RESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Huanglian Jiedu Decoction (HLJDD) is an ancient formula of traditional Chinese medicine that is commonly utilized in a range of disorders, and it has been shown to have pharmacological effects on glucose and lipid metabolism. However, the specific mechanism of HLJDD for the treatment of obesity and related metabolic disorders remains to be further investigated. AIM OF THE STUDY: It has been thought that encouraging adipose thermogenesis to raise the body's energy expenditure is a useful tactic for improving metabolic abnormalities and losing weight. In this study, we investigated the ability and underlying mechanisms of HLJDD to regulate fat cell thermogenesis to improve energy expenditure in obesity. METHODS: The obese mouse model was established on a high-fat diet for 12 weeks. All mice were divided into NC, HFD, HFD with HLJDD of a low dose (2.25 g/kg/d), and HFD with HLJDD of a high dose (4.5 g/kg/d) groups and kept for 4 weeks. In vitro experiments were conducted to evaluate the effects of 5% and 10% HLJDD-containing serum on differentiated 3T3-L1 cells and HDAC3-knocking-down 3T3-L1 cells. RESULTS: The results showed that HLJDD treatment significantly improved glucose and insulin tolerance and decreased the adipocyte radius of WATs, as well as increased energy consumption in obese mice. Besides, HLJDD treatment dramatically increased the levels of thermogenic genes UCP-1 and PGC-1α while suppressing HDAC3 levels in WATs and 3T3-L1 adipocytes. Importantly, the effects of HLJDD on PGC-1α and UCP-1 were blocked in HDAC3 knockdown adipocytes. CONCLUSIONS: Therefore, these results suggest that HLJDD enhanced adipose thermogenesis and improved energy expenditure by inhibiting HDAC3, thereby increasing UCP-1 and PGC-1α expression. These findings amplified the mechanisms of HLJDD and its potential to treat obesity and related metabolic disorders.
Asunto(s)
Células 3T3-L1 , Dieta Alta en Grasa , Medicamentos Herbarios Chinos , Histona Desacetilasas , Obesidad , Termogénesis , Animales , Masculino , Ratones , Medicamentos Herbarios Chinos/farmacología , Metabolismo Energético/efectos de los fármacos , Histona Desacetilasas/metabolismo , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/tratamiento farmacológico , Termogénesis/efectos de los fármacos , Proteína Desacopladora 1/metabolismo , Proteína Desacopladora 1/genéticaRESUMEN
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.
Asunto(s)
Frío , Medicamentos Herbarios Chinos , Metabolismo Energético , Microbioma Gastrointestinal , Termogénesis , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Termogénesis/efectos de los fármacos , Ratones , Metabolismo Energético/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Masculino , Ratones Endogámicos C57BL , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Pardo/efectos de los fármacosRESUMEN
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.
Asunto(s)
Tejido Adiposo Pardo , Tejido Adiposo Blanco , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Termogénesis , Triyodotironina , Triyodotironina/metabolismo , Triyodotironina/farmacología , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Tejido Adiposo Blanco/metabolismo , Ratones , Tejido Adiposo Pardo/metabolismo , Masculino , Humanos , Obesidad/metabolismo , Ratones Endogámicos C57BL , Metabolismo EnergéticoRESUMEN
The adipose organ is well recognized for its role in energy storage and mobilization, responding to nutrient availability, the body's needs, and thermogenesis, thereby regulating the organism's energy balance [...].
Asunto(s)
Tejido Adiposo , Metabolismo Energético , Humanos , Tejido Adiposo/metabolismo , Animales , Termogénesis , Obesidad/metabolismoRESUMEN
Macrophages play a multifaceted role in maintaining tissue homeostasis, fighting infections, and regulating cold-induced thermogenesis. The brown adipose tissue (BAT) is crucial for maintaining body temperature during cold exposure. Cold stress triggers the sympathetic nervous system to release norepinephrine (NE), which activates BAT via ß3-adrenergic receptors, initiating lipolysis and glycolysis. BAT-infiltrating macrophages can either hinder or enhance thermogenesis by controlling the interplay between BAT cells and sympathetic nerves. In this study we report on a unique population of CD3+F4/80+ dual lineage co-expressing (DE) cells within the interscapular BAT (iBAT), that increased following chronic adrenergic stimulation. In forward scatter/side scatter plots, they formed a cluster distinct from lymphocytes, appearing larger and more complex. These CD3+F4/80+ DE cells demonstrated the lack of T cell markers CD62L and TCRß and expressed higher levels of Ly6C, F4/80, and CD11b markers compared to T cells and CD3- macrophages. Furthermore, analysis revealed two subpopulations within the CD3+F4/80+ DE population based on MHCII expression, with the proportion of MHCII-low subset increasing with adrenergic stimulation. This novel DE population within iBAT, unequivocally identified by the its unique surface marker profile, warrants further investigation into the intricate mechanisms governing adaptive thermogenesis regulation.
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Tejido Adiposo Pardo , Complejo CD3 , Macrófagos , Termogénesis , Animales , Tejido Adiposo Pardo/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Complejo CD3/metabolismo , Norepinefrina/farmacología , Norepinefrina/metabolismo , Masculino , Ratones Endogámicos C57BL , Receptores Adrenérgicos beta 3/metabolismoRESUMEN
Beige fat activation involves a fuel switch to fatty acid oxidation following chronic cold adaptation. Mitochondrial acyl-CoA synthetase long-chain family member 1 (ACSL1) localizes in the mitochondria and plays a key role in fatty acid oxidation; however, the regulatory mechanism of the subcellular localization remains poorly understood. Here, we identify an endosomal trafficking component sortilin (encoded by Sort1) in adipose tissues that shows dynamic expression during beige fat activation and facilitates the translocation of ACSL1 from the mitochondria to the endolysosomal pathway for degradation. Depletion of sortilin in adipocytes results in an increase of mitochondrial ACSL1 and the activation of AMPK/PGC1α signaling, thereby activating beige fat and preventing high-fat diet (HFD)-induced obesity and insulin resistance. Collectively, our findings indicate that sortilin controls adipose tissue fatty acid oxidation by substrate fuel selection during beige fat activation and provides a potential targeted approach for the treatment of metabolic diseases.
Asunto(s)
Proteínas Adaptadoras del Transporte Vesicular , Adipocitos , Coenzima A Ligasas , Dieta Alta en Grasa , Metabolismo Energético , Mitocondrias , Animales , Masculino , Ratones , Células 3T3-L1 , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/genética , Adipocitos/metabolismo , Tejido Adiposo Beige/metabolismo , Coenzima A Ligasas/metabolismo , Coenzima A Ligasas/genética , Ácidos Grasos/metabolismo , Resistencia a la Insulina , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias/metabolismo , Obesidad/metabolismo , Obesidad/genética , Oxidación-Reducción , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Transporte de Proteínas , Transducción de Señal , TermogénesisRESUMEN
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.
Asunto(s)
Caquexia , Suplementos Dietéticos , Receptores ErbB , Aceites de Pescado , Lipólisis , Selenio , Termogénesis , Animales , Caquexia/tratamiento farmacológico , Caquexia/patología , Ratones , Selenio/farmacología , Selenio/uso terapéutico , Lipólisis/efectos de los fármacos , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inhibidores , Termogénesis/efectos de los fármacos , Aceites de Pescado/farmacología , Aceites de Pescado/uso terapéutico , Ratones Endogámicos C57BL , Masculino , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/patología , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismoRESUMEN
Brown adipose tissue (BAT) participates in thermogenesis and energy homeostasis. Studies on factors capable of influencing BAT function, such as a high-fat diet (HFD) or exposure to environmental pollutants, could be useful for finding metabolic targets for maintaining energy homeostasis. We evaluated the effect of chronic exposure to dichlorodiphenyldichloroethylene (DDE), the major metabolite of dichlorodiphenyltrichloroethane (DDT), and/or a HFD on BAT morphology, mitochondrial mass, dynamics, and oxidative stress in rats. To this end, male Wistar rats were treated for 4 weeks with a standard diet, or a HFD alone, or together with DDE. An increase in paucilocular adipocytes and the lipid droplet size were observed in HFD-treated rats, which was associated with a reduction in mitochondrial mass and in mitochondrial fragmentation, as well as with increased oxidative stress and upregulation of the superoxide dismutase-2. DDE administration mimics most of the effects induced by a HFD on BAT, and it aggravates the increase in the lipid droplet size when administered together with a HFD. Considering the known role of oxidative stress in altering BAT functionality, it could underlie the ability of both DDE and a HFD to induce similar metabolic adaptations in BAT, leading to reduced tissue thermogenesis, which can result in a predisposition to the onset of energy homeostasis disorders.
Asunto(s)
Tejido Adiposo Pardo , Diclorodifenil Dicloroetileno , Dieta Alta en Grasa , Contaminantes Ambientales , Estrés Oxidativo , Ratas Wistar , Animales , Masculino , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Dieta Alta en Grasa/efectos adversos , Estrés Oxidativo/efectos de los fármacos , Contaminantes Ambientales/toxicidad , Ratas , Diclorodifenil Dicloroetileno/toxicidad , Superóxido Dismutasa/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Adaptación Fisiológica/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Termogénesis/efectos de los fármacos , Gotas Lipídicas/metabolismo , Gotas Lipídicas/efectos de los fármacosRESUMEN
Nonalcoholic fatty liver disease (NAFLD) affects over a third of the US population and 25% globally, with current treatments proving ineffective. This study investigates whether manipulating brown adipose tissue (BAT) and beige fat activity by housing C57BL/6J mice at thermoneutral (27 °C) or standard temperatures (22 °C) impacts NAFLD development. Male mice were fed either a chow diet (CHD) or a "fast food" diet (FFD) for 10 weeks. Mice at 27 °C had reduced food intake but increased body weight and plasma leptin levels. FFD-fed mice at 27 °C had greater liver weight (2.6 vs. 1.8 g), triglyceride content (7.6 vs. 3.9 mg/g), and hepatic steatosis compared to those at 22 °C. Gene expression of fatty acid synthase, sterol regulatory element-binding protein 1, and fatty acid translocase CD36 was elevated in FFD-fed mice at 27 °C, but not in CHD-fed mice. Thermoneutral housing also reduced expression of thermogenic markers in BAT and inguinal white adipose tissue (WAT) and caused BAT whitening. In conclusion, thermoneutrality inhibits thermogenic markers and exacerbates NAFLD. Activating BAT or promoting WAT browning via cold exposure or other stimuli may offer a strategy for managing NAFLD.
Asunto(s)
Tejido Adiposo Pardo , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico , Termogénesis , Animales , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Ratones , Tejido Adiposo Pardo/metabolismo , Masculino , Tejido Adiposo Blanco/metabolismo , Hígado/metabolismo , Hígado/patología , Biomarcadores , Modelos Animales de Enfermedad , Peso Corporal , Leptina/sangre , Leptina/metabolismo , Triglicéridos/sangre , Triglicéridos/metabolismoRESUMEN
BACKGROUND: Shengmai San Formula (SMS) is a traditional Chinese medicine (TCM) that has been used to treat wasting-thirst regarded as diabetes mellitus, which occurs disproportionately in obese patients. Therefore, we investigated whether SMS could be used to treat obesity, and explored possible mechanisms by which it might improve glucose and fat metabolism. METHODS: To investigate the effects of SMS on a high-fat diet (HFD)-induced obesity (DIO) model, we studied glucose metabolism via glucose tolerance testing (GTT) and insulin tolerance testing (ITT). Browning of white adipose tissue (WAT) was evaluated using H&E staining, along with browning-related gene and protein expression. Changes in bile acid (BA) levels in serum, liver, ileum, and inguinal white adipose tissue were detected by Ultra performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). In addition, antimicrobial mixture (ABX) and fecal microbial transplantation (FMT) experiments were used to verify the role of gut flora in the effects produced by SMS on HFD-induced obesity model. RESULTS: SMS ameliorated diet-induced dyslipidemia in a dose-dependent manner and reduced glucose intolerance and insulin resistance in DIO mice, helping to restore energy metabolism homeostasis. SMS significantly altered the structure of intestinal microbiome composition, decreasing the abundance of Lactobacillus carrying bile salt hydrolase (BSH) enzymes and thereby increasing the level of conjugated BAs in the blood, ileum, and iWAT. Increased TCA content promoted the secretion of Slit3 from M2 macrophages in iWAT, which activates the protein kinase A/calmodulin-dependent protein kinase II (PKA/CaMKII) signaling pathway in sympathetic neurons via the roundabouts receptor 1(ROBO1). This pathway promotes the synthesis and release of norepinephrine (NE), inducing cyclic adenosine monophosphate (cAMP) release in adipose tissue that activates the cyclic adenosine monophosphate/protein kinase A/phosphorylated hormone-sensitive lipase (cAMP/PKA/pHSL) pathway and enhances WAT browning. ABX treatment eliminated SMS effects on glucose and lipid metabolism in DIO mice, whereas glucose and lipid metabolism in obese mice improved following SMS-FMT and increased the level of serum bile acids. CONCLUSION: SMS affects intestinal flora and bile acid composition in vivo and increased TCA promotes M2 macrophage polarization and Slit3 release in adipose tissue. This induces NE release and increases WAT browning in obese mice, which may be a mechanism by which SMS could be used to treat obesity.
Asunto(s)
Ácidos y Sales Biliares , Dieta Alta en Grasa , Medicamentos Herbarios Chinos , Microbioma Gastrointestinal , Macrófagos , Ratones Endogámicos C57BL , Obesidad , Termogénesis , Animales , Dieta Alta en Grasa/efectos adversos , Microbioma Gastrointestinal/efectos de los fármacos , Obesidad/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Masculino , Ácidos y Sales Biliares/metabolismo , Termogénesis/efectos de los fármacos , Ratones , Macrófagos/efectos de los fármacos , Tejido Adiposo Blanco/efectos de los fármacos , Prueba de Tolerancia a la Glucosa , Modelos Animales de EnfermedadRESUMEN
Brown fat is a therapeutic target for the treatment of obesity-associated metabolic diseases. However, nutritional intervention strategies for increasing the mass and activity of human brown adipocytes have not yet been established. To identify vitamins required for brown adipogenesis and adipocyte browning, chemical compound-induced brown adipocytes (ciBAs) were converted from human dermal fibroblasts under serum-free and vitamin-free conditions. Choline was found to be essential for adipogenesis. Additional treatment with pantothenic acid (PA) provided choline-induced immature adipocytes with browning properties and metabolic maturation, including uncoupling protein 1 (UCP1) expression, lipolysis, and mitochondrial respiration. However, treatment with high PA concentrations attenuated these effects along with decreased glycolysis. Transcriptome analysis showed that a low PA concentration activated metabolic genes, including the futile creatine cycle-related thermogenic genes, which was reversed by a high PA concentration. Riboflavin treatment suppressed thermogenic gene expression and increased lipolysis, implying a metabolic pathway different from that of PA. Thiamine treatment slightly activated thermogenic genes along with decreased glycolysis. In summary, our results suggest that specific B vitamins and choline are uniquely involved in the regulation of adipocyte browning via cellular energy metabolism in a concentration-dependent manner.
Asunto(s)
Adipocitos Marrones , Colina , Ácido Pantoténico , Riboflavina , Tiamina , Humanos , Riboflavina/farmacología , Ácido Pantoténico/farmacología , Ácido Pantoténico/metabolismo , Adipocitos Marrones/metabolismo , Adipocitos Marrones/efectos de los fármacos , Tiamina/farmacología , Tiamina/metabolismo , Colina/metabolismo , Colina/farmacología , Proteína Desacopladora 1/metabolismo , Proteína Desacopladora 1/genética , Lipólisis/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Termogénesis/efectos de los fármacos , Adipogénesis/efectos de los fármacos , Glucólisis/efectos de los fármacos , Células Cultivadas , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacosRESUMEN
Thermogenic adipose tissue, consisting of brown and beige fat, regulates nutrient utilization and energy metabolism. Human brown fat is relatively scarce and decreases with obesity and aging. Hence, inducing thermogenic differentiation of white fat offers an attractive way to enhance whole-body metabolic capacity. Here, we show the role of endothelin 3 (EDN3) and endothelin receptor type B (EDNRB) in promoting the browning of white adipose tissue (WAT). EDNRB overexpression stimulates thermogenic differentiation of human white preadipocytes through cAMP-EPAC1-ERK activation. In mice, cold induces the expression of EDN3 and EDNRB in WAT. Deletion of EDNRB in adipose progenitor cells impairs cold-induced beige adipocyte formation in WAT, leading to excessive weight gain, glucose intolerance, and insulin resistance upon high-fat feeding. Injection of EDN3 into WAT promotes browning and improved whole-body glucose metabolism. The findings shed light on the mechanism of WAT browning and offer potential therapeutics for obesity and metabolic disorders.
Asunto(s)
Tejido Adiposo Blanco , Diferenciación Celular , Endotelina-3 , Receptor de Endotelina B , Transducción de Señal , Termogénesis , Animales , Tejido Adiposo Blanco/metabolismo , Termogénesis/genética , Humanos , Ratones , Receptor de Endotelina B/metabolismo , Receptor de Endotelina B/genética , Endotelina-3/metabolismo , Endotelina-3/genética , Masculino , Obesidad/metabolismo , Obesidad/genética , Ratones Endogámicos C57BL , Dieta Alta en Grasa , Resistencia a la Insulina , Adipocitos Blancos/metabolismo , Ratones Noqueados , Adipocitos Beige/metabolismo , Tejido Adiposo Pardo/metabolismo , Intolerancia a la Glucosa/metabolismo , FríoRESUMEN
Crosstalk between peripheral metabolic organs and the central nervous system is essential for body weight control. At the base of the hypothalamus, ß-tanycytes surround the portal capillaries and function as gatekeepers to facilitate transfer of substances from the circulation into the cerebrospinal fluid and vice versa. Here, we investigated the role of the neuroplasticity gene doublecortin-like (DCL), highly expressed by ß-tanycytes, in body weight control and whole-body energy metabolism. We demonstrated that DCL-knockdown through a doxycycline-inducible shRNA expression system prevents body weight gain by reducing adiposity in mice. DCL-knockdown slightly increased whole-body energy expenditure possibly as a result of elevated circulating thyroid hormones. In white adipose tissue (WAT) triglyceride uptake was increased while the average adipocyte cell size was reduced. At histological level we observed clear signs of browning, and thus increased thermogenesis in WAT. We found no indications for stimulated thermogenesis in brown adipose tissue (BAT). Altogether, we demonstrate an important, though subtle, role of tanycytic DCL in body weight control through regulation of energy expenditure, and specifically WAT browning. Elucidating mechanisms underlying the role of DCL in regulating brain-peripheral crosstalk further might identify new treatment targets for obesity.
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Tejido Adiposo Blanco , Metabolismo Energético , Obesidad , Animales , Ratones , Obesidad/metabolismo , Obesidad/genética , Tejido Adiposo Blanco/metabolismo , Masculino , Tejido Adiposo Pardo/metabolismo , Termogénesis/genética , Técnicas de Silenciamiento del Gen , Proteínas de Dominio Doblecortina , Peso Corporal , Ratones Endogámicos C57BL , Tejido Adiposo/metabolismo , Adiposidad/genéticaRESUMEN
Obesity is one of the threats to human health and survival. High fat diet (HFD)-induced obesity leads to adipose tissue fibrosis and a series of metabolic diseases. There are some people still thin under HFD, a phenomenon known as the "obesity resistance (OR) phenotype". It was found that Iroquois homeobox 3 (IRX3) is considered as a regulator in obesity, but the regulatory mechanism between OR and IRX3 is still unclear. In this study, we investigated OR on a HFD and the role of the IRX3 gene. Using mice, we observed that OR mice had lower body weights, reduced liver lipid synthesis, and increased white adipose tissue (WAT) lipolysis compared to obesity-prone (OP) mice. Additionally, OR mice exhibited spontaneous WAT browning and less fibrosis, correlating with higher Irx3 expression. Utilizing 3T3-L1 differentiated adipocytes, our study demonstrated that overexpression of Irx3 promoted thermogenesis-related gene expression and reduced adipocyte fibrosis. Therefore, Irx3 promotes WAT browning and inhibits fibrosis in OR mice. These results provide insight into the differences between obesity and OR, new perspectives on obesity treatment, and guidance for lessening adipose tissue fibrosis.
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Tejido Adiposo Pardo , Dieta Alta en Grasa , Fibrosis , Proteínas de Homeodominio , Obesidad , Factores de Transcripción , Animales , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Ratones , Obesidad/metabolismo , Obesidad/genética , Obesidad/patología , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Pardo/patología , Dieta Alta en Grasa/efectos adversos , Masculino , Ratones Endogámicos C57BL , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/patología , Células 3T3-L1 , Termogénesis/genéticaRESUMEN
Enhancing thermogenic brown adipose tissue (BAT) function is a promising therapeutic strategy for metabolic disease. However, predominantly thermoneutral modern human living conditions deactivate BAT. We demonstrate that selective adipocyte deficiency of the oxygen-sensor HIF-prolyl hydroxylase (PHD2) gene overcomes BAT dormancy at thermoneutrality. Adipocyte-PHD2-deficient mice maintain higher energy expenditure having greater BAT thermogenic capacity. In human and murine adipocytes, a PHD inhibitor increases Ucp1 levels. In murine brown adipocytes, antagonising the major PHD2 target, hypoxia-inducible factor-(HIF)-2a abolishes Ucp1 that cannot be rescued by PHD inhibition. Mechanistically, PHD2 deficiency leads to HIF2 stabilisation and binding of HIF2 to the Ucp1 promoter, thus enhancing its expression in brown adipocytes. Serum proteomics analysis of 5457 participants in the deeply phenotyped Age, Gene and Environment Study reveal that serum PHD2 associates with increased risk of metabolic disease. Here we show that adipose-PHD2-inhibition is a therapeutic strategy for metabolic disease and identify serum PHD2 as a disease biomarker.
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Tejido Adiposo Pardo , Metabolismo Energético , Prolina Dioxigenasas del Factor Inducible por Hipoxia , Termogénesis , Proteína Desacopladora 1 , Animales , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Prolina Dioxigenasas del Factor Inducible por Hipoxia/genética , Humanos , Ratones , Tejido Adiposo Pardo/metabolismo , Termogénesis/genética , Proteína Desacopladora 1/metabolismo , Proteína Desacopladora 1/genética , Masculino , Ratones Noqueados , Femenino , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Adipocitos/metabolismo , Oxígeno/metabolismo , Ratones Endogámicos C57BL , Adipocitos Marrones/metabolismo , Adulto , Regiones Promotoras Genéticas , Persona de Mediana EdadRESUMEN
Choline is an essential nutrient for the biosynthesis of phospholipids, neurotransmitters, and one-carbon metabolism with a critical step being its import into mitochondria. However, the underlying mechanisms and biological significance remain poorly understood. Here, we report that SLC25A48, a previously uncharacterized mitochondrial inner-membrane carrier protein, controls mitochondrial choline transport and the synthesis of choline-derived methyl donors. We found that SLC25A48 was required for brown fat thermogenesis, mitochondrial respiration, and mitochondrial membrane integrity. Choline uptake into the mitochondrial matrix via SLC25A48 facilitated the synthesis of betaine and purine nucleotides, whereas loss of SLC25A48 resulted in increased production of mitochondrial reactive oxygen species and imbalanced mitochondrial lipids. Notably, human cells carrying a single nucleotide polymorphism on the SLC25A48 gene and cancer cells lacking SLC25A48 exhibited decreased mitochondrial choline import, increased oxidative stress, and impaired cell proliferation. Together, this study demonstrates that SLC25A48 regulates mitochondrial choline catabolism, bioenergetics, and cell survival.
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Colina , Mitocondrias , Colina/metabolismo , Humanos , Mitocondrias/metabolismo , Animales , Ratones , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/genética , Transporte Biológico , Ratones Endogámicos C57BL , Masculino , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Termogénesis/genéticaRESUMEN
BACKGROUND: Brown adipose tissue (BAT) is a thermogenic tissue that uncouples oxidative phosphorylation from ATP synthesis and increases energy expenditure via non-shivering thermogenesis in mammals. Cold exposure and exercise have been shown to increase BAT and browning of white adipose tissue (WAT) in mice. This study aimed to determine whether there is an additive effect of exercise during cold exposure on markers related to browning of adipose tissue. in Wistar rats. METHODS: Twenty-four male Wistar rats were randomly divided into three groups: Control (C, 25ËC), Swimming in Neutral (SN, 30ËC) water, and Swimming in Cold (SC, 15ËC) water. Swimming included intervals of 2-3 min, 1 min rest, until exhausted, three days a week for six weeks, with a training load of 3-6% body weight. After the experimental protocol, interscapular BAT and inguinal subcutaneous white adipose tissue (WAT) were excised, weighed, and processed for beiging marker gene expression. RESULTS: SN and SC resulted in lower body weight gain, associated with reduced WAT and BAT volume and increased BAT number with greater effects observed in SC. Myostatin protein expression was lower in BAT, WAT, soleus muscle, and serum NC and SC compared to the C group. Expression of the interferon regulatory factor-4 (IRF4) gene in both BAT and WAT tissues was significantly greater in the SC than in the C. Expression of the PGC-1α in BAT was significantly increased in the SC compared to C and increased in WAT in NC and SC. Expression of the UCP1 in BAT and WAT increased in the SC group compared to other groups. CONCLUSION: The findings demonstrate that six weeks of swimming training in cold water promotes additive effects of the expression of genes and proteins involved in the browning process of adipose tissue in Wistar rats. Myostatin inhibition may possess a regulator effect on the PGC-1α - UCP1 pathway that mediates adipose tissue browning.
Asunto(s)
Tejido Adiposo Pardo , Tejido Adiposo Blanco , Frío , Miostatina , Condicionamiento Físico Animal , Ratas Wistar , Natación , Termogénesis , Animales , Masculino , Ratas , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Peso Corporal , Metabolismo Energético , Miostatina/metabolismo , Miostatina/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Transducción de Señal , Natación/fisiología , Termogénesis/fisiología , Agua/metabolismoRESUMEN
Obesity and its complications have become a global health problem that needs to be addressed urgently. White adipose tissue (WAT) browning contributes to consuming excess energy in WAT, which is important for improving obesity and maintaining a healthy energy homeostasis. Mitochondria, as the energy metabolism center of cells, are extensively involved in many metabolic processes, including the browning of WAT. NADH: Ubiquinone oxidoreductase subunit A8 (NDUFA8) is a constituent subunit of respiratory chain complex I (CI), which has been found to participate in a wide range of physiological processes by affecting the activity of respiratory CI. However, the regulatory effect of Ndufa8 on the browning of WAT has not been reported. Here, we used ß3-adrenergic agonis CL316, 243 to construct WAT browning models in vivo and in vitro to investigate the role and mechanism of Ndufa8 in the regulation of WAT browning. Briefly, Ndufa8 significantly increased CI activity and suppressed mitochondrial ROS levels in vitro, thereby improving mitochondrial function. Ndufa8 also increased the transcriptional levels and protein levels of UCP1 in vitro and in vivo, which promoted WAT browning. Our findings provide a new molecular approach for the research of browning of WAT in animals, as well as a new target for animal metabolism improvement and obesity treatments.
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Tejido Adiposo Pardo , Tejido Adiposo Blanco , Complejo I de Transporte de Electrón , Ratones Endogámicos C57BL , Mitocondrias , Obesidad , Animales , Complejo I de Transporte de Electrón/metabolismo , Obesidad/metabolismo , Tejido Adiposo Blanco/metabolismo , Ratones , Mitocondrias/metabolismo , Tejido Adiposo Pardo/metabolismo , Masculino , Especies Reactivas de Oxígeno/metabolismo , Proteína Desacopladora 1/metabolismo , Proteína Desacopladora 1/genética , Dioxoles/farmacología , Dieta Alta en Grasa , TermogénesisRESUMEN
Rhein, a component derived from rhubarb, has been proven to possess anti-inflammatory properties. Here, we show that rhein mitigates obesity by promoting adipose tissue thermogenesis in diet-induced obese mice. We construct a macrophage-adipocyte co-culture system and demonstrate that rhein promotes adipocyte thermogenesis through inhibiting NLRP3 inflammasome activation in macrophages. Moreover, clues from acetylome analysis identify SIRT2 as a potential drug target of rhein. We further verify that rhein directly interacts with SIRT2 and inhibits NLRP3 inflammasome activation in a SIRT2-dependent way. Myeloid knockdown of SIRT2 abrogates adipose tissue thermogenesis and metabolic benefits in obese mice induced by rhein. Together, our findings elucidate that rhein inhibits NLRP3 inflammasome activation in macrophages by regulating SIRT2, and thus promotes white adipose tissue thermogenesis during obesity. These findings uncover the molecular mechanism underlying the anti-inflammatory and anti-obesity effects of rhein, and suggest that rhein may become a potential drug for treating obesity.
Asunto(s)
Antraquinonas , Macrófagos , Obesidad , Sirtuina 2 , Termogénesis , Animales , Masculino , Ratones , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Tejido Adiposo/efectos de los fármacos , Antraquinonas/farmacología , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Obesidad/metabolismo , Obesidad/tratamiento farmacológico , Sirtuina 2/metabolismo , Sirtuina 2/genética , Termogénesis/efectos de los fármacosRESUMEN
BACKGROUND: Adaptation to cold was essential for human migration across Eurasia. Non-shivering thermogenesis through brown adipose tissue (BAT) participates in cold adaptation because some genes involved in the differentiation and function of BAT exhibit signatures of positive natural selection in populations at high latitudes. Whether these genes are associated with the inter-individual variability in BAT thermogenesis remains unclear. In this study, we evaluated the potential associations between BAT activity and single nucleotide polymorphisms (SNPs) in candidate gene regions in East Asian populations. METHODS: BAT activity induced by mild cold exposure was measured in 399 healthy Japanese men and women using fluorodeoxyglucose-positron emission tomography and computed tomography (FDG-PET/CT). The capacity for cold-induced thermogenesis and fat oxidation was measured in 56 men. Association analyses with physiological traits were performed for 11 SNPs at six loci (LEPR, ANGPTL8, PLA2G2A, PLIN1, TBX15-WARS2, and FADS1) reported to be under positive natural selection. Associations found in the FDG-PET/CT population were further validated in 84 healthy East Asian men and women, in whom BAT activity was measured using infrared thermography. Associations between the SNP genotypes and BAT activity or other related traits were tested using multiple logistic and linear regression models. RESULTS: Of the 11 putative adaptive alleles of the six genes, two intronic SNPs in LEPR (rs1022981 and rs12405556) tended to be associated with higher BAT activity. However, these did not survive multiple test comparisons. Associations with lower body fat percentage, plasma triglyceride, insulin, and HOMA-IR levels were observed in the FDG-PET/CT population (P < 0.05). Other loci, including TBX15-WARS2, which is speculated to mediate cold adaptation in Greenland Inuits, did not show significant differences in BAT thermogenesis. CONCLUSIONS: Our results suggest a marginal but significant association between LEPR SNPs. However, robust supporting evidence was not established for the involvement of other loci under positive natural selection in cold adaptation through BAT thermogenesis in East Asian adults. Given the pleiotropic function of these genes, factors other than cold adaptation through BAT thermogenesis, such as diet adaptation, may contribute to positive natural selection at these loci.