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1.
Gene ; 766: 145155, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32950634

RESUMO

Expression of browning genes are lower in both humans and animals with type 2 diabetes (T2D). This study aims at determining effects of long-term nitrate administration on protein and mRNA levels of uncoupling protein 1 (UCP1), peroxisome proliferator activated receptor gamma (PPAR-γ), and PPAR-γ coactivator 1 alpha (PGC1-α) in epididymal adipose tissue (eAT) of rats with T2D. Male Wistar rats were divided into 4 groups (n = 6/group): Control, diabetes, control + nitrate (CN), and diabetes + nitrate (DN). T2D was induced using high fat diet combined with a low-dose of streptozotocin (30 mg/kg body weight). Sodium nitrate was administrated at a dose of 100 mg/L for 6 months in nitrate-treated rats. Fasting serum glucose and insulin concentrations were measured at months 0 (i.e. at start of the protocol), 3, and 6. At month 6, protein and mRNA levels of UCP1, PPAR-γ, and PGC1-α were measured in eAT samples. In addition, tissue concentration of cyclic guanosine monophosphate (cGMP) was measured and histological analyses were done at month 6. In rats with T2D, 6-month administration of nitrate decreased serum glucose and insulin concentrations by 13% and 23%, respectively and increased cGMP level by 85%. Rats with T2D had lower mRNA and protein levels of PPAR-γ (62%, P < 0.0001 and 18%, P = 0.0472), PGC1-α (49%, P = 0.0019 and 21%, P = 0.0482), and UCP1 (35%, P = 0.0613 and 30%, P = 0.0031) in eAT; 6-month nitrate administration restored these decreased levels to near control values. In addition, nitrate increased adipocyte density by 193% and decreased adipocyte area by 53% in rats with T2D. In conclusion, long-term low-dose nitrate administration increased mRNA and protein expressions of browning genes in white adipose tissue of male rats with T2D; these findings partly explain favorable metabolic effects of nitrate administration in diabetes.


Assuntos
Adipócitos Marrons/efeitos dos fármacos , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 2/genética , Epididimo/efeitos dos fármacos , Nitratos/administração & dosagem , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipócitos Marrons/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Epididimo/metabolismo , Glucose/metabolismo , Insulina/sangue , Masculino , PPAR gama/genética , PPAR gama/metabolismo , RNA Mensageiro/genética , Ratos , Ratos Wistar , Estreptozocina/farmacologia
2.
Sci Rep ; 10(1): 20203, 2020 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-33214601

RESUMO

Brown adipose tissue (BAT) thermogenesis is considered a potential target for treatment of obesity and diabetes. In vitro data suggest dopamine receptor signaling as a promising approach; however, the biological relevance of dopamine receptors in the direct activation of BAT thermogenesis in vivo remains unclear. We investigated BAT thermogenesis in vivo in mice using peripheral administration of D1-agonist SKF38393 or D2-agonist Sumanirole, infrared thermography, and in-depth molecular analyses of potential target tissues; and ex vivo in BAT explants to identify direct effects on key thermogenic markers. Acute in vivo treatment with the D1- or D2-agonist caused a short spike or brief decrease in BAT temperature, respectively. However, repeated daily administration did not induce lasting effects on BAT thermogenesis. Likewise, neither agonist directly affected Ucp1 or Dio2 mRNA expression in BAT explants. Taken together, the investigated agonists do not seem to exert lasting and physiologically relevant effects on BAT thermogenesis after peripheral administration, demonstrating that D1- and D2-receptors in iBAT are unlikely to constitute targets for obesity treatment via BAT activation.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D2/agonistas , Termogênese/efeitos dos fármacos , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Tecido Adiposo Marrom/metabolismo , Animais , Benzimidazóis/farmacologia , Masculino , Camundongos , Transdução de Sinais/efeitos dos fármacos , Termografia
3.
Toxicol Appl Pharmacol ; 409: 115298, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33091441

RESUMO

Maternal nicotine exposure during pregnancy and lactation is associated with obesity in female offspring. Brown adipose tissue (BAT) is related to energy metabolism and obesity. In this study, we explored the mechanism of maternal nicotine exposure on BAT "whitening" in female offspring. Pregnant rats were randomly assigned to nicotine (1.0 mg/kg twice per day, subcutaneous administration) or control groups. The weight, structure, and microvascular density of interscapular BAT (iBAT) and the expression of PGC-1αUCP1 signals, mitochondrial biogenesis-related genes and angiogenesis-related genes were tested in 4- and 26-week-aged female offspring. In vitro, C3H10T1/2 cells were induced to differentiate into mature brown adipocytes, and 0-50 µM nicotine was treated on cells during the differentiation process. Nicotine-exposed females had higher iBAT weight, white-like adipocytes and abnormal mitochondrial structure in iBAT at 26 weeks rather than 4 weeks. The PGC-1αUCP1 signals and brown-like genes were down-regulated at 26 weeks, but the microvascular density and the expression of pro-angiogenic factors reduced more at 4 weeks in the nicotine group. In vitro, 50 µM nicotine significantly decreased the expression of PGC-1αUCP1 signals and angiogenesis-related genes. In conclusion, maternal nicotine exposure during pregnancy and lactation led to the "whitening" of BAT in adult female offspring: nicotine decreased BAT angiogenesis in the early development stage, and then, the impairment of blood vessels programed for the reduction of BAT phenotype through down-regulating the PGC-1αUCP1 signals in adulthood. This impairment of BAT may be a potential mechanism of nicotine-induced obesity in female offspring.


Assuntos
Adipócitos Marrons/efeitos dos fármacos , Tecido Adiposo Marrom/efeitos dos fármacos , Lactação/efeitos dos fármacos , Exposição Materna/efeitos adversos , Nicotina/efeitos adversos , Animais , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Feminino , Masculino , Camundongos , Obesidade/fisiopatologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Ratos , Ratos Wistar
4.
Am J Physiol Endocrinol Metab ; 319(5): E912-E922, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32954821

RESUMO

Numerous studies have shown that the recruitment and activation of thermogenic adipocytes, which are brown and beige/brite, reduce the mass of adipose tissue and normalize abnormal glycemia and lipidemia. However, the impact of these adipocytes on the inflammatory state of adipose tissue is still not well understood, especially in response to endotoxemia, which is a major aspect of obesity and metabolic diseases. First, we analyzed the phenotype and metabolic function of white and brite primary adipocytes in response to lipopolysaccharide (LPS) treatment in vitro. Then, 8-wk-old male BALB/c mice were treated for 1 wk with a ß3-adrenergic receptor agonist (CL316,243, 1 mg/kg/day) to induce recruitment and activation of brown and brite adipocytes and were subsequently injected with LPS (Escherichia coli lipopolysaccharide, 100 µg/mouse ip) to generate acute endotoxemia. The metabolic and inflammatory parameters of the mice were analyzed 6 h later. Our results showed that in response to LPS, thermogenic activity promoted a local anti-inflammatory environment with high secretion of IL-1 receptor antagonist (IL-1RA) without affecting other anti- or proinflammatory cytokines. Interestingly, activation of brite adipocytes reduced the LPS-induced secretion of leptin. However, thermogenic activity and adipocyte function were not altered by LPS treatment in vitro or by acute endotoxemia in vivo. In conclusion, these results suggest an IL-1RA-mediated immunomodulatory activity of thermogenic adipocytes specifically in response to endotoxemia. This encourages potential therapy involving brown and brite adipocytes for the treatment of obesity and associated metabolic diseases.NEW & NOTEWORTHY Recruitment and activation of brown and brite adipocytes in the adipose tissue of mice lead to a local low-grade anti-inflammatory phenotype in response to acute endotoxemia without alteration of adipocyte phenotype and function.


Assuntos
Adipócitos/efeitos dos fármacos , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Adipogenia/fisiologia , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Termogênese/efeitos dos fármacos , Termogênese/fisiologia
5.
Toxicol Lett ; 334: 27-35, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32956827

RESUMO

Methyl- and propyl- parabens are generally regarded as safe by the U.S Food and Drug Administration and as such are commonly used in personal care products. These parabens have been associated with increased white adipogenesis in vitro and methyl paraben also increased the white adipose mass of mice. Given brown adipose also plays a role in energy balance, we sought to evaluate whether the effects of methyl- and propyl- parabens on white adipocytes extended to brown adipocytes. We challenged white and brown pre-adipocytes at low doses of both parabens (up to 1 µM) during the differentiation process and examined adipogenesis with the ORO assay. The impact of each paraben on glucose uptake and lipolytic activity of adipocytes were measured with a fluorescent glucose analog and enzymatically, respectively. Methyl- and propyl- parabens increased adipogenesis of 3T3-L1 white adipocytes but not brown adipocytes. In white adipocytes, methyl paraben increased glucose uptake and both parabens reduced basal lipolysis. However, in brown adipocytes, parabens had no effect on basal lipolysis and instead attenuated isoproterenol induced lipolysis. These data indicate that methyl- and propyl- parabens target the differentiation and metabolic processes of multiple types of adipocytes in a cell autonomous manner.


Assuntos
Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Parabenos/toxicidade , Conservantes Farmacêuticos/toxicidade , Células 3T3-L1 , Adipócitos/metabolismo , Adipócitos/patologia , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Animais , Diferenciação Celular/efeitos dos fármacos , Cosméticos , Glucose/metabolismo , Lipólise/efeitos dos fármacos , Camundongos
6.
Cardiovasc Pathol ; 49: 107259, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32692664

RESUMO

Perivascular adipose tissue (PVAT) is a fat tissue deposit that encircles the vasculature. PVAT is traditionally known to protect the vasculature from external stimuli that could cause biological stress. In addition to the protective role of PVAT, it secretes certain biologically active substances known as adipokines that induce paracrine effects on proximate blood vessels. These adipokines influence vascular tones. There are different types of PVAT and they are phenotypically and functionally distinct. These are the white and brown PVATs. Under certain conditions, white PVAT could undergo phenotypic switch to attain a brown PVAT-like phenotype. This type of PVAT is referred to as Beige PVAT. The morphology of adipose tissue is influenced by species, age, and sex. These factors play significant roles in adipose tissue mass, functionality, paracrine activity, and predisposition to vascular diseases. The difficulty that is currently experienced in extrapolating animal models to human physiology could be traceable to these factors. Up till now, the involvement of PVAT in the development of vascular pathology is still not well understood. Brown and white PVAT contribute differently to vascular pathology. Thus, the PVAT could be a therapeutic target in curbing certain vascular diseases. In this review, knowledge would be updated on the multifaceted involvement of PVAT in vascular pathology and also explore its vascular therapeutic potential.


Assuntos
Tecido Adiposo Bege/patologia , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/patologia , Artérias/patologia , Doenças Vasculares/patologia , Adipocinas/metabolismo , Tecido Adiposo Bege/efeitos dos fármacos , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Bege/fisiopatologia , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/fisiopatologia , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/fisiopatologia , Adiposidade , Animais , Artérias/efeitos dos fármacos , Artérias/metabolismo , Artérias/fisiopatologia , Fármacos Cardiovasculares/uso terapêutico , Hemodinâmica , Humanos , Mediadores da Inflamação/metabolismo , Comunicação Parácrina , Transdução de Sinais , Doenças Vasculares/tratamento farmacológico , Doenças Vasculares/metabolismo , Doenças Vasculares/fisiopatologia
7.
Am J Physiol Endocrinol Metab ; 319(3): E494-E508, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32691632

RESUMO

Hydroxysteroid 17ß dehydrogenase 12 (HSD17B12) is suggested to be involved in the elongation of very long chain fatty acids. Previously, we have shown a pivotal role for the enzyme during mouse development. In the present study we generated a conditional Hsd17b12 knockout (HSD17B12cKO) mouse model by breeding mice homozygous for a floxed Hsd17b12 allele with mice expressing the tamoxifen-inducible Cre recombinase at the ROSA26 locus. Gene inactivation was induced by administering tamoxifen to adult mice. The gene inactivation led to a 20% loss of body weight within 6 days, associated with drastic reduction in both white (83% males, 75% females) and brown (65% males, 60% females) fat, likely due to markedly reduced food and water intake. Furthermore, the knockout mice showed sickness behavior and signs of liver toxicity, specifically microvesicular hepatic steatosis and increased serum alanine aminotransferase (4.6-fold in males, 7.7-fold in females). The hepatic changes were more pronounced in females than males. Proinflammatory cytokines, such as interleukin-6 (IL-6), IL-17, and granulocyte colony-stimulating factor, were increased in the HSD17B12cKO mice indicating an inflammatory response. Serum lipidomics study showed an increase in the amount of dihydroceramides, despite the dramatic overall loss of lipids. In line with the proposed role for HSD17B12 in fatty acid elongation, we observed accumulation of ceramides, dihydroceramides, hexosylceramides, and lactosylceramides with shorter than 18-carbon fatty acid side chains in the serum. The results indicate that HSD17B12 is essential for proper lipid homeostasis and HSD17B12 deficiency rapidly results in fatal systemic inflammation and lipolysis in adult mice.


Assuntos
17-Hidroxiesteroide Desidrogenases/fisiologia , Homeostase/fisiologia , 17-Hidroxiesteroide Desidrogenases/genética , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Comportamento Animal , Peso Corporal/genética , Citocinas/metabolismo , Ácidos Graxos/metabolismo , Comportamento Alimentar , Feminino , Homeostase/genética , Metabolismo dos Lipídeos/genética , Metabolismo dos Lipídeos/fisiologia , Lipidômica , Hepatopatias/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Caracteres Sexuais , Tamoxifeno/farmacologia
8.
Sci Rep ; 10(1): 11209, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641756

RESUMO

Multiplexed imaging is essential for the evaluation of substrate utilization in metabolically active organs, such as the heart and brown adipose tissue (BAT), where substrate preference changes in pathophysiologic states. Optical imaging provides a useful platform because of its low cost, high throughput and intrinsic ability to perform composite readouts. However, the paucity of probes available for in vivo use has limited optical methods to image substrate metabolism. Here, we present a novel near-infrared (NIR) free fatty acid (FFA) tracer suitable for in vivo imaging of deep tissues such as the heart. Using click chemistry, Alexa Fluor 647 DIBO Alkyne was conjugated to palmitic acid. Mice injected with 0.05 nmol/g bodyweight of the conjugate (AlexaFFA) were subjected to conditions known to increase FFA uptake in the heart (fasting) and BAT [cold exposure and injection with the ß3 adrenergic agonist CL 316, 243(CL)]. Organs were subsequently imaged both ex vivo and in vivo to quantify AlexaFFA uptake. The blood kinetics of AlexaFFA followed a two-compartment model with an initial fast compartment half-life of 0.14 h and a subsequent slow compartment half-life of 5.2 h, consistent with reversible protein binding. Ex vivo fluorescence imaging after overnight cold exposure and fasting produced a significant increase in AlexaFFA uptake in the heart (58 ± 12%) and BAT (278 ± 19%) compared to warm/fed animals. In vivo imaging of the heart and BAT after exposure to CL and fasting showed a significant increase in AlexaFFA uptake in the heart (48 ± 20%) and BAT (40 ± 10%) compared to saline-injected/fed mice. We present a novel near-infrared FFA tracer, AlexaFFA, that is suitable for in vivo quantification of FFA metabolism and can be applied in the context of a low cost, high throughput, and multiplexed optical imaging platform.


Assuntos
Tecido Adiposo Marrom/diagnóstico por imagem , Corantes Fluorescentes/administração & dosagem , Coração/diagnóstico por imagem , Microscopia Intravital/métodos , Imagem Óptica/métodos , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Animais , Linhagem Celular , Dioxóis/farmacologia , Ácidos Graxos não Esterificados/metabolismo , Feminino , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacocinética , Fluordesoxiglucose F18 , Meia-Vida , Coração/efeitos dos fármacos , Injeções Intravenosas , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Microscopia de Fluorescência , Imagem Molecular/métodos , Miocárdio/metabolismo , Ratos
9.
Clin Nucl Med ; 45(8): 628-631, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32453085

RESUMO

Brown adipose tissue (BAT), which produces energy and is known to play a role as a hibernating gland, is sometimes visualized on F-FDG PET in children or in slender young adults in a cold environment. Because BAT is activated by catecholamines, FDG uptake in BAT is also observed in patients with pheochromocytoma or paraganglioma. We present the case of an elderly woman with remarkable FDG uptake in BAT. Activation of BAT by a ß3-adrenergic receptor agonist (mirabegron) prescribed for overactive bladder was suspected as the cause of the marked visualization of BAT in this patient.


Assuntos
Acetanilidas/efeitos adversos , Tecido Adiposo Marrom/diagnóstico por imagem , Agonistas Adrenérgicos/efeitos adversos , Fluordesoxiglucose F18/farmacocinética , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/farmacocinética , Tiazóis/efeitos adversos , Acetanilidas/uso terapêutico , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Neoplasias das Glândulas Suprarrenais/diagnóstico por imagem , Agonistas Adrenérgicos/uso terapêutico , Idoso de 80 Anos ou mais , Feminino , Humanos , Feocromocitoma/diagnóstico por imagem , Tiazóis/uso terapêutico , Bexiga Urinária Hiperativa/tratamento farmacológico
10.
Nat Commun ; 11(1): 2379, 2020 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-32404872

RESUMO

Brown and beige fat share a remarkably similar transcriptional program that supports fuel oxidation and thermogenesis. The chromatin-remodeling machinery that governs genome accessibility and renders adipocytes poised for thermogenic activation remains elusive. Here we show that BAF60a, a subunit of the SWI/SNF chromatin-remodeling complexes, serves an indispensable role in cold-induced thermogenesis in brown fat. BAF60a maintains chromatin accessibility at PPARγ and EBF2 binding sites for key thermogenic genes. Surprisingly, fat-specific BAF60a inactivation triggers more pronounced cold-induced browning of inguinal white adipose tissue that is linked to induction of MC2R, a receptor for the pituitary hormone ACTH. Elevated MC2R expression sensitizes adipocytes and BAF60a-deficient adipose tissue to thermogenic activation in response to ACTH stimulation. These observations reveal an unexpected dichotomous role of BAF60a-mediated chromatin remodeling in transcriptional control of brown and beige gene programs and illustrate a pituitary-adipose signaling axis in the control of thermogenesis.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Cromatina/metabolismo , Proteínas Cromossômicas não Histona/deficiência , Temperatura Baixa , Adipócitos Marrons/efeitos dos fármacos , Adipócitos Marrons/metabolismo , Adipócitos Marrons/ultraestrutura , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Hormônio Adrenocorticotrópico/farmacologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Sítios de Ligação/genética , Células Cultivadas , Cromatina/genética , Proteínas Cromossômicas não Histona/genética , Expressão Gênica/efeitos dos fármacos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Termogênese/efeitos dos fármacos , Termogênese/genética
11.
Diabetes ; 69(8): 1662-1674, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32409491

RESUMO

Maternal stress during pregnancy exposes fetuses to hyperglucocorticoids, which increases the risk of metabolic dysfunctions in offspring. Despite being a key tissue for maintaining metabolic health, the impacts of maternal excessive glucocorticoids (GC) on fetal brown adipose tissue (BAT) development and its long-term thermogenesis and energy expenditure remain unexamined. For testing, pregnant mice were administered dexamethasone (DEX), a synthetic GC, in the last trimester of gestation, when BAT development is the most active. DEX offspring had glucose, insulin resistance, and adiposity and also displayed cold sensitivity following cold exposure. In BAT of DEX offspring, Ppargc1a expression was suppressed, together with reduced mitochondrial density, and the brown progenitor cells sorted from offspring BAT demonstrated attenuated brown adipogenic capacity. Increased DNA methylation in Ppargc1a promoter had a fetal origin; elevated DNA methylation was also detected in neonatal BAT and brown progenitors. Mechanistically, fetal GC exposure increased GC receptor/DNMT3b complex in binding to the Ppargc1a promoter, potentially driving its de novo DNA methylation and transcriptional silencing, which impaired fetal BAT development. In summary, maternal GC exposure during pregnancy increases DNA methylation in the Ppargc1a promoter, which epigenetically impairs BAT thermogenesis and energy expenditure, predisposing offspring to metabolic dysfunctions.


Assuntos
Tecido Adiposo Marrom/metabolismo , Glucocorticoides/efeitos adversos , Adipogenia/efeitos dos fármacos , Adipogenia/genética , Tecido Adiposo Marrom/efeitos dos fármacos , Adiposidade/efeitos dos fármacos , Adiposidade/genética , Animais , Western Blotting , Temperatura Corporal , Calorimetria Indireta , Proliferação de Células , Imunoprecipitação da Cromatina , Dexametasona/efeitos adversos , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Feminino , Citometria de Fluxo , Teste de Tolerância a Glucose , Imunoprecipitação , Resistência à Insulina/genética , Exposição Materna/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Gravidez , Regiões Promotoras Genéticas/genética , Termogênese/efeitos dos fármacos , Termogênese/genética
12.
Diabetes ; 69(8): 1650-1661, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32444367

RESUMO

An adverse maternal in utero and lactation environment can program offspring for increased risk for metabolic disease. The aim of this study was to determine whether N-acetylcysteine (NAC), an anti-inflammatory antioxidant, attenuates programmed susceptibility to obesity and insulin resistance in offspring of mothers on a high-fat diet (HFD) during pregnancy. CD1 female mice were acutely fed a standard breeding chow or HFD. NAC was added to the drinking water (1 g/kg) of the treatment cohorts from embryonic day 0.5 until the end of lactation. NAC treatment normalized HFD-induced maternal weight gain and oxidative stress, improved the maternal lipidome, and prevented maternal leptin resistance. These favorable changes in the in utero environment normalized postnatal growth, decreased white adipose tissue (WAT) and hepatic fat, improved glucose and insulin tolerance and antioxidant capacity, reduced leptin and insulin, and increased adiponectin in HFD offspring. The lifelong metabolic improvements in the offspring were accompanied by reductions in proinflammatory gene expression in liver and WAT and increased thermogenic gene expression in brown adipose tissue. These results, for the first time, provide a mechanistic rationale for how NAC can prevent the onset of metabolic disease in the offspring of mothers who consume a typical Western HFD.


Assuntos
Acetilcisteína/uso terapêutico , Dieta Hiperlipídica/efeitos adversos , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Adiposidade/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Temperatura Corporal , Calorimetria Indireta , Feminino , Teste de Tolerância a Glucose , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Injeções Intraperitoneais , Resistência à Insulina , Masculino , Camundongos , Ganho de Peso/efeitos dos fármacos
13.
J Agric Food Chem ; 68(24): 6715-6725, 2020 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-32450691

RESUMO

Brown adipocytes, which contain abundant mitochondria, use stored energy as fuel during a process named nonshivering thermogenesis. Thus, the pharmacological activation of thermogenesis in brown adipose tissue (BAT) has become a promising target for treating obesity. We investigated the effect of fruit of Hovenial dulcis Thunb. (FHD), a frequently used herbal treatment for liver diseases, on thermogenesis and its mechanism using primary cultured brown adipocytes and BAT of high-fat-diet (HFD)-induced obese mice. Thermogenesis-related factors including UCP1 and PGC1α increased with FHD treatment. FHD also increased mitochondrial biogenesis and activation factors such as nuclear respiratory factor (NRF)1 and oxidative phosphorylation (OXPHOS) complex. Furthermore, FHD increased the intercellular nicotinamide adenine dinucleotide (NAD+) level and sirtuin 1 (SIRT1) activity, which may be responsible for the activation of the thermogenic reaction. Overall, our results suggest that FHD can be a novel option for obesity treatment due to its thermogenic action through mitochondrial biogenesis and activation.


Assuntos
Adipócitos Marrons/efeitos dos fármacos , Mitocôndrias/metabolismo , Obesidade/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Rhamnaceae/química , Termogênese/efeitos dos fármacos , Adipócitos Marrons/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Mitocôndrias/efeitos dos fármacos , Obesidade/etiologia , Obesidade/genética , Obesidade/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
14.
Metabolism ; 107: 154228, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32289346

RESUMO

OBJECTIVE: Mangiferin (MF), a xanthonoid derived from Mangifera indica, has shown therapeutic effects on various human diseases including cancer, diabetes, and obesity. Nonetheless, the influence of MF on non-shivering thermogenesis and its underlying mechanism in browning remains unclear. Here, our aim was to investigate the effects of MF on browning and its molecular mechanisms in murine C3H10T1/2 mesenchymal stem cells (MSCs). MATERIALS/METHODS: To determine the function of MF on browning, murine C3H10T1/2 MSCs were treated with MF in an adipogenic differentiation cocktail and the thermogenic and correlated metabolic responses were assessed using MF-mediated signalling. Human adipose-derived MSCs were differentiated and treated with MF to confirm its role in thermogenic induction. RESULTS: MF treatment induced the expression of a brown-fat signature, UCP1, and reduced triglyceride (TG) in C3H10T1/2 MSCs. MF also induced the expression of major thermogenesis regulators: PGC1α, PRDM16, and PPARγ and up-regulated the expression of beiging markers CD137, HSPB7, TBX1, and COX2 in both murine C3H10T1/2 MSCs and human adipose-derived mesenchymal stem cells (hADMSC). We also observed that MF treatment increased the mitochondrial DNA and improved mitochondrial homeostasis by regulating mitofission-fusion plasticity via suppressing PINK1-PRKN-mediated mitophagy. Furthermore, MF treatment improved mitochondrial respiratory function by increasing mitochondrial oxygen consumption and expression of oxidative-phosphorylation (OXPHOS)-related proteins. Chemical-inhibition and gene knockdown experiments revealed that ß3-AR-dependent PKA-p38 MAPK-CREB signalling is crucial for MF-mediated brown-fat formation via suppression of mitophagy in C3H10T1/2 MSCs. CONCLUSIONS: MF promotes the brown adipocyte phenotype by suppressing mitophagy, which is regulated by PKA-p38MAPK-CREB signalling in C3H10T1/2 MSCs. Thus, we propose that MF may be a good browning inducer that can ameliorate obesity.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Mitofagia/genética , Proteínas Quinases/genética , Ubiquitina-Proteína Ligases/genética , Xantonas/farmacologia , Adipócitos Marrons/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C3H , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Proteínas Quinases/efeitos dos fármacos , Termogênese/efeitos dos fármacos , Termogênese/genética , Ubiquitina-Proteína Ligases/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos
15.
J Agric Food Chem ; 68(17): 4876-4883, 2020 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-32293174

RESUMO

Some amino acids (AAs) have been proven to suppress fat mass and improve insulin sensitivity. However, the impact of important essential AAs, threonine, lysine, and methionine, on obesity has not been clarified. In the present study, after an 8 week period of obesity induction, mice were grouped to receive either a high-fat diet (HFD) or HFD supplemented with lysine, threonine, or methionine (3% in drinking water) for another 10 weeks. The results showed that dietary supplementation with threonine significantly decreased body weight, epididymal and perirenal fat pad weights, serum concentrations of glucose, triacylglycerols, total cholesterol, and LDL-cholesterol compared to the HFD group. HOMA-IR and serum leptin and adiponectin were improved by threonine supplementation. In epididymal adipose tissue, threonine treatment significantly down-regulated the expression levels of lipogenesis and up-regulated expressions of lipolysis compared to the HFD group. Threonine addition stimulated the expression of UCP-1 and related genes in brown adipose tissue. However, lysine or methionine supplementation showed little effect on body weight, WAT weight, serum lipid profiles, and lipid-metabolism-related gene expressions of HFD-fed mice. These findings suggest that threonine inhibited fat mass and improved lipid metabolism of already obese mice, providing a potential agent in treating obesity.


Assuntos
Fármacos Antiobesidade/administração & dosagem , Metabolismo dos Lipídeos/efeitos dos fármacos , Lisina/administração & dosagem , Metionina/administração & dosagem , Obesidade/tratamento farmacológico , Treonina/administração & dosagem , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Humanos , Resistência à Insulina , Lipogênese/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/genética , Obesidade/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
16.
Int J Mol Sci ; 21(6)2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32245100

RESUMO

Obesity results from an imbalance between energy intake and energy expenditure, in which excess fat is stored as triglycerides (TGs) in white adipocytes. Recent studies have explored the anti-obesity effects of certain edible phytochemicals, which suppress TG accumulation and stimulate a brown adipocyte-like phenotype in white adipocytes. Gomisin N (GN) is an important bioactive component of Schisandra chinensis, a woody plant endemic to Asia. GN has antioxidant, anti-inflammatory and hepatoprotective effects in vivo and in vitro. However, the anti-obesity effects of GN in lipid metabolism and adipocyte browning have not yet been investigated. In the present study, we aimed to determine whether GN suppresses lipid accumulation and regulates energy metabolism, potentially via AMP-activated protein kinase (AMPK), in 3T3-L1 adipocytes. Our findings demonstrate that GN inhibited adipogenesis and lipogenesis in adipocyte differentiation. Also, GN not only increased the expression of thermogenic factors, including uncoupling protein 1 (UCP1), but also enhanced fatty acid oxidation (FAO) in 3T3-L1 cells. Therefore, GN may have a therapeutic benefit as a promising natural agent to combat obesity.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos/metabolismo , Tecido Adiposo Marrom/metabolismo , Lignanas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Compostos Policíclicos/farmacologia , Schisandra/química , Células 3T3-L1 , Acetil-CoA Carboxilase/metabolismo , Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Tecido Adiposo Marrom/efeitos dos fármacos , Animais , Biomarcadores/metabolismo , Proteína Morfogenética Óssea 4/farmacologia , Ciclo-Octanos/química , Ciclo-Octanos/farmacologia , Ativação Enzimática/efeitos dos fármacos , Ácidos Graxos/metabolismo , Lignanas/química , Camundongos , Oxirredução/efeitos dos fármacos , Fenótipo , Compostos Policíclicos/química , Termogênese/efeitos dos fármacos , Proteína Desacopladora 1/metabolismo
17.
Nutr Metab Cardiovasc Dis ; 30(4): 616-624, 2020 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-32127340

RESUMO

BACKGROUND AND AIMS: Several studies have shown that glucagon-like peptide-1 (GLP-1) analogues can affect resting energy expenditure, and preclinical studies suggest that they may activate brown adipose tissue (BAT). The aim of the present study was to investigate the effect of treatment with liraglutide on energy metabolism and BAT fat fraction in patients with type 2 diabetes. METHODS AND RESULTS: In a 26-week double-blind, placebo-controlled trial, 50 patients with type 2 diabetes were randomized to treatment with liraglutide (1.8 mg/day) or placebo added to standard care. At baseline and after treatment for 4, 12 and 26 weeks, we assessed resting energy expenditure (REE) by indirect calorimetry. Furthermore, at baseline and after 26 weeks, we determined the fat fraction in the supraclavicular BAT depot using chemical-shift water-fat MRI at 3T. Liraglutide reduced REE after 4 weeks, which persisted after 12 weeks and tended to be present after 26 weeks (week 26 vs baseline: liraglutide -52 ± 128 kcal/day; P = 0.071, placebo +44 ± 144 kcal/day; P = 0.153, between group P = 0.057). Treatment with liraglutide for 26 weeks did not decrease the fat fraction in supraclavicular BAT (-0.4 ± 1.7%; P = 0.447) compared to placebo (-0.4 ± 1.4%; P = 0.420; between group P = 0.911). CONCLUSION: Treatment with liraglutide decreases REE in the first 12 weeks and tends to decrease this after 26 weeks without affecting the fat fraction in the supraclavicular BAT depot. These findings suggest reduction in energy intake rather than an increase in REE to contribute to the liraglutide-induced weight loss. TRIAL REGISTRY NUMBER: NCT01761318.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Adiposidade/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Metabolismo Energético/efeitos dos fármacos , Hipoglicemiantes/uso terapêutico , Incretinas/uso terapêutico , Liraglutida/uso terapêutico , Perda de Peso/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/fisiopatologia , Idoso , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Método Duplo-Cego , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Incretinas/efeitos adversos , Liraglutida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Países Baixos , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento
18.
Endocrinology ; 161(4)2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32157301

RESUMO

Apolipoprotein A-IV (ApoA-IV) synthesized by the gut regulates lipid metabolism. Sympathetic innervation of adipose tissues also controls lipid metabolism. We hypothesized that ApoA-IV required sympathetic innervation to increase fatty acid (FA) uptake by adipose tissues and brown adipose tissue (BAT) thermogenesis. After 3 weeks feeding of either a standard chow diet or a high-fat diet (HFD), mice with unilateral denervation of adipose tissues received intraperitoneal administration of recombinant ApoA-IV protein and intravenous infusion of lipid mixture with radioactive triolein. In chow-fed mice, ApoA-IV administration increased FA uptake by intact BAT but not the contralateral denervated BAT or intact white adipose tissue (WAT). Immunoblots showed that, in chow-fed mice, ApoA-IV increased expression of lipoprotein lipase and tyrosine hydroxylase in both intact BAT and inguinal WAT (IWAT), while ApoA-IV enhanced protein levels of ß3 adrenergic receptor, adipose triglyceride lipase, and uncoupling protein 1 in the intact BAT only. In HFD-fed mice, ApoA-IV elevated FA uptake by intact epididymal WAT (EWAT) but not intact BAT or IWAT. ApoA-IV increased sympathetic activity assessed by norepinephrine turnover (NETO) rate in BAT and EWAT of chow-fed mice, whereas it elevated NETO only in EWAT of HFD-fed mice. These observations suggest that, in chow-fed mice, ApoA-IV activates sympathetic activity of BAT and increases FA uptake by BAT via innervation, while in HFD-fed mice, ApoA-IV stimulates sympathetic activity of EWAT to shunt FAs into the EWAT.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Apolipoproteínas A/farmacologia , Ácidos Graxos/metabolismo , Sistema Nervoso Simpático/metabolismo , Termogênese/efeitos dos fármacos , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Animais , Dieta Hiperlipídica , Masculino , Camundongos , Norepinefrina/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacos
19.
Chin J Nat Med ; 18(2): 90-102, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32172952

RESUMO

With the occurrence of aging process, decreased neuron dopamine, disrupted brown adipose tissue (BAT) remodeling and decreased butyrate level all reflect a weak host healthy in certain degree. Nevertheless, the signs of mid-adult gut microbiota, and its association with host healthy are not well understood. In current study, we deemed to illustrate the associations of age, neuron dopamine, BAT remodeling, butyrate and gut microbiota with the aid of traditional herbal formula Kang Shuai Lao Pian (KSLP), which is known for its anti-aging effect. Here, ELISA was performed to detect the production of brain dopamine, the mass of inguinal white adipose tissue versus interscapular brown adipose tissue (iWAT/iBAT) was calculated and considered as a sign of BAT remodeling, 16S rRNA gene sequencing was used to the detection of gut microbiota profiling and gas chromatography was used to measure the butyrate level in mice feces. Our results indicated mid-adult mice already present distinctive gut microbiota profiling compared with young mice, concomitant with which are the lower brain dopamine level and disrupted brown adipose remodeling. KSLP treatment improved the host healthy and regulated gut microbiota with enriched Firmicutes at the expense of Bacteroidetes, particularly increased the relative abundance of bacteria functionally related to dopamine and butyrate productions, which suggest KSLP treatment constructs a healthier gut environment. In conclusion, modulation of gut microbiota and butyrate may connectively regulate dopamine production and BAT remodeling through gut-brain axis and gut-metabolism axis.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Butiratos/metabolismo , Dopamina/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Tecido Adiposo Marrom/fisiopatologia , Fatores Etários , Animais , Ceco/microbiologia , Fezes/microbiologia , Feminino , Camundongos
20.
J Med Food ; 23(3): 233-241, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32191577

RESUMO

Eriocitrin (EC) is an abundant flavonoid in lemons, which is known as a strong antioxidant agent. This study investigated the biological and molecular mechanisms underlying the anti-obesity effect of EC in high-fat diet (HFD)-fed obese mice. C57BL/6N mice were fed an HFD (40 kcal% fat) with or without 0.005% (w/w) EC for 16 weeks. Dietary EC improved adiposity by increasing adipocyte fatty acid (FA) oxidation, energy expenditure, and mRNA expression of thermogenesis-related genes in brown adipose tissue (BAT) and skeletal muscle, whereas it also decreased lipogenesis-related gene expression in white adipose tissue. In addition to adiposity, EC prevented hepatic steatosis by diminishing lipogenesis while enhancing FA oxidation in the liver and fecal lipid excretion, which was linked to attenuation of hyperlipidemia. Moreover, EC improved insulin sensitivity by decreasing hepatic gluconeogenesis and proinflammatory responses. These findings indicate that EC may protect against diet-induced adiposity and related metabolic disorders by controlling thermogenesis of BAT and skeletal muscle, FA oxidation, lipogenesis, fecal lipid excretion, glucose utilization, and gluconeogenesis.


Assuntos
Adiposidade/efeitos dos fármacos , Flavanonas/administração & dosagem , Obesidade/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/fisiopatologia , Animais , Citrus/química , Dieta Hiperlipídica , Lipogênese/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/fisiopatologia , Fitoterapia , Termogênese/efeitos dos fármacos
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