RESUMO
White adipose tissue (WAT) is essential for lipid storage and systemic energy homeostasis. Understanding adipocyte formation and stability is key to developing therapies for obesity and metabolic disorders. Through a high-throughput cDNA screen, we identified PATZ1, a POZ/BTB and AT-Hook Containing Zinc Finger 1 protein, as an important adipogenic transcription factor. PATZ1 is expressed in human and mouse adipocyte precursor cells (APCs) and adipocytes. In cellular models, PATZ1 promotes adipogenesis via protein-protein interactions and DNA binding. PATZ1 ablation in mouse adipocytes and APCs leads to a reduced APC pool, decreased fat mass, and hypertrophied adipocytes. ChIP-Seq and RNA-seq analyses show that PATZ1 supports adipogenesis by interacting with transcriptional machinery at the promoter regions of key early adipogenic factors. Mass-spec results show that PATZ1 associates with GTF2I, with GTF2I modulating PATZ1's function during differentiation. These findings underscore PATZ1's regulatory role in adipocyte differentiation and adiposity, offering insights into adipose tissue development.
Assuntos
Adipócitos , Adipogenia , Regiões Promotoras Genéticas , Fatores de Transcrição , Adipogenia/genética , Animais , Camundongos , Humanos , Adipócitos/metabolismo , Adipócitos/citologia , Regiões Promotoras Genéticas/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Diferenciação Celular/genética , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/citologia , Masculino , Células 3T3-L1 , Camundongos Endogâmicos C57BL , Regulação da Expressão GênicaRESUMO
Traditional Chinese medical literature contains numerous records of many traditional Chinese herbal medicines that exhibit efficacy in enhancing resistance to cold, yet there is a lack of scientific explanation. Lycium barbarum is among the herbal medicines that are explicitly documented to enhance resistance to cold in the "Ben Cao Gang Mu (Compendium of Materia Medica)". Herein, we investigated L. barbarum polysaccharide (LBP)-induced browning of inguinal white adipose tissue (iWAT), energy expenditure and thermogenic function in a long-term (4 months) treatment mouse model. LBP supplementation resulted in a significant reduction in weight and adipocyte size in iWAT, along with increased gut microbiota diversity. Specifically, the levels of Lachnospiraceae, Ruminococcaceae and Bacteroidaceae (short-chain fatty acid-producing bacteria) were elevated, leading to a higher level of short-chain fatty acids (SCFAs) in the caecal content. These effects subsequently triggered the release of glucagon-like peptide-1 (GLP-1) and activated the CREB/PGC1α signaling pathway in iWAT, thereby increasing energy expenditure and enhancing thermogenic function. The antibiotic treatment experiments confirmed that the LBP-mediated gut microbiota participated in the process of iWAT browning. In summary, our findings provide the first scientific explanation and mechanistic insights into the cold resistance of L. barbarum and identify potentially safe natural product supplements for individuals in alpine areas.
Assuntos
Temperatura Baixa , Medicamentos de Ervas Chinesas , Metabolismo Energético , Microbioma Gastrointestinal , Termogênese , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Termogênese/efeitos dos fármacos , Camundongos , Metabolismo Energético/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacosRESUMO
The central nervous system has been implicated in the age-induced reduction in adipose tissue lipolysis. However, the underlying mechanisms remain unclear. Here, we show the expression of SLC7A14 is reduced in proopiomelanocortin (POMC) neurons of aged mice. Overexpression of SLC7A14 in POMC neurons alleviates the aging-reduced lipolysis, whereas SLC7A14 deletion mimics the age-induced lipolysis impairment. Metabolomics analysis reveals that POMC SLC7A14 increased taurochenodeoxycholic acid (TCDCA) content, which mediates the SLC7A14 knockout- or age-induced WAT lipolysis impairment. Furthermore, SLC7A14-increased TCDCA content is dependent on intestinal apical sodium-dependent bile acid transporter (ASBT), which is regulated by intestinal sympathetic afferent nerves. Finally, SLC7A14 regulates the intestinal sympathetic afferent nerves by inhibiting mTORC1 signaling through inhibiting TSC1 phosphorylation. Collectively, our study suggests the function for central SLC7A14 and an upstream mechanism for the mTORC1 signaling pathway. Moreover, our data provides insights into the brain-gut-adipose tissue crosstalk in age-induced lipolysis impairment.
Assuntos
Tecido Adiposo Branco , Envelhecimento , Sistema y+ de Transporte de Aminoácidos , Hipotálamo , Lipólise , Animais , Masculino , Camundongos , Tecido Adiposo Branco/metabolismo , Envelhecimento/metabolismo , Sistema y+ de Transporte de Aminoácidos/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética , Hipotálamo/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Pró-Opiomelanocortina/metabolismo , Pró-Opiomelanocortina/genética , Transdução de Sinais , Simportadores/metabolismo , Simportadores/genéticaRESUMO
Postprandial IL-1ß surges are predominant in the white adipose tissue (WAT), but its consequences are unknown. Here, we investigate the role of IL-1ß in WAT energy storage and show that adipocyte-specific deletion of IL-1 receptor 1 (IL1R1) has no metabolic consequences, whereas ubiquitous lack of IL1R1 reduces body weight, WAT mass, and adipocyte formation in mice. Among all major WAT-resident cell types, progenitors express the highest IL1R1 levels. In vitro, IL-1ß potently promotes adipogenesis in murine and human adipose-derived stem cells. This effect is exclusive to early-differentiation-stage cells, in which the adipogenic transcription factors C/EBPδ and C/EBPß are rapidly upregulated by IL-1ß and enriched near important adipogenic genes. The pro-adipogenic, but not pro-inflammatory effect of IL-1ß is potentiated by acute treatment and blocked by chronic exposure. Thus, we propose that transient postprandial IL-1ß surges regulate WAT remodeling by promoting adipogenesis, whereas chronically elevated IL-1ß levels in obesity blunts this physiological function.
Assuntos
Adipócitos , Adipogenia , Tecido Adiposo Branco , Proteína beta Intensificadora de Ligação a CCAAT , Interleucina-1beta , Receptores Tipo I de Interleucina-1 , Adipogenia/efeitos dos fármacos , Adipogenia/genética , Animais , Interleucina-1beta/metabolismo , Humanos , Adipócitos/metabolismo , Adipócitos/citologia , Receptores Tipo I de Interleucina-1/metabolismo , Receptores Tipo I de Interleucina-1/genética , Camundongos , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/genética , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/citologia , Proteína delta de Ligação ao Facilitador CCAAT/metabolismo , Proteína delta de Ligação ao Facilitador CCAAT/genética , Masculino , Camundongos Knockout , Células-Tronco/metabolismo , Células-Tronco/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Diferenciação Celular/efeitos dos fármacosRESUMO
Background: Current anti-obesity medications suffer from limited efficacy and side-effects because they act indirectly on either the central nervous system or gastrointestinal system. Herein, this work aims to introduce a transdermal photothermal and nanocatalytic therapy enabled by Prussian blue nanoparticles, which directly act on obese subcutaneous white adipose tissue (sWAT) to induce its beneficial remodeling including stimulation of browning, lipolysis, secretion of adiponectin, as well as reduction of oxidative stress, hypoxia, and inflammation. Methods: Prussian blue nanoparticles were synthesized and incorporated into silk fibroin hydrogel for sustained retention. The efficacy of mild photothermal (808 nm, 0.4 W/cm2, 5 min) and nanocatalytic therapy (mPTT-NCT) was assessed both in vitro (3T3-L1 adipocytes) and in vivo (obese mice). The underlying signaling pathways are carefully revealed. Additionally, biosafety studies were conducted to further validate the potential of this therapy for practical application. Results: On 3T3-L1 adipocytes, mPTT-NCT was able to induce browning, enhance lipolysis, and alleviate oxidative stress. On obese mice model, the synergistic treatment led to not only large mass reduction of the targeted sWAT (53.95%) but also significant improvement of whole-body metabolism as evidenced by the substantial decrease of visceral fat (65.37%), body weight (9.78%), hyperlipidemia, and systemic inflammation, as well as total relief of type 2 diabetes. Conclusions: By directly targeting obese sWAT to induce its beneficial remodeling, this synergistic therapy leads to significant improvements in whole-body metabolism and the alleviation of obesity-related conditions, including type 2 diabetes. The elucidation of underlying signaling pathways provides fundamental insights and shall inspire new strategies to combat obesity and its associated diseases.
Assuntos
Células 3T3-L1 , Ferrocianetos , Nanopartículas , Obesidade , Animais , Camundongos , Obesidade/terapia , Nanopartículas/química , Ferrocianetos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Masculino , Terapia Fototérmica/métodos , Camundongos Endogâmicos C57BL , Adipócitos/metabolismo , Camundongos Obesos , Lipólise/efeitos dos fármacos , Modelos Animais de Doenças , Tecido Adiposo Branco/metabolismoRESUMO
Reactive oxygen species, when produced in a controlled manner, are physiological modulators of healthy white adipose tissue (WAT) expansion and metabolic function. By contrast, unbridled production of oxidants is associated with pathological WAT expansion and the establishment of metabolic dysfunctions, most notably insulin resistance and type 2 diabetes mellitus. NADPH oxidases (NOXs) produce oxidants in an orderly fashion and are present in adipocytes and in other diverse WAT-constituent cell types. Recent studies have established several links between aberrant NOX-derived oxidant production, adiposity, and metabolic homeostasis. The objective of this review is to highlight the physiological roles attributed to diverse NOX isoforms in healthy WAT and summarize current knowledge of the metabolic consequences related to perturbations in their adequate oxidant production. We detail WAT-related alterations in preclinical investigations conducted in NOX-deficient murine models. In addition, we review clinical studies that have employed NOX inhibitors and currently available data related to human NOX mutations in metabolic disturbances. Future investigations aimed at understanding the integration of NOX-derived oxidants in the regulation of the WAT cellular redox network are essential for designing successful redox-related precision therapies to curb obesity and attenuate obesity-associated metabolic pathologies.
Assuntos
Tecido Adiposo Branco , NADPH Oxidases , Obesidade , Espécies Reativas de Oxigênio , Humanos , Obesidade/metabolismo , NADPH Oxidases/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Espécies Reativas de Oxigênio/metabolismo , Resistência à Insulina , Oxirredução , Camundongos , Diabetes Mellitus Tipo 2/metabolismo , Adipócitos/metabolismoRESUMO
Obesity-related metabolic diseases are associated with a chronic inflammatory state. Calenduloside E (CE) is a triterpene saponin from sugar beet. In mouse models, CE reduced pro-inflammatory cytokines in white adipose tissue (WAT) and decreased macrophage infiltration of WAT. And CE inhibited pyroptosis in J774A.1 cells and WAT by inhibiting the activation of the nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome. Moreover, CE could trigger the activation of Sirtuin 2 (SIRT2), leading to a decrease in the acetylation of NLRP3, particularly at the K24 site. In addition, it has been shown that CE can reduce inflammation in adipocytes that have been induced by macrophage-conditioned medium. However, the selective SIRT2 inhibitor AGK2 hindered the beneficial effects of CE. In summary, CE has the capacity to impede NLRP3-mediated pyroptosis by triggering SIRT2 activity, thus positioning CE as a promising therapeutic avenue for combating obesity-related metabolic disorders.
Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Sirtuína 2 , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Animais , Camundongos , Sirtuína 2/metabolismo , Sirtuína 2/genética , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/imunologia , Saponinas/farmacologia , Saponinas/química , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/imunologiaRESUMO
Oxylipins and specialized pro-resolving lipid mediators (SPMs) derived from polyunsaturated fatty acids (PUFAs) are mediators that coordinate an active process of inflammation resolution. While these mediators have potential as circulating biomarkers for several disease states with inflammatory components, the source of plasma oxylipins/SPMs remains a matter of debate but may involve white adipose tissue (WAT). Here, we aimed to investigate to what extent high or low omega (n)-3 PUFA enrichment affects the production of cytokines and adipokines (RT-PCR), as well as oxylipins/SPMs (liquid chromatography-tandem mass spectrometry) in the WAT of mice during lipopolysaccharide (LPS)-induced systemic inflammation (intraperitoneal injection, 2.5 mg/kg, 24 h). For this purpose, n-3 PUFA genetically enriched mice (FAT-1), which endogenously synthesize n-3 PUFAs, were compared to wild-type mice (WT) and combined with n-3 PUFA-sufficient or deficient diets. LPS-induced systemic inflammation resulted in the decreased expression of most adipokines and interleukin-6 in WAT, whereas the n-3-sufficient diet increased them compared to the deficient diet. The n-6 PUFA arachidonic acid was decreased in WAT of FAT-1 mice, while n-3 derived PUFAs (eicosapentaenoic acid, docosahexaenoic acid) and their metabolites (oxylipins/SPMs) were increased in WAT by genetic and nutritional n-3 enrichment. Several oxylipins/SPMs were increased by LPS treatment in WAT compared to PBS-treated controls in genetically n-3 enriched FAT-1 mice. Overall, we show that WAT may significantly contribute to circulating oxylipin production. Moreover, n-3-sufficient or n-3-deficient diets alter adipokine production. The precise interplay between cytokines, adipokines, and oxylipins remains to be further investigated.
Assuntos
Adipocinas , Citocinas , Ácidos Graxos Ômega-3 , Oxilipinas , Animais , Oxilipinas/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Camundongos , Citocinas/metabolismo , Adipocinas/metabolismo , Masculino , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Inflamação/metabolismo , Inflamação/induzido quimicamente , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/efeitos dos fármacosRESUMO
Lipid droplets (LDs) are highly specialized energy storage organelles involved in the maintenance of lipid homoeostasis by regulating lipid flux within white adipose tissue (WAT). The physiological function of adipocytes and LDs can be compromised by mutations in several genes, leading to NEFA-induced lipotoxicity, which ultimately manifests as metabolic complications, predominantly in the form of dyslipidemia, ectopic fat accumulation, and insulin resistance. In this review, we delineate the effects of mutations and deficiencies in genes - CIDEC, PPARG, BSCL2, AGPAT2, PLIN1, LIPE, LMNA, CAV1, CEACAM1, and INSR - involved in lipid droplet metabolism and their associated pathophysiological impairments, highlighting their roles in the development of lipodystrophies and metabolic dysfunction.
Assuntos
Gotículas Lipídicas , Metabolismo dos Lipídeos , Humanos , Gotículas Lipídicas/metabolismo , Metabolismo dos Lipídeos/genética , Animais , Comorbidade , Resistência à Insulina , Mutação , Tecido Adiposo Branco/metabolismo , Adipócitos/metabolismo , Lipodistrofia/metabolismo , Lipodistrofia/genéticaRESUMO
There are at least two types of adipose tissues in the body, defined as brown adipose tissues (BATs) and white adipose tissues (WATs). These tissues comprise brown and white adipocytes, respectively. The adipocytes are commonly endowed with mitochondria, but they have diverse characteristics and roles. Brown adipocytes have abundant mitochondria that contribute to the ß-oxidation of fatty acids to produce chemical energy and the production of heat via uncoupling of the mitochondrial membrane potential from ATP synthesis. Alternatively, white adipocytes have fewer mitochondria that contribute to the generation of free fatty acids via lipogenesis by providing key intermediates. Besides the described types of adipocytes, brown-like adipocytes, termed beige adipocytes, are developed in WAT depots during cold exposure. Beige adipocytes also contribute to thermogenesis. Notably, beige adipocytes may transform into white-like adipocytes after the withdrawal of cold exposure. This process is marked by the elimination of mitochondria through the activation of mitochondria autophagy (mitophagy). This review aims to describe the mitophagy that occurs during the beige-to-white transition and discuss recent insights into the molecular mechanisms of this transformation. Additionally, we describe the mitophagy monitoring strategy in adipose tissues using three independent reporter systems and discuss the availabilities and limitations of the method.
Assuntos
Mitocôndrias , Mitofagia , Termogênese , Mitofagia/fisiologia , Animais , Humanos , Mitocôndrias/metabolismo , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/citologia , Adipócitos Bege/metabolismo , Adipócitos Bege/citologia , Temperatura , Tecido Adiposo/metabolismo , Adipócitos Brancos/metabolismo , Adipócitos Brancos/citologiaRESUMO
Pannexin1 (Panx1) ATP channels are important in adipocyte biology, potentially influencing energy storage and expenditure. We compared the metabolic phenotype of young (14 weeks old) and mature (20 weeks old) wild-type (WT) and Panx1-/- mice exposed or not to cold (6 °C) during 28 days, a condition promoting adipocyte browning. Young Panx1-/- mice weighed less and exhibited increased fat mass, improved glucose tolerance, and lower insulin sensitivity than WT mice. Their energy expenditure and respiratory exchange ratio (RER) were increased, and their fatty acid oxidation decreased. These metabolic effects were no longer observed in mature Panx1-/- mice. The exposure of mature mice to cold exacerbated their younger metabolic phenotype. The white adipose tissue (WAT) of cold-exposed Panx1-/- mice contained more small-sized adipocytes, but, in contrast to WT mice, white adipocytes did not increase their expression of Ucp1 nor of other markers of browning adipocytes. Interestingly, Glut4 expression was already enhanced in the WAT of young Panx1-/- mice kept at 22 °C as compared to WT mice. Thus, Panx1 deletion exerts overall beneficial metabolic effects in mice that are pre-adapted to chronic cold exposure. Panx1-/- mice show morphological characteristics of WAT browning, which are exacerbated upon cold exposure, an effect that appears to be associated with Ucp1-independent thermogenesis.
Assuntos
Tecido Adiposo Branco , Temperatura Baixa , Conexinas , Metabolismo Energético , Camundongos Knockout , Proteínas do Tecido Nervoso , Animais , Conexinas/genética , Conexinas/metabolismo , Camundongos , Metabolismo Energético/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Tecido Adiposo Branco/metabolismo , Fenótipo , Masculino , Camundongos Endogâmicos C57BL , Termogênese/genéticaRESUMO
The distinct anatomic environment in which adipose tissues arise during organogenesis is a principle determinant of their adult expansion capacity. Metabolic disease results from a deficiency in hyperplastic adipose expansion within the dermal/subcutaneous depot; thus, understanding the embryonic origins of dermal adipose is imperative. Using single-cell transcriptomics throughout murine embryogenesis, we characterized cell populations, including Bcl11b + cells, that regulate the development of dermal white adipose tissue (dWAT). We discovered that BCL11b expression modulates the Wnt signaling microenvironment to enable adipogenic differentiation in the dermal compartment. Subcutaneous and visceral adipose arises from a distinct population of Nefl + cells during embryonic organogenesis, whereas Pi16 + /Dpp4 + fibroadipogenic progenitors support obesity-stimulated hypertrophic expansion in the adult. Together, these results highlight the unique regulatory pathways used by anatomically distinct adipose depots, with important implications for human metabolic disease.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Proteínas Repressoras , Animais , Camundongos , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas Supressoras de Tumor/metabolismo , Proteínas Supressoras de Tumor/genética , Adipogenia/genética , Tecido Adiposo Branco/embriologia , Tecido Adiposo Branco/metabolismo , Via de Sinalização Wnt/genética , Tecido Adiposo/metabolismo , Tecido Adiposo/embriologia , Diferenciação Celular/genética , HumanosRESUMO
Obesity and type 2 diabetes mellitus are global public health issues. Although males show higher obesity and insulin resistance prevalence, current treatments often neglect sex-specific differences. White adipose tissue (WAT) is crucial in preventing lipotoxicity and inflammation and has become a key therapeutic target. Rosiglitazone (RSG), a potent PPARγ agonist, promotes healthy WAT growth and mitochondrial function through MitoNEET modulation. Recent RSG-based strategies specifically target white adipocytes, avoiding side effects. Our aim was to investigate whether sex-specific differences in the insulin-sensitizing effects of RSG exist on WAT during obesity and inflammation. We used Wistar rats of both sexes fed a high-fat diet (HFD, 22.5% fat content) for 16 weeks. Two weeks before sacrifice, a group of HFD-fed rats received RSG treatment (4 mg/kg of body weight per day) within the diet. HFD male rats showed greater insulin resistance, inflammation, mitochondrial dysfunction, and dyslipidemia than females. RSG had more pronounced effects in males, significantly improving insulin sensitivity, fat storage, mitochondrial function, and lipid handling in WAT while reducing ectopic fat deposition and enhancing adiponectin signaling in the liver. Our study suggests a significant sexual dimorphism in the anti-diabetic effects of RSG on WAT, correlating with the severity of metabolic dysfunction.
Assuntos
Tecido Adiposo Branco , Dieta Hiperlipídica , Resistência à Insulina , Ratos Wistar , Rosiglitazona , Animais , Rosiglitazona/farmacologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Masculino , Feminino , Dieta Hiperlipídica/efeitos adversos , Ratos , Hipoglicemiantes/farmacologia , Fatores Sexuais , Obesidade/tratamento farmacológico , Obesidade/metabolismo , PPAR gama/metabolismo , PPAR gama/agonistas , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Caracteres Sexuais , Inflamação/tratamento farmacológico , Fígado/metabolismo , Fígado/efeitos dos fármacos , Adiponectina/metabolismoRESUMO
BACKGROUND: Targeting white adipose tissue (WAT) browning to increase systemic energy expenditure is a promising therapeutic strategy to combat obesity. Actein from Actaea cimicifuga L. has recently been reported to ameliorate high fat-induced hepatic steatosis. However, the effect of actein on diet-induced obesity merits more and further investigation. PURPOSE: We aimed to examine the anti-obesity potential of actein and unravel its actions on WAT browning. METHODS: The effect of actein on diet-induced obesity was evaluated using a high-fat diet model in C57BL/6 mice. Systemic energy expenditure of mice was measured with a combined indirect calorimetry system. Quantitative real-time PCR analyses were performed to investigate the mRNA levels of genes involved in thermogenesis, browning, and lipolysis. The protein levels were assessed by Western blot. Moreover, WAT explants and a transwell co-culture system consisting of SVFs and adipocytes were constructed to study the mechanisms of actein on promoting WAT browning and lipolysis. RESULTS: At a dosage of 5 mg/kg/d, actein not only protected mice against diet-induced obesity and insulin resistance, but also reversed pre-established obesity and glucose intolerance in mice. Meanwhile, actein facilitated systemic energy expenditure by activating WAT lipolysis and browning. Further, mechanistic studies revealed that actein indirectly induced epididymal adipocyte lipolysis and directly promoted a white-to-beige conversion of subcutaneous adipocytes by activating the AMPK signaling. CONCLUSION: Actein ameliorated diet-induced obesity and was discovered as a natural lead compound directly targeting white-to-beige conversion of subcutaneous adipocytes, suggesting the potential of developing new therapies for obesity and associated metabolic disorders.
Assuntos
Tecido Adiposo Marrom , Tecido Adiposo Branco , Dieta Hiperlipídica , Metabolismo Energético , Obesidade , Animais , Masculino , Camundongos , Adipócitos/efeitos dos fármacos , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Fármacos Antiobesidade/farmacologia , Metabolismo Energético/efeitos dos fármacos , Resistência à Insulina , Lipólise/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Termogênese/efeitos dos fármacosRESUMO
Cachexia, which affects 50-80% of cancer patients, is a debilitating syndrome that leads to 20% of cancer-related deaths. A key feature of cachexia is adipose tissue atrophy, but how it contributes to the development of cachexia is poorly understood. Here, we demonstrate in mouse models of cancer cachexia that white adipose tissue browning, which can be a characteristic early-onset manifestation, occurs prior to the loss of body weight and skeletal muscle wasting. By analysing the proteins differentially expressed in extracellular vesicles derived from cachexia-inducing tumours, we identified a molecular chaperone, Glucose-regulated protein 75 (GRP75), as a critical mediator of adipocyte browning. Mechanistically, GRP75 binds adenine nucleotide translocase 2 (ANT2) to form a GRP75-ANT2 complex. Strikingly, stabilized ANT2 enhances its interaction with uncoupling protein 1, leading to elevated expression of the latter, which, in turn, promotes adipocyte browning. Treatment with withanone, a GRP75 inhibitor, can reverse this browning and alleviate cachectic phenotypes in vivo. Overall, our findings reveal a novel mechanism by which tumour-derived GRP75 regulates white adipose tissue browning during cachexia development and suggest a potential white adipose tissue-centred targeting approach for early cachexia intervention.
Assuntos
Tecido Adiposo Marrom , Tecido Adiposo Branco , Caquexia , Proteínas de Choque Térmico HSP70 , Neoplasias , Animais , Caquexia/genética , Caquexia/patologia , Caquexia/metabolismo , Camundongos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Translocador 2 do Nucleotídeo Adenina/genética , Translocador 2 do Nucleotídeo Adenina/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMO
As one of the main pathogenic factors of cardiovascular and cerebrovascular diseases, the incidence of metabolic diseases such as adiposity and metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing annually. It is urgent and crucial to find more therapeutic targets to treat these diseases. Mainly expressed in brown adipocytes, mitochondrial uncoupling protein 1 (UCP1) is key to the thermogenesis of classical brown adipose tissue (BAT). Furthermore, white adipose tissue (WAT) is likely to express more UCP1 and subsequently acquire the ability to undergo thermogenesis under certain stimuli. Therefore, targeting and activating UCP1 to promote increased BAT thermogenesis and browning of WAT are helpful in treating metabolic diseases, such as adiposity and MASLD. In this case, the stimuli that activate UCP1 are emerging. Therefore, we summarize the thermogenic stimuli that have activated UCP1 in recent decades, among which cold exposure is one of the stimuli first discovered to activate BAT thermogenesis. As a convenient and efficient therapy with few side effects and good metabolic benefits, physical exercise can also activate the expression of UCP1 in adipose tissue. Notably, for the first time, we have summarized and demonstrated the stimuli of traditional Chinese medicines that can activate UCP1, such as acupuncture, Chinese herbal formulas, and Chinese medicinal herbs. Moreover, pharmacological agents, functional foods, food ingredients, and the gut microbiota are also commonly associated with regulating and activating UCP1. The identification and analysis of UCP1 stimuli can greatly facilitate our understanding of adipose tissue thermogenesis, including the browning of WAT. Thus, it is more conducive to further research and therapy for glucose and lipid metabolism disorders.
Assuntos
Tecido Adiposo Marrom , Tecido Adiposo Branco , Termogênese , Proteína Desacopladora 1 , Proteína Desacopladora 1/metabolismo , Proteína Desacopladora 1/genética , Humanos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Medicamentos de Ervas Chinesas/farmacologia , Exercício Físico , Temperatura BaixaRESUMO
Lung cancer and cachexia are the leading causes of cancer-related deaths worldwide. Cachexia is manifested by weight loss and white adipose tissue (WAT) atrophy. Limited nutritional supplements are conducive to lung cancer patients, whereas the underlying mechanisms are poorly understood. In this study, we used a murine cancer cachexia model to investigate the effects of a nutritional formula (NuF) rich in fish oil and selenium yeast as an adjuvant to enhance the drug efficacy of an EGFR inhibitor (Tarceva). In contrast to the healthy control, tumor-bearing mice exhibited severe cachexia symptoms, including tissue wasting, hypoalbuminemia, and a lower food efficiency ratio. Experimentally, Tarceva reduced pEGFR and HIF-1α expression. NuF decreased the expression of pEGFR and HIF-2α, suggesting that Tarceva and NuF act differently in prohibiting tumor growth and subsequent metastasis. NuF blocked LLC tumor-induced PTHrP and expression of thermogenic factor UCP1 and lipolytic enzymes (ATGL and HSL) in WAT. NuF attenuated tumor progression, inhibited PTHrP-induced adipose tissue browning, and maintained adipose tissue integrity by modulating heat shock protein (HSP) 72. Added together, Tarceva in synergy with NuF favorably improves cancer cachexia as well as drug efficacy.
Assuntos
Caquexia , Suplementos Nutricionais , Receptores ErbB , Óleos de Peixe , Lipólise , Selênio , Termogênese , Animais , Caquexia/tratamento farmacológico , Caquexia/patologia , Camundongos , Selênio/farmacologia , Selênio/uso terapêutico , Lipólise/efeitos dos fármacos , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inibidores , Termogênese/efeitos dos fármacos , Óleos de Peixe/farmacologia , Óleos de Peixe/uso terapêutico , Camundongos Endogâmicos C57BL , Masculino , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismoRESUMO
Obesity arises from an imbalance between energy consumption and energy expenditure, and thyroid hormone levels serve as a determinant of energy expenditure. We conducted experiments at the animal and cellular levels and combined those findings with clinical data to elucidate the role of triiodothyronine (T3) in facilitating the browning of white adipose tissue (WAT) and its underlying mechanism. The results showed (i) the impaired metabolic function of local WAT and the compensatory elevation of systemic thermogenesis in obesity; (ii) T3 treatment of white adipocytes in vitro and local WAT in vivo induced a shift towards a morphologically "brown" phenotype, accompanied by upregulation of mRNA and protein expression of browning-related and mitochondrial function markers, which suggest that T3 intervention promotes the browning of WAT; and (iii) the aforementioned processes could be modulated through inhibition of the PI3K/AKT signalling pathway; however, whether T3 affects the PI3K/AKT signalling pathway by affecting insulin signalling remains to be studied and clarified. The results of our study indicate that T3 treatment promotes browning of WAT through inhibition of the PI3K/AKT signalling pathway; these findings offer novel perspectives regarding the potential of localised therapies for addressing WAT volume in individuals with obesity.
Assuntos
Tecido Adiposo Marrom , Tecido Adiposo Branco , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Termogênese , Tri-Iodotironina , Tri-Iodotironina/metabolismo , Tri-Iodotironina/farmacologia , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Tecido Adiposo Branco/metabolismo , Camundongos , Tecido Adiposo Marrom/metabolismo , Masculino , Humanos , Obesidade/metabolismo , Camundongos Endogâmicos C57BL , Metabolismo EnergéticoRESUMO
Erythropoietin (EPO) plays a key role in energy metabolism, with EPO receptor (EpoR) expression in white adipose tissue (WAT) mediating its metabolic activity. Here, we show that male mice lacking EpoR in adipose tissue exhibit increased fat mass and susceptibility to diet-induced obesity. Our findings indicate that EpoR is present in WAT, brown adipose tissue, and skeletal muscle. Elevated EPO in male mice improves glucose tolerance and insulin sensitivity while reducing expression of lipogenic-associated genes in WAT, which is linked to an increase in transcription factor RUNX1 that directly inhibits lipogenic genes expression. EPO treatment in wild-type male mice decreases fat mass and lipogenic gene expression and increase in RUNX1 protein in adipose tissue which is not observed in adipose tissue EpoR ablation mice. EPO treatment decreases WAT ubiquitin ligase FBXW7 expression and increases RUNX1 stability, providing evidence that EPO regulates energy metabolism in male mice through the EPO-EpoR-RUNX1 axis.
Assuntos
Tecido Adiposo Branco , Subunidade alfa 2 de Fator de Ligação ao Core , Metabolismo Energético , Eritropoetina , Receptores da Eritropoetina , Animais , Eritropoetina/metabolismo , Eritropoetina/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Masculino , Metabolismo Energético/efeitos dos fármacos , Camundongos , Receptores da Eritropoetina/metabolismo , Receptores da Eritropoetina/genética , Tecido Adiposo Branco/metabolismo , Camundongos Knockout , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Obesidade/genética , Músculo Esquelético/metabolismo , Resistência à Insulina , Lipogênese/genética , Lipogênese/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Dermal white adipose tissue (DWAT) is a distinctive adipose depot located within the lower dermis of the skin. Its significance as an ancillary fat in skin homoeostasis has recently received increased attention. New research has revealed that DWAT responses to skin pathology and physiology changes, impacting skin development, hair cycling, defense mechanisms, and fibrotic conditions. In this review, we explore the developmental process of DWAT and the adipose commitment timing of hypodermal. We explore the development process of DWAT and its pivotal role in regulating the hair cycle. We conclude the antibacterial activity and reversible dedifferentiation of dermal adipocytes in response to skin defense. Furthermore, we underscore the potentially crucial yet underestimated anti-fibrotic functions of DWAT-derived adipokines and adipocyte-myofibroblast transition.