulatory expression of IL-6 in activated brown adipocytes.
Assuntos
Adipócitos Marrons , Proteína Quinase 14 Ativada por Mitógeno , Animais , Camundongos , Adipócitos Brancos , Adipocinas , Colforsina/farmacologia , Interleucina-6RESUMO
Adipose tissue, a central player in energy balance, exhibits significant metabolic flexibility that is often compromised in obesity and type 2 diabetes (T2D). Mitochondrial dysfunction within adipocytes leads to inefficient lipid handling and increased oxidative stress, which together promote systemic metabolic disruptions central to obesity and its complications. This review explores the pivotal role that mitochondria play in altering the metabolic functions of the primary adipocyte types, white, brown, and beige, within the context of obesity and T2D. Specifically, in white adipocytes, these dysfunctions contribute to impaired lipid processing and an increased burden of oxidative stress, worsening metabolic disturbances. Conversely, compromised mitochondrial function undermines their thermogenic capabilities, reducing the capacity for optimal energy expenditure in brown adipocytes. Beige adipocytes uniquely combine the functional properties of white and brown adipocytes, maintaining morphological similarities to white adipocytes while possessing the capability to transform into mitochondria-rich, energy-burning cells under appropriate stimuli. Each type of adipocyte displays unique metabolic characteristics, governed by the mitochondrial dynamics specific to each cell type. These distinct mitochondrial metabolic phenotypes are regulated by specialized networks comprising transcription factors, co-activators, and enzymes, which together ensure the precise control of cellular energy processes. Strong evidence has shown impaired adipocyte mitochondrial metabolism and faulty upstream regulators in a causal relationship with obesity-induced T2D. Targeted interventions aimed at improving mitochondrial function in adipocytes offer a promising therapeutic avenue for enhancing systemic macronutrient oxidation, thereby potentially mitigating obesity. Advances in understanding mitochondrial function within adipocytes underscore a pivotal shift in approach to combating obesity and associated comorbidities. Reigniting the burning of calories in adipose tissues, and other important metabolic organs such as the muscle and liver, is crucial given the extensive role of adipose tissue in energy storage and release.
Assuntos
Diabetes Mellitus Tipo 2 , Metabolismo Energético , Mitocôndrias , Obesidade , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Humanos , Obesidade/metabolismo , Obesidade/patologia , Mitocôndrias/metabolismo , Animais , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Estresse Oxidativo , TermogêneseRESUMO
Human obesity is related with intrinsic impairments of adipocyte lipolysis and ectopic lipid accumulation. Small regulatory RNAs, such as tRNA-derived fragments (tRFs) and tRNA halves (tiRNAs), are enriched in exosomes and play a crucial role in lipid metabolism. To determine certain tRFs for lipolysis, brown adipocytes were treated with forskolin. Using tRFs sequencing, 207 different expressed exosomal tRFs were determined. In forskolin samples, 145 downregulated and 62 upregulated tRFs were identified. Further, qRT-PCR validated that three notably upregulated tRFs (tRF-Gly-GCC-007, tRF-Gly-GCC-008, and tRF-Gly-GCC-009) were in accordance with the sequencing result. Target genes of tRFs were involved in positive regulation of protein phosphorylation and cell adhesion process by significantly downregulating UCHL1 expression, which might participate in lipolysis. This study might provide therapeutic targets and potential diagnostic biomarkers for obesity treatment.
Assuntos
Adipócitos Marrons , Metabolismo dos Lipídeos , Humanos , Adipócitos Marrons/metabolismo , Colforsina , RNA de Transferência/genética , RNA de Transferência/metabolismo , Obesidade/genéticaRESUMO
Brown and beige adipocytes harbor the thermogenic capacity to adapt to environmental thermal or nutritional changes. Histone methylation is an essential epigenetic modification involved in the modulation of nonshivering thermogenesis in adipocytes. Here, we describe a molecular network leading by KMT5c, a H4K20 methyltransferase, that regulates adipocyte thermogenesis and systemic energy expenditure. The expression of Kmt5c is dramatically induced by a ß3-adrenergic signaling cascade in both brown and beige fat cells. Depleting Kmt5c in adipocytes in vivo leads to a decreased expression of thermogenic genes in both brown and subcutaneous (s.c.) fat tissues. These mice are prone to high-fat-diet-induced obesity and develop glucose intolerance. Enhanced transformation related protein 53 (Trp53) expression in Kmt5c knockout (KO) mice, that is due to the decreased repressive mark H4K20me3 on its proximal promoter, is responsible for the metabolic phenotypes. Together, these findings reveal the physiological role for KMT5c-mediated H4K20 methylation in the maintenance and activation of the thermogenic program in adipocytes.
Assuntos
Adipócitos Bege/fisiologia , Adipócitos Marrons/fisiologia , Histona-Lisina N-Metiltransferase , Termogênese/fisiologia , Proteína Supressora de Tumor p53/metabolismo , Adipócitos Bege/metabolismo , Adipócitos Marrons/metabolismo , Animais , Dieta Hiperlipídica , Feminino , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Masculino , Camundongos , Camundongos Knockout , Proteína Supressora de Tumor p53/genéticaRESUMO
Brown fats specialize in thermogenesis by increasing the utilization of circulating blood glucose and fatty acids. Emerging evidence suggests that brown adipose tissue (BAT) prevents the incidence of obesity-associated metabolic diseases and several types of cancers in humans. Mitochondrial energy metabolism in brown/beige adipocytes regulates both uncoupling protein 1 (UCP1)-dependent and -independent thermogenesis for cold adaptation and the utilization of excess nutrients and energy. Many studies on the quantification of human BAT indicate that mass and activity are inversely correlated with the body mass index (BMI) and visceral adiposity. Repression is caused by obesity-associated positive and negative factors that control adipocyte browning, de novo adipogenesis, mitochondrial energy metabolism, UCP1 expression and activity, and noradrenergic response. Systemic and local factors whose levels vary between lean and obese conditions include growth factors, inflammatory cytokines, neurotransmitters, and metal ions such as selenium and iron. Modulation of obesity-associated repression in human brown fats is a promising strategy to counteract obesity and related metabolic diseases through the activation of thermogenic capacity. In this review, we highlight recent advances in mitochondrial metabolism, thermogenic regulation of brown fats, and human metabolic diseases.
Assuntos
Tecido Adiposo Marrom , Doenças Metabólicas , Humanos , Tecido Adiposo Marrom/metabolismo , Obesidade/metabolismo , Adipócitos Marrons/metabolismo , Metabolismo Energético , Doenças Metabólicas/metabolismo , Termogênese , Proteína Desacopladora 1/metabolismo , Tecido Adiposo Branco/metabolismoRESUMO
Metabolic physiology plays a key role in maintaining our health and resilience. Metabolic disorders can lead to serious illnesses, including obesity. The pathogenesis of the new long COVID syndrome in individuals with long-term recovery after SARS-Co-2 infection is still incomplete. Thus there is growing attention in the study of adipose tissue activities, especially brown adipose tissue (BAT) and associated resilience which plays a crucial role in different types of obesity as potential targets for pharmacologic and nutritional interventions in the context of obesity and long COVID. The number of studies examining mechanisms underlying BAT has grown rapidly in the last 10 years despite of role of BAT in individuals with COVID-19 and long COVID is modest. Therefore, this review aims to sum up data examining BAT activities, its resilience in health, obesity, and the possible link to long COVID. The search was conducted on studies published in English mostly between 2004 and 2022 in adult humans and animal models. Database searches were conducted using PubMed, Scopus, and Google Scholar for key terms including adipose tissue, BAT, adipokinins, obesity, VPF/VEGF, and pathogenesis. From the initial search through the database were identified relevant articles that met inclusion and exclusion criteria and our data regarding adipose tissues were presented in this review. It will discuss adiposity tissue activities. Current literature suggests that there are BAT integral effects to whitening and browning fat phenomenons which reflect the homeostatic metabolic adaptive ability for environmental demand or survival/adaptive mechanisms. We also review neural and vascular impacts in BAT that play a role in resilience and obesity. Finally, we discuss the role of BAT in the context of long COVID in basic research and clinical research.
RESUMO
Metabolic physiology plays a key role in maintaining our health and resilience. Metabolic disorders can lead to serious illnesses, including obesity. The pathogenesis of the new long COVID syndrome in individuals with long-term recovery after SARS-Co-2 infection is still incomplete. Thus there is growing attention in the study of adipose tissue activities, especially brown adipose tissue (BAT) and associated resilience which plays a crucial role in different types of obesity as potential targets for pharmacologic and nutritional interventions in the context of obesity and long COVID. The number of studies examining mechanisms underlying BAT has grown rapidly in the last 10 years despite of role of BAT in individuals with COVID-19 and long COVID is modest. Therefore, this review aims to sum up data examining BAT activities, its resilience in health, obesity, and the possible link to long COVID. The search was conducted on studies published in English mostly between 2004 and 2022 in adult humans and animal models. Database searches were conducted using PubMed, Scopus, and Google Scholar for key terms including adipose tissue, BAT, adipokines, obesity, VPF/VEGF, and pathogenesis. From the initial search through the database were identified relevant articles that met inclusion and exclusion criteria and our data regarding adipose tissues were presented in this review. It will discuss adiposity tissue activities. Current literature suggests that there are BAT integral effects to whitening and browning fat phenomena which reflect the homeostatic metabolic adaptive ability for environmental demand or survival/adaptive mechanisms. We also review neural and vascular impacts in BAT that play a role in resilience and obesity. Finally, we discuss the role of BAT in the context of long COVID in basic research and clinical research.
Assuntos
Tecido Adiposo Marrom , COVID-19 , Animais , Adulto , Humanos , Tecido Adiposo Marrom/metabolismo , Síndrome de COVID-19 Pós-Aguda , COVID-19/metabolismo , Obesidade/metabolismoRESUMO
Aerobic exercise is an effective intervention in preventing obesity and is also an important factor associated with thermogenesis. There is an increasing interest in the factors and mechanisms induced by aerobic exercise that can influence the metabolism and thermogenic activity in an individual. Recent studies suggest that exercise induced circulating factors (known as 'exerkines'), which are able to modulate activation of brown adipose tissue (BAT) and browning of white adipose tissue. However, the underlying molecular mechanisms associated with the effect of exercise-induced peripheral factors on BAT activation remain poorly understood. Furthermore, the role of exercise training in BAT activation is still debatable. Hence, the purpose of our study is to assess whether exercise training affects the expression of uncoupled protein 1 (UCP1) in brown adipocytes via release of different blood factors. Four weeks of exercise training significantly decreased the body weight gain and fat mass gain. Furthermore, trained mice exhibit higher levels of energy expenditure and UCP1 expression than untrained mice. Surprisingly, treatment with serum from exercise-trained mice increased the expression of UCP1 in differentiated brown adipocytes. To gain a better understanding of these mechanisms, we analysed the conditioned media obtained after treating the C2C12 myotubes with an AMP-activated protein kinase (AMPK) activator (AICAR; 5-aminoimidazole-4-carboxamide ribonucleotide), which leads to an increased expression of UCP1 when added to brown adipocytes. Our observations suggest the possibility of aerobic exercise-induced BAT activation via activation of AMPK in skeletal muscles. KEY POINTS: Exercise promotes thermogenesis by activating uncoupling protein 1 (UCP1), which leads to a decrease in the body weight gain and body fat content. However, little is known about the role of exerkines in modulating UCP1 expression and subsequent brown adipose tissue (BAT) activation. Four weeks of voluntary wheel-running exercise reduces body weight and fat content. Exercise induces the increase in AMP-activated protein kinase (AMPK) and slow-type muscle fibre marker genes in skeletal muscles and promotes UCP1 expression in white and brown adipose tissues. Incubation of brown adipocytes with serum isolated from exercise-trained mice significantly increased their UCP1 gene and protein levels; moreover, conditioned media of AMPK-activator-treated C2C12 myotubes induces increased UCP1 expression in brown adipocytes. These results show that aerobic exercise-induced skeletal muscle AMPK has a significant effect on UCP1 expression in BAT.
Assuntos
Proteínas Quinases Ativadas por AMP , Adipócitos Marrons , Proteína Desacopladora 1 , Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos Marrons/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Peso Corporal , Meios de Cultivo Condicionados/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Termogênese , Proteína Desacopladora 1/genéticaRESUMO
Single-cell sequencing technologies have revealed an unexpectedly broad repertoire of cells required to mediate complex functions in multicellular organisms. Despite the multiple roles of adipose tissue in maintaining systemic metabolic homeostasis, adipocytes are thought to be largely homogenous with only 2 major subtypes recognized in humans so far. Here we report the existence and characteristics of 4 distinct human adipocyte subtypes, and of their respective mesenchymal progenitors. The phenotypes of these distinct adipocyte subtypes are differentially associated with key adipose tissue functions, including thermogenesis, lipid storage, and adipokine secretion. The transcriptomic signature of "brite/beige" thermogenic adipocytes reveals mechanisms for iron accumulation and protection from oxidative stress, necessary for mitochondrial biogenesis and respiration upon activation. Importantly, this signature is enriched in human supraclavicular adipose tissue, confirming that these cells comprise thermogenic depots in vivo, and explain previous findings of a rate-limiting role of iron in adipose tissue browning. The mesenchymal progenitors that give rise to beige/brite adipocytes express a unique set of cytokines and transcriptional regulators involved in immune cell modulation of adipose tissue browning. Unexpectedly, we also find adipocyte subtypes specialized for high-level expression of the adipokines adiponectin or leptin, associated with distinct transcription factors previously implicated in adipocyte differentiation. The finding of a broad adipocyte repertoire derived from a distinct set of mesenchymal progenitors, and of the transcriptional regulators that can control their development, provides a framework for understanding human adipose tissue function and role in metabolic disease.
Assuntos
Adipócitos Bege/metabolismo , Adiponectina/biossíntese , Leptina/sangue , Células-Tronco Mesenquimais/metabolismo , Termogênese , Transcriptoma , Adipócitos Bege/citologia , Tecido Adiposo Marrom/citologia , Tecido Adiposo Marrom/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Células-Tronco Mesenquimais/citologiaRESUMO
Accumulating evidence suggests that brown adipose tissue (BAT) is a potential therapeutic target for managing obesity and related diseases. PGAM family member 5, mitochondrial serine/threonine protein phosphatase (PGAM5), is a protein phosphatase that resides in the mitochondria and regulates many biological processes, including cell death, mitophagy, and immune responses. Because BAT is a mitochondria-rich tissue, we have hypothesized that PGAM5 has a physiological function in BAT. We previously reported that PGAM5-knockout (KO) mice are resistant to severe metabolic stress. Importantly, lipid accumulation is suppressed in PGAM5-KO BAT, even under unstressed conditions, raising the possibility that PGAM5 deficiency stimulates lipid consumption. However, the mechanism underlying this observation is undetermined. Here, using an array of biochemical approaches, including quantitative RT-PCR, immunoblotting, and oxygen consumption assays, we show that PGAM5 negatively regulates energy expenditure in brown adipocytes. We found that PGAM5-KO brown adipocytes have an enhanced oxygen consumption rate and increased expression of uncoupling protein 1 (UCP1), a protein that increases energy consumption in the mitochondria. Mechanistically, we found that PGAM5 phosphatase activity and intramembrane cleavage are required for suppression of UCP1 activity. Furthermore, utilizing a genome-wide siRNA screen in HeLa cells to search for regulators of PGAM5 cleavage, we identified a set of candidate genes, including phosphatidylserine decarboxylase (PISD), which catalyzes the formation of phosphatidylethanolamine at the mitochondrial membrane. Taken together, these results indicate that PGAM5 suppresses mitochondrial energy expenditure by down-regulating UCP1 expression in brown adipocytes and that its phosphatase activity and intramembrane cleavage are required for UCP1 suppression.
Assuntos
Adipócitos Marrons/metabolismo , Regulação para Baixo , Metabolismo Energético , Proteínas Mitocondriais/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Proteína Desacopladora 1/genética , Animais , Células Cultivadas , Células HeLa , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Mitocondriais/genética , Consumo de Oxigênio , Fosfoproteínas Fosfatases/genética , Proteína Desacopladora 1/metabolismoRESUMO
Fat infiltration in skeletal muscle is observed in several myopathies, is associated with muscular dysfunction, and is strongly correlated with insulin resistance, diabetes, obesity, and aging. In animal production, skeletal muscle fat (also known as intermuscular and intramuscular fat) is positively related to meat quality including tenderness, flavor, and juiciness. Thus, understanding the cell origin and regulation mechanism of skeletal muscle fat infiltration is important for developing therapies against human myopathies as well as for improving meat quality. Notably, age, sarcopenia, oxidative stress, injury, and regeneration can activate adipogenic differentiation potential in myoblasts and affect fat accumulation in skeletal muscle. In addition, several transcriptional and nutritional factors can directly induce transdifferentiation of myoblasts into adipocytes. In this review, we focused on the recent progress in understanding the muscle-to-adipocyte differentiation and summarized and discussed the genetic, nutritional, and physiological factors that can induce transdifferentiation of myoblasts into adipocytes. Moreover, the regulatory roles and mechanisms of these factors during the transdifferentiation process were also discussed.
Assuntos
Adipócitos/metabolismo , Adipogenia , Transdiferenciação Celular , Desenvolvimento Muscular , Músculo Esquelético/metabolismo , Mioblastos Esqueléticos/metabolismo , Adipócitos/patologia , Fatores Etários , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Composição Corporal , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Músculo Esquelético/patologia , Mioblastos Esqueléticos/patologia , Estado Nutricional , Estresse Oxidativo , Fenótipo , Transdução de SinaisRESUMO
Obesity is a health problem worldwide, and brown adipose tissue (BAT) is important for energy expenditure. Here, we explored the role of leukotriene A4 hydrolase (LTA4 H), a key enzyme in the synthesis of the lipid mediator leukotriene B4 (LTB4 ), in diet-induced obesity. LTA4 H-deficient (LTA4 H-KO) mice fed a high-fat diet (HFD) showed a lean phenotype, and bone-marrow transplantation studies revealed that LTA4 H-deficiency in non-hematopoietic cells was responsible for this lean phenotype. LTA4 H-KO mice exhibited greater energy expenditure, but similar food intake and fecal energy loss. LTA4 H-KO BAT showed higher expression of thermogenesis-related genes. In addition, the plasma thyroid-stimulating hormone and thyroid hormone concentrations, as well as HFD-induced catecholamine secretion, were higher in LTA4 H-KO mice. In contrast, LTB4 receptor (BLT1)-deficient mice did not show a lean phenotype, implying that the phenotype of LTA4 H-KO mice is independent of the LTB4 /BLT1 axis. These results indicate that LTA4 H mediates the diet-induced obesity by reducing catecholamine and thyroid hormone secretion.
Assuntos
Metabolismo Energético , Epóxido Hidrolases/metabolismo , Obesidade/genética , Hormônios Tireóideos/sangue , Tireotropina/sangue , Tecido Adiposo Marrom/metabolismo , Animais , Catecolaminas/metabolismo , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Epóxido Hidrolases/deficiência , Epóxido Hidrolases/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/metabolismo , Fenótipo , Receptores do Leucotrieno B4/genética , Receptores do Leucotrieno B4/metabolismo , TermogêneseRESUMO
In recent years, brown adipose tissue (BAT), which has a high heat-producing capacity, has been confirmed to exist even in adults, and it has become a focal point for the prevention and the improvement of obesity and lifestyle-related diseases. However, the influences of obesity and physical activity (PA) on the fluid factors secreted from BAT (brown adipokines) are not well understood. In this study, therefore, we focused on brown adipokines and investigated the effects of obesity and PA. The abnormal expressions of gene fluid factors such as galectin-3 (Lgals3) and Lgals3 binding protein (Lgals3bp), whose proteins are secreted from HB2 brown adipocytes, were observed in the interscapular BAT of obese mice fed a high-fat diet for 4 months. PA attenuated the abnormalities in the expressions of these genes. Furthermore, although the gene expressions of factors related to brown adipocyte differentiation such as peroxisome proliferator-activated receptor gamma coactivator 1-α were also down-regulated in the BAT of the obese mice, PA suppressed the down-regulation of these factors. On the other hand, lipogenesis was increased more in HB2 cells overexpressing Lgals3 compared with that in control cells, and the overexpression of Lgals3bp decreased the mitochondrial mass. These results indicate that PA attenuates the obesity-induced dysregulated expression of brown adipokines and suggests that Lgals3 and Lgals3bp are involved in brown adipocyte differentiation.
Assuntos
Adipócitos Marrons/metabolismo , Adipocinas/biossíntese , Tecido Adiposo Marrom/metabolismo , Galectina 3/biossíntese , Regulação da Expressão Gênica , Obesidade/metabolismo , Condicionamento Físico Animal , Animais , Diferenciação Celular , CamundongosRESUMO
Cellular repressor of E1A-stimulated genes 1 (CREG1) is a secreted glycoprotein that accelerates p16-dependent cellular senescence in vitro. We recently reported the ability of CREG1 to stimulate brown adipogenesis using adipocyte P2-CREG1-transgenic (Tg) mice; however, little is known about the effect of CREG1 on aging-associated phenotypes. In this study, we investigated the effects of CREG1 on age-related obesity and renal dysfunction in Tg mice. Increased brown fat formation was detected in aged Tg mice, in which age-associated metabolic phenotypes such as body weight gain and increases in blood glucose were improved compared with those in wild-type (WT) mice. Blood CREG1 levels increased significantly in WT mice with age, whereas the age-related increase was suppressed, and its levels were reduced, in the livers and kidneys of Tg mice relative to those in WT mice at 25 months. Intriguingly, the mRNA levels of Ink4a, Arf, and senescence-associated secretory phenotype (SASP)-related genes and p38MAPK activity were significantly lowered in the aged kidneys of Tg mice, in which the morphological abnormalities of glomeruli as well as filtering function seen in WT kidneys were alleviated. These results suggest the involvement of CREG1 in kidney aging and its potential as a target for improving age-related renal dysfunction.
Assuntos
Tecido Adiposo Marrom/metabolismo , Envelhecimento/genética , Rim/metabolismo , Obesidade/genética , Proteínas Repressoras/genética , Adipócitos Marrons/metabolismo , Adipócitos Marrons/patologia , Adipogenia/genética , Tecido Adiposo Marrom/patologia , Envelhecimento/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica , Rim/patologia , Testes de Função Renal , Masculino , Camundongos , Camundongos Transgênicos , Obesidade/metabolismo , Obesidade/patologia , Fenótipo , Proteínas Repressoras/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Inhibitors of methionine aminopeptidase 2 (MetAP2) have been shown to reduce body weight in obese mice and humans. The target tissue and cellular mechanism of MetAP2 inhibitors, however, have not been extensively examined. Using compounds with diverse chemical scaffolds, we showed that MetAP2 inhibition decreases body weight and fat mass and increases lean mass in the obese mice but not in the lean mice. Obesity is associated with catecholamine resistance and blunted ß-adrenergic receptor signaling activities, which could dampen lipolysis and energy expenditure resulting in weight gain. In the current study, we examined effect of MetAP2 inhibition on brown adipose tissue and brown adipocytes. Norepinephrine increases energy expenditure in brown adipose tissue by providing fatty acid substrate through lipolysis and by increasing expression of uncoupled protein-1 (UCP1). Metabolomic analysis shows that in response to MetAP2 inhibitor treatment, fatty acid metabolites in brown adipose tissue increase transiently and subsequently decrease to basal or below basal levels, suggesting an effect on fatty acid metabolism in this tissue. Treatment of brown adipocytes with MetAP2 inhibitors enhances norepinephrine-induced lipolysis and energy expenditure, and prolongs the activity of norepinephrine to increase ucp1 gene expression and energy expenditure in norepinephrine-desensitized brown adipocytes. In summary, we showed that the anti-obesity activity of MetAP2 inhibitors can be mediated, at least in part, through direct action on brown adipocytes by enhancing ß-adrenergic-signaling-stimulated activities.
Assuntos
Adipócitos Marrons/fisiologia , Aminopeptidases/antagonistas & inibidores , Peso Corporal/efeitos dos fármacos , Clorobenzenos/farmacologia , Metabolismo Energético/efeitos dos fármacos , Metaloendopeptidases/antagonistas & inibidores , Obesidade/prevenção & controle , Adipócitos Marrons/citologia , Adipócitos Marrons/efeitos dos fármacos , Animais , Humanos , Lipólise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Ratos , Transdução de Sinais , TermogêneseRESUMO
The effects of insulin on the bioenergetic and thermogenic capacity of brown adipocyte mitochondria were investigated by focusing on key mitochondrial proteins. Two-month-old male Wistar rats were treated acutely or chronically with a low or high dose of insulin. Acute low insulin dose increased expression of all electron transport chain complexes and complex IV activity, whereas high dose increased complex II expression. Chronic low insulin dose decreased complex I and cyt c expression while increasing complex II and IV expression and complex IV activity. Chronic high insulin dose decreased complex II, III, cyt c, and increased complex IV expression. Uncoupling protein (UCP) 1 expression was decreased after acute high insulin but increased following chronic insulin treatment. ATP synthase expression was increased after acute and decreased after chronic insulin treatment. Only a high dose of insulin increased ATP synthase activity in acute and decreased it in chronic treatment. ATPase inhibitory factor protein expression was increased in all treated groups. Confocal microscopy showed that key mitochondrial proteins colocalize differently in different mitochondria within a single brown adipocyte, indicating mitochondrial mosaicism. These results suggest that insulin modulates the bioenergetic and thermogenic capacity of rat brown adipocytes in vivo by modulating mitochondrial mosaicism.
Assuntos
Adipócitos Marrons/metabolismo , Metabolismo Energético , Insulina/metabolismo , Mitocôndrias/metabolismo , Termogênese , Adipócitos Marrons/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Animais , Biomarcadores , Complexo de Proteínas da Cadeia de Transporte de Elétrons/genética , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Metabolismo Energético/efeitos dos fármacos , Ativação Enzimática , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Imunofluorescência , Expressão Gênica , Insulina/farmacologia , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Mitocôndrias/ultraestrutura , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Mosaicismo , Ratos , Termogênese/efeitos dos fármacos , Termogênese/genéticaRESUMO
The ongoing obesity pandemic generates a constant need to develop new therapeutic strategies to restore the energy balance. Therefore, the concept of activating brown adipose tissue (BAT) in order to increase energy expenditure has been revived. In mammals, two developmentally distinct types of brown adipocytes exist; the classical or constitutive BAT that arises during embryogenesis, and the beige adipose tissue that is recruited postnatally within white adipose tissue (WAT) in the process called browning. Research of recent years has significantly increased our understanding of the mechanisms involved in BAT activation and WAT browning. They also allowed for the identification of critical molecules and critical steps of both processes and, therefore, many new therapeutic targets. Several non-pharmacological approaches, as well as chemical compounds aiming at the induction of WAT browning and BAT activation, have been tested in vitro as well as in animal models of genetically determined and/or diet-induced obesity. The therapeutic potential of some of these strategies has also been tested in humans. In this review, we summarize present concepts regarding potential therapeutic targets in the process of BAT activation and WAT browning and available strategies aiming at them.
Assuntos
Tecido Adiposo Bege/metabolismo , Tecido Adiposo Marrom/metabolismo , Obesidade/metabolismo , Animais , Dieta , Metabolismo Energético , Regulação da Expressão Gênica , Redes Reguladoras de Genes , HumanosRESUMO
Adipose tissue harbors plasticity to adapt to environmental thermal changes. While brown adipocyte is a thermogenic cell which produces heat acutely in response to cold stimuli, beige (or brite) adipocyte is an inducible form of thermogenic adipocytes which emerges in the white adipose depots in response to chronic cold exposure. Such adaptability of adipocytes is regulated by epigenetic mechanisms. Among them, histone methylation is chemically stable and thus is an appropriate epigenetic mark for mediating cellular memory to induce and maintain the beige adipocyte characteristics. The enzymes that catalyze the methylation or demethylation of H3K27 and H3K9 regulate brown adipocyte biogenesis through their catalytic activity-dependent and -independent mechanisms. Resolving the bivalency of H3K4me3 and H3K27me3 as well as "opening" the chromatin structure by demethylation of H3K9 both mediate beige adipogenesis. In addition, it is recently reported that maintenance of beige adipocyte, beige-to-white transition, and cellular memory of prior cold exposure in beige adipocyte are also regulated by histone methylation. A further understanding of the epigenetic mechanism of beige adipocyte biogenesis would unravel the mechanism of the cellular memory of environmental stimuli and provide a novel therapeutics for the metabolic disorders such as obesity and diabetes that are influenced by environmental factors.