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1.
EBioMedicine ; 37: 344-355, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30348622

RESUMO

BACKGROUND: The pharmacological activation of thermogenesis in brown adipose tissue has long been considered promising strategies to treat obesity. However, identification of safe and effective agents remains a challenge. In this study, we addressed this challenge by developing a cellular system with a fluorescence readout, and applied in a high-throughput manner to screen for FDA-approved drugs that may activate endogenous UCP1 expression in adipocytes. METHODS: We have generated a Ucp1-2A-GFP reporter mouse, in which GFP intensity serves as a surrogate of the endogenous expression level of UCP1 protein; and immortalized brown adipocytes were derived from this mouse model and applied in drug screening. Candidate drugs were further tested in mouse models either fed with normal chow or high fat diet to induce obesity. FINDINGS: By using the cellular screening platform, we identified a group of FDA-approved drugs that can upregulate UCP1 expression in brown adipocyte, including previously known UCP1 activators and new candidate drugs. Further studies focusing on a previously unreported drug-sutent, revealed that sutent treatment could increase the energy expenditure and inhibit lipid synthesis in mouse adipose and liver tissues, resulting in improved metabolism and resistance to obesity. INTERPRETATION: This study offered an easy-to-use cellular screening system for UCP1 activators, and provided a candidate list of FDA-approved drugs that can potentially treat obesity. Further study of these candidates may shed new light on the drug discovery towards obesity. FUND: National Key Research and Development Program and the Strategic Priority Research Program of the Chinese Academy of Sciences, etc. (250 words).


Assuntos
Adipócitos Marrons/metabolismo , Tecido Adiposo Marrom/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Desacopladora 1/biossíntese , Adipócitos Marrons/patologia , Tecido Adiposo Marrom/patologia , Animais , Linhagem Celular Transformada , Aprovação de Drogas , Avaliação Pré-Clínica de Medicamentos , Camundongos , Camundongos Transgênicos , Proteína Desacopladora 1/genética , Estados Unidos , United States Food and Drug Administration
2.
EMBO J ; 37(20)2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30177570

RESUMO

Expression of mitochondrial proton transporter uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) is essential for mammalian thermogenesis. While human UCP1 mRNA exists in a long form only, alternative polyadenylation creates two different isoforms in mice with 10% of UCP1 mRNA found in the long form (Ucp1L) and ~90% in the short form (Ucp1S). We generated a mouse model expressing only Ucp1S and found that it showed impaired thermogenesis due to a 60% drop in UCP1 protein levels, suggesting that Ucp1L is more efficiently translated than Ucp1S. In addition, we found that ß3 adrenergic receptor signaling promoted the translation of mouse Ucp1L and human Ucp1 in a manner dependent on cytoplasmic polyadenylation element binding protein 2 (CPEB2). CPEB2-knockout mice showed reduced UCP1 levels and impaired thermogenesis in BAT, which was rescued by ectopic expression of CPEB2. Hence, long 3'-UTR Ucp1 mRNA translation activated by CPEB2 is likely conserved and important in humans to produce UCP1 for thermogenesis.


Assuntos
Regiões 3' não Traduzidas/fisiologia , Tecido Adiposo Marrom/metabolismo , Biossíntese de Proteínas/fisiologia , Proteínas de Ligação a RNA/metabolismo , Termogênese/fisiologia , Proteína Desacopladora 1/biossíntese , Animais , Expressão Ectópica do Gene , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Isoformas de Proteínas/biossíntese , Isoformas de Proteínas/genética , Proteínas de Ligação a RNA/genética , Receptores Adrenérgicos beta 3/genética , Receptores Adrenérgicos beta 3/metabolismo , Transdução de Sinais/fisiologia , Proteína Desacopladora 1/genética
3.
EMBO Mol Med ; 10(8)2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29973382

RESUMO

Most antidiabetic drugs treat disease symptoms rather than adipose tissue dysfunction as a key pathogenic cause in the metabolic syndrome and type 2 diabetes. Pharmacological targeting of adipose tissue through the nuclear receptor PPARg, as exemplified by glitazone treatments, mediates efficacious insulin sensitization. However, a better understanding of the context-specific PPARg responses is required for the development of novel approaches with reduced side effects. Here, we identified the transcriptional cofactor Cited4 as a target and mediator of rosiglitazone in human and murine adipocyte progenitor cells, where it promoted specific sets of the rosiglitazone-dependent transcriptional program. In mice, Cited4 was required for the proper induction of thermogenic expression by Rosi specifically in subcutaneous fat. This phenotype had high penetrance in females only and was not evident in beta-adrenergically stimulated browning. Intriguingly, this specific defect was associated with reduced capacity for systemic thermogenesis and compromised insulin sensitization upon therapeutic rosiglitazone treatment in female but not male mice. Our findings on Cited4 function reveal novel unexpected aspects of the pharmacological targeting of PPARg.


Assuntos
Adipócitos/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Rosiglitazona/uso terapêutico , Fatores de Transcrição/metabolismo , Adipócitos/metabolismo , Animais , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Masculino , Camundongos , Terapia de Alvo Molecular , PPAR gama/metabolismo , Fatores Sexuais , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Termogênese , Fatores de Transcrição/biossíntese , Transcrição Genética/efeitos dos fármacos , Proteína Desacopladora 1/biossíntese
4.
FASEB J ; 32(10): 5640-5646, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29715048

RESUMO

Brown adipose tissue (BAT) thermogenic functions are primarily mediated by uncoupling protein (UCP)-1. Ucp1 gene expression is highly induced by cold temperature, via sympathetic nervous system and ß-adrenergic receptors (ßARs). Ucp1 is also repressed by the clock gene Rev-erbα, contributing to its circadian rhythmicity. In this study, we investigated mice lacking ßARs (ß-less mice) to test the relationship between ßAR signaling and the BAT molecular clock. We found that in addition to controlling the induction of Ucp1 and other key BAT genes at near freezing temperatures, ßARs are essential for the basal expression of BAT Ucp1 at room temperature. Remarkably, although basal Ucp1 expression is low throughout day and night in ß-less mice, the circadian rhythmicity of Ucp1 and clock genes in BAT is maintained. Thus, the requirement of ßAR signaling for BAT activity is independent of the circadian rhythmicity of Ucp1 expression and circadian oscillation of the molecular clock genes. On the other hand, we found that ßARs are essential for the normal circadian rhythms of locomotor activity. Our results demonstrate that in addition to controlling the BAT response to extreme cold, ßAR signaling is necessary to maintain basal Ucp1 tone and to couple BAT circadian rhythmicity to the central clock.-Razzoli, M., Emmett, M. J., Lazar, M. A., Bartolomucci, A. ß-Adrenergic receptors control brown adipose UCP-1 tone and cold response without affecting its circadian rhythmicity.


Assuntos
Tecido Adiposo Marrom/metabolismo , Ritmo Circadiano/fisiologia , Temperatura Baixa , Receptores Adrenérgicos beta/metabolismo , Termogênese/fisiologia , Proteína Desacopladora 1/biossíntese , Tecido Adiposo Marrom/citologia , Animais , Regulação da Expressão Gênica/fisiologia , Camundongos , Camundongos Knockout , Receptores Adrenérgicos beta/genética , Transdução de Sinais/fisiologia , Proteína Desacopladora 1/genética
5.
J Nutr Biochem ; 56: 224-233, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29631143

RESUMO

This study investigated the effects of a grape pomace extract (GPE) rich in phenolic compounds on brown-like adipocyte induction and adiposity in spontaneously hypertensive (SHR) and control normotensive Wistar-Kyoto (WKY) rats fed a high-fat diet (HFD). HFD consumption for 10 weeks significantly increased epididymal white adipose tissue (eWAT) in WKY but not in SHR rats. Supplementation with GPE (300 mg/kg body weight/day) reduced adipocyte diameter and increased levels of proteins that participate in adipogenesis and angiogenesis, i.e., peroxisome-proliferator activated receptor gamma (PPARγ), vascular endothelial grow factor-A (VEGF-A) and its receptor 2 (VEGF-R2), and partially increased the uncoupling protein 1 (UCP-1) in WKY. In both strains, GPE attenuated adipose inflammation. In eWAT from SHR, GPE increased the expression of proteins involved in adipose tissue "browning," i.e., PPARγ-coactivator-1α (PGC-1α), PPARγ, PR domain containing 16 (PRDM16) and UCP-1. In primary cultures of SHR adipocytes, GPE-induced UCP-1 up-regulation was dependent on p38 and ERK activation. Accordingly, in 3T3-L1 adipocytes treated with palmitate, the addition of GPE (30 µM) activated the ß-adrenergic signaling cascade (PKA, AMPK, p38, ERK). This led to the associated up-regulation of proteins involved in mitochondrial biogenesis (PGC-1α, PPARγ, PRDM16 and UCP-1) and fatty acid oxidation (ATGL). These effects were similar to those exerted by (-)-epicatechin and quercetin, major phenolic compounds in GPE. Overall, in HFD-fed rats, supplementation with GPE promoted brown-like cell formation in eWAT and diminished adipose dysfunction. Thus, winemaking residues, rich in bioactive compounds, could be useful to mitigate the adverse effects of HFD-induced adipose dysfunction.


Assuntos
Adipócitos Bege/citologia , Tecido Adiposo Branco/citologia , Extratos Vegetais/farmacologia , Vitis/química , Células 3T3-L1 , Adipogenia , Tecido Adiposo , Tecido Adiposo Marrom/citologia , Animais , Peso Corporal , Diferenciação Celular , Dieta Hiperlipídica , Suplementos Nutricionais , Epididimo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Masculino , Camundongos , Estresse Oxidativo , PPAR gama/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Proteína Desacopladora 1/biossíntese , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
6.
Sci Rep ; 8(1): 6672, 2018 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-29704006

RESUMO

Release of fatty acids from lipid droplets upon activation of the sympathetic nervous system (SNS) is a key step in nonshivering thermogenesis in brown adipose tissue (BAT). However, intracellular lipolysis appears not to be critical for cold-induced thermogenesis. As activation of the SNS increases glucose uptake, we studied whether intracellular glycolysis plays a role in BAT thermogenesis. To stimulate BAT-innervating sympathetic nerves in vivo, we expressed channelrhodopsin-2 (ChR2) in catecholaminergic fibers by crossbreeding tyrosine hydroxylase-Cre mice with floxed-stop ChR2 mice. Acute optogenetic stimulation of sympathetic efferent fibers of BAT increased body temperature and lowered blood glucose levels that were completely abolished by the ß-adrenergic receptor antagonist. Knockdown of the Ucp1 gene in BAT blocked the effects of optogenetic stimulation on body temperature and glucose uptake. Inhibition of glucose uptake in BAT and glycolysis abolished optogenetically induced thermogenesis. Stimulation of sympathetic nerves upregulated expression of the lactate dehydrogenase-A and -B genes in BAT. Optogenetic stimulation failed to induce thermogenesis following treatment with the LDH inhibitor. Pharmacological blockade and genetic deletion of the monocarboxylate transporter 1 completely abolished the effects of sympathetic activation. Our results suggest that intracellular glycolysis and lactate shuttle play an important role in regulating acute thermogenesis in BAT.


Assuntos
Tecido Adiposo Marrom/metabolismo , Glicólise , Termogênese , Animais , Animais Geneticamente Modificados , Glicemia , Temperatura Corporal , Channelrhodopsins/análise , Channelrhodopsins/genética , Técnicas de Silenciamento de Genes , Lactatos/metabolismo , Camundongos , Optogenética , Proteína Desacopladora 1/biossíntese
7.
Physiol Behav ; 190: 28-33, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29447836

RESUMO

White adipose tissue (WAT) and brown adipose tissue (BAT) have sympathetic nervous system (SNS) and sensory innervations. Previous studies from our laboratory revealed central neuroanatomical evidence of WAT sensory and BAT SNS crosstalk with double labeling of inguinal WAT (IWAT) sensory and interscapular BAT (IBAT) SNS neurons. We previously demonstrated that WAT lipolysis increases IBAT temperature, but this effect is absent when IWAT afferents are surgically denervated, which severs both sensory and SNS nerves. It is possible that WAT sensory feedback can regulate SNS drive to itself and other WAT and BAT depots, and thus contribute to the existence of differential SNS outflow to fat during different energy challenges. Here we selectively denervated IWAT sensory nerves in Siberian hamsters using capsaicin and measured norepinephrine turnover (NETO) i.e., SNS drive to WAT and BAT depots, IBAT uncoupling protein 1 (UCP1) expression, body mass, fat mass, blood glucose, and food consumed after a 24-h cold exposure. IWAT sensory denervation decreased both IWAT and IBAT NETO and IBAT UCP1 expression. IWAT sensory denervation, however, increased mesenteric WAT (MWAT) NETO after the 24-h cold exposure and did not modify epididymal WAT (EWAT) and retroperitoneal WAT (RWAT) NETO compared with respective controls. Body mass, fat mass, blood glucose, and food consumed were unchanged across groups. RWAT and EWAT mass decreased in capsaicin-injected hamsters, but did not in the vehicle hamsters. These results functionally demonstrate the existence of IWAT sensory and IBAT SNS crosstalk and that a disruption in this sensory-SNS feedback mechanism modifies SNS drive to IWAT, IBAT, and MWAT, but not EWAT and RWAT.


Assuntos
Tecido Adiposo Marrom/inervação , Tecido Adiposo Branco/inervação , Denervação , Gordura Intra-Abdominal/inervação , Sistema Nervoso Simpático/fisiologia , Animais , Glicemia/metabolismo , Índice de Massa Corporal , Capsaicina , Cricetinae , Ingestão de Alimentos/fisiologia , Masculino , Norepinefrina/metabolismo , Nervos Periféricos/efeitos dos fármacos , Phodopus , Proteína Desacopladora 1/biossíntese
8.
Br J Pharmacol ; 175(9): 1439-1450, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29315511

RESUMO

BACKGROUND AND PURPOSE: Increasing energy expenditure through adipocyte thermogenesis is generally accepted as a promising strategy to mitigate obesity and its related diseases. However, few clinically effective and safe agents are known to promote adipocyte thermogenesis. In this study, 20 traditional Chinese herbal medicines were screened to examine whether they induced adipocyte thermogenesis. EXPERIMENTAL APPROACH: The effects of Chinese herbal medicines or components isolated from extracts of A. membranaceus, on adipocyte thermogenesis were analysed by assessing expression of uncoupling protein 1 (UCP1) by qPCR. Eight-week-old C57BL6/J male mice were fed a high-fat diet for 8 weeks and then randomized to two groups treated with vehicle or formononetin for another 8 weeks. Glucose tolerance tests and staining of adipose tissue with haematoxylin and eosin were carried out. Whole-body oxygen consumption was measured with an open-circuit indirect calorimetry system. KEY RESULTS: Extracts of A. membranaceus increased expression of Ucp1 in primary cultures of mouse adipocytes. Formononetin was the only known component of A. membranaceus extracts to increase adipocyte Ucp1 expression. Diet-induced obese mice treated with formononetin gained less weight and showed higher energy expenditure than untreated mice. In addition, formononetin binds directly with PPARγ. CONCLUSIONS AND IMPLICATION: Taken together, our study demonstrates that the Chinese herbal medicine from A. membranaceus and its constituent formononetin have the potential to reduce obesity and associated metabolic disorders. Our results suggest that formononetin regulates adipocyte thermogenesis as a non-classical PPARγ agonist.


Assuntos
Adipócitos/efeitos dos fármacos , Astragalus propinquus/química , Isoflavonas/isolamento & purificação , Isoflavonas/farmacologia , PPAR gama/metabolismo , Termogênese/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/farmacologia , Metabolismo Energético/efeitos dos fármacos , Teste de Tolerância a Glucose , Masculino , Camundongos , Obesidade/induzido quimicamente , Obesidade/prevenção & controle , Consumo de Oxigênio/efeitos dos fármacos , PPAR gama/fisiologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Cultura Primária de Células , RNA Interferente Pequeno/farmacologia , Termogênese/fisiologia , Proteína Desacopladora 1/biossíntese
9.
Gene ; 641: 111-116, 2018 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-29054764

RESUMO

Skeletal muscle serving as the major organ is responsible for energy expenditure and exercise endurance, which directly influence cardiometabolic risk factors. Transient receptor potential melastatin 8 (TRPM8), a Ca2+-permeable non-selective cation channel, plays vital roles in the regulation of various cellular functions. It has been reported that TRPM8 activation enhanced the energy metabolism of adipocytes. However, the involvement of TRPM8 in the energy metabolism of skeletal muscle remains unexplored. Our data revealed that TRPM8 was expressed in cultured C2C12 myocytes. Menthol treatment increased uncoupling protein 1 (UCP1) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) expression in C2C12 myotubes through TRPM8 activation. Moreover, dietary menthol upregulated the expression of UCP1 and PGC1α in skeletal muscle of mice. In addition, dietary menthol enhanced exercise endurance and reduced blood lactic acid and triglycerides through TRPM8 activation. It is concluded that dietary menthol improves energy metabolism and exercise endurance by increasing UCP1 and PGC1α in skeletal muscles, suggesting dietary menthol might be a novel therapeutic approach for cardiometabolic diseases management and prevention.


Assuntos
Metabolismo Energético/fisiologia , Mentol/farmacologia , Músculo Esquelético/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/biossíntese , Resistência Física/fisiologia , Canais de Cátion TRPM/metabolismo , Proteína Desacopladora 1/biossíntese , Animais , Linhagem Celular , Ativação Enzimática , Ácido Láctico/sangue , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Triglicerídeos/sangue , Regulação para Cima/efeitos dos fármacos
10.
Physiol Behav ; 190: 11-20, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28694154

RESUMO

Changes in photoperiod length are transduced into neuroendocrine signals by melatonin (MEL) secreted by the pineal gland triggering seasonally adaptive responses in many animal species. Siberian hamsters, transferred from a long-day 'summer-like' photoperiod (LD) to a short-day 'winter-like' photoperiod (SD), exhibit a naturally-occurring reversal in obesity. Photoperiod-induced changes in adiposity are mediated by the duration of MEL secretion and can be mimicked by exogenously administered MEL into animals housed in LD. Evidence suggests that MEL increases the sympathetic nervous system (SNS) drive to white adipose tissue (WAT). Here, we investigated whether MEL-driven seasonally adaptive losses in body fat are associated with WAT lipolysis and browning. Hamsters were subcutaneously administered vehicle (LD+VEH) or 0.4mg/kg MEL (LD+MEL) daily for 10weeks while animals housed in SD served as a positive control. MEL and SD exposure significantly decreased the retroperitoneal (RWAT), inguinal (IWAT), epididymal (EWAT) WAT, food intake and caused testicular regression compared with the LD+VEH group. MEL/SD induced lipolysis in the IWAT and EWAT, browning of the RWAT, IWAT, and EWAT, and increased UCP1 expression in the IBAT. Additionally, MEL/SD significantly increased the number of shared MEL receptor 1a and dopamine beta-hydroxylase-immunoreactive neurons in discrete brain sites, notably the paraventricular hypothalamic nucleus, dorsomedial hypothalamic nucleus, arcuate nucleus, locus coeruleus and dorsal motor nucleus of vagus. Collectively, these findings support our hypothesis that SD-exposed Siberian hamsters undergo adaptive decreases in body adiposity due to SNS-stimulated lipid mobilization and generalized WAT browning.


Assuntos
Tecido Adiposo Marrom/fisiologia , Tecido Adiposo Branco/fisiologia , Lipólise/fisiologia , Phodopus , Fotoperíodo , Tecido Adiposo Marrom/metabolismo , Animais , Peso Corporal/fisiologia , Encéfalo/metabolismo , Colo/metabolismo , Cricetinae , Dopamina beta-Hidroxilase/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Masculino , Melatonina/farmacologia , Melatonina/fisiologia , Neurônios/metabolismo , Receptor MT1 de Melatonina/metabolismo , Testículo/efeitos dos fármacos , Proteína Desacopladora 1/biossíntese
11.
Physiol Rep ; 5(21)2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29138356

RESUMO

Earlier we reported that the recombinant soluble (pro) renin receptor sPRR-His upregulates renal aquoporin-2 (AQP2) expression, and attenuates polyuria associated with nephrogenic diabetes insipidus (NDI) induced by vasopressin type 2 receptor (V2R) antagonism. Patients that receive lithium therapy develop polyuria associated NDI that might be secondary to downregulation of renal AQP2. We hypothesized that sPRR-His attenuates indices of NDI associated with lithium treatment. Eight-week-old male C57/BL6 mice consumed chow supplemented with LiCl (40 mmol/kg diets) for 14 days. For the last 7 days mice received either sPRR-His [30 µg/(kg day), i.v.; sPRR] or vehicle (Veh) via minipump. Control (Con) mice consumed standard chow for 14 days. Compared to Con mice, 14-d LiCl treatment elevated water intake and urine volume, and decreased urine osmolality, regardless of sPRR-His or Veh administration. These data indicate that sPRR-His treatment does not attenuate indices of NDI evoked by lithium. Unexpectedly, epididymal fat mass was lower, adipocyte UCP1 mRNA and protein expression were higher, and multilocular lipid morphology was enhanced, in LiCl-fed mice treated with sPRR-His versus vehicle. The beiging of white adipose tissue is a novel metabolic benefit of manipulating the sPRR in the context of lithium-induced NDI.


Assuntos
Tecido Adiposo Branco/efeitos dos fármacos , Antimaníacos/toxicidade , Diabetes Insípido Nefrogênico/induzido quimicamente , Cloreto de Lítio/toxicidade , Receptores de Superfície Celular/uso terapêutico , Animais , Aquaporina 2/biossíntese , Diabetes Insípido Nefrogênico/metabolismo , Diabetes Insípido Nefrogênico/fisiopatologia , Diabetes Insípido Nefrogênico/prevenção & controle , Avaliação Pré-Clínica de Medicamentos/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , Proteínas Recombinantes/farmacologia , Solubilidade , Proteína Desacopladora 1/biossíntese , Proteína Desacopladora 1/genética , Micção/efeitos dos fármacos
12.
J Biol Chem ; 292(40): 16616-16625, 2017 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-28794154

RESUMO

Thermogenesis is an important homeostatic mechanism essential for survival and normal physiological functions in mammals. Both brown adipose tissue (BAT) (i.e. uncoupling protein 1 (UCP1)-based) and skeletal muscle (i.e. sarcolipin (SLN)-based) thermogenesis processes play important roles in temperature homeostasis, but their relative contributions differ from small to large mammals. In this study, we investigated the functional interplay between skeletal muscle- and BAT-based thermogenesis under mild versus severe cold adaptation by employing UCP1-/- and SLN-/- mice. Interestingly, adaptation of SLN-/- mice to mild cold conditions (16 °C) significantly increased UCP1 expression, suggesting increased reliance on BAT-based thermogenesis. This was also evident from structural alterations in BAT morphology, including mitochondrial architecture, increased expression of electron transport chain proteins, and depletion of fat droplets. Similarly, UCP1-/- mice adapted to mild cold up-regulated muscle-based thermogenesis, indicated by increases in muscle succinate dehydrogenase activity, SLN expression, mitochondrial content, and neovascularization, compared with WT mice. These results further confirm that SLN-based thermogenesis is a key player in muscle non-shivering thermogenesis (NST) and can compensate for loss of BAT activity. We also present evidence that the increased reliance on BAT-based NST depends on increased autonomic input, as indicated by abundant levels of tyrosine hydroxylase and neuropeptide Y. Our findings demonstrate that both BAT and muscle-based NST are equally recruited during mild and severe cold adaptation and that loss of heat production from one thermogenic pathway leads to increased recruitment of the other, indicating a functional interplay between these two thermogenic processes.


Assuntos
Aclimatação/fisiologia , Tecido Adiposo Marrom/metabolismo , Temperatura Baixa , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Termogênese/fisiologia , Animais , Camundongos , Camundongos Knockout , Mitocôndrias Musculares/genética , Proteínas Musculares/biossíntese , Proteínas Musculares/genética , Proteolipídeos/biossíntese , Proteolipídeos/genética , Proteína Desacopladora 1/biossíntese , Proteína Desacopladora 1/genética , Regulação para Cima/fisiologia
13.
Nature ; 546(7656): 107-112, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28538730

RESUMO

Menopause is associated with bone loss and enhanced visceral adiposity. A polyclonal antibody that targets the ß-subunit of the pituitary hormone follicle-stimulating hormone (Fsh) increases bone mass in mice. Here, we report that this antibody sharply reduces adipose tissue in wild-type mice, phenocopying genetic haploinsufficiency for the Fsh receptor gene Fshr. The antibody also causes profound beiging, increases cellular mitochondrial density, activates brown adipose tissue and enhances thermogenesis. These actions result from the specific binding of the antibody to the ß-subunit of Fsh to block its action. Our studies uncover opportunities for simultaneously treating obesity and osteoporosis.


Assuntos
Tecido Adiposo/metabolismo , Adiposidade , Subunidade beta do Hormônio Folículoestimulante/antagonistas & inibidores , Termogênese , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo Bege/efeitos dos fármacos , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Adiposidade/efeitos dos fármacos , Animais , Anticorpos/imunologia , Anticorpos/farmacologia , Dieta Hiperlipídica/efeitos adversos , Feminino , Subunidade beta do Hormônio Folículoestimulante/imunologia , Haploinsuficiência , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Obesidade/tratamento farmacológico , Obesidade/prevenção & controle , Osteoporose/tratamento farmacológico , Ovariectomia , Consumo de Oxigênio/efeitos dos fármacos , Receptores do FSH/antagonistas & inibidores , Receptores do FSH/genética , Receptores do FSH/metabolismo , Termogênese/efeitos dos fármacos , Proteína Desacopladora 1/biossíntese
14.
Sci Rep ; 7(1): 1123, 2017 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-28442748

RESUMO

Browning white adipocytes may be a new target in anti-obesity therapy. Pentamethylquercetin (PMQ) has been shown to have anti-obesity effects in monosodium glutamate-induced obese mice. Here, we aimed to study the anti-obesity effects of PMQ in vitro and in vivo and to determine if adipose browning is involved in the mechanism underlying the anti-obesity effects of PMQ. We evaluated the effects of PMQ on cell proliferation, cell differentiation, glucose consumption, cellular lipid metabolism, and related brown gene expression in 3T3-L1 adipocytes. We also investigated the effects of PMQ in a mouse model of high-fat diet (HFD)-induced obesity. Our results demonstrated that PMQ increased the consumption of glucose, inhibited the accumulation of cellular triglycerides (TGs), and induced the expression of brown adipocyte-specific genes, such as uncoupling protein 1 (UCP-1), during the early stage of differentiation in 3T3-L1 adipocytes. In HFD mice, PMQ treatment reduced waist circumference, LEE index, white adipose tissue (WAT) weight and white adipocyte size and increased brown adipose tissue (BAT) weight. Moreover, PMQ treatment induced mitochondrial biogenesis and upregulated UCP-1 expression in WAT. These findings suggest that PMQ may induce browning of adipose tissue, a phenomenon that is at least partly related to its anti-obesity effects.


Assuntos
Adipócitos/efeitos dos fármacos , Adipócitos/fisiologia , Obesidade/tratamento farmacológico , Quercetina/análogos & derivados , Células 3T3-L1 , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dieta Hiperlipídica , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Metabolismo dos Lipídeos , Camundongos , Camundongos Obesos , Quercetina/administração & dosagem , Quercetina/metabolismo , Resultado do Tratamento , Proteína Desacopladora 1/biossíntese
15.
Exp Clin Endocrinol Diabetes ; 125(3): 163-170, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28073126

RESUMO

Aim: The present study aimed to analyze the expression of IL6, UCP1 and SIRT1 in adipose tissue (WAT and BAT) in association to clinical, metabolic and anthropometric parameters in obese humans. Methods: WAT and BAT samples from obese patients (n=27) were collected. IL6, UCP1 and SIRT1 markers were measured by qRT-PCR. The association between IL6, UCP1 and SIRT1 mRNA expression and anthropometric and clinical parameters were evaluated, using appropriate statistical tests. Results: Our results demonstrated that high levels of IL6 are associated with altered glucose levels in the WAT (p=0.01). In contrast, high levels of IL6 in the BAT were associated with decreased % fat (p=0.01) and fat weight (p=0.02) and increased mVO2 (p=0.02) and VO2 (p=0.02). For UCP1, a higher expression in the BAT was observed when compared to the WAT (p=0.0001). This gene expression was associated with lower values of BMI (p=0.03), % fat (P=0.02) and fat weight (P=0.02) and increased mVO2 (p=0.041) and VO2 (p=0.001). In the WAT, decreased levels of SIRT1 were associated with increased fat weight (p=0.02); in the BAT, associations were found for % fat (p=0.018) and mVO2 (p=0.03). Conclusion: These results reveal different characteristics in the biological actions between WAT and BAT in obese humans. Increased levels of IL6, UCP1 and SIRT1 in the BAT were associated with metabolic parameters improvements.


Assuntos
Tecido Adiposo Marrom , Tecido Adiposo Branco , Regulação da Expressão Gênica , Interleucina-6/biossíntese , Obesidade , Sirtuína 1/biossíntese , Proteína Desacopladora 1/biossíntese , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/metabolismo , Obesidade/patologia
16.
Can J Physiol Pharmacol ; 95(2): 129-139, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27918207

RESUMO

Dipeptidyl peptidase 4 (DPP-4) inhibitors are widely used antihyperglycemic agents for type 2 diabetes mellitus. Recently, increasing attention has been focused on the pleiotropic actions of DPP-4 inhibitors. The aim of the present study was to examine whether gemigliptin, a recently developed DPP-4 inhibitor, could ameliorate features of metabolic syndrome. Mice were fed a Western diet (WD) for 12 weeks and were subsequently divided into 2 groups: mice fed a WD diet alone or mice fed a WD diet supplemented with gemigliptin for an additional 4 weeks. Gemigliptin treatment attenuated WD-induced body mass gain, hypercholesterolemia, adipocyte hypertrophy, and macrophage infiltration into adipose tissue, which were accompanied by an increased expression of uncoupling protein 1 in subcutaneous fat. These events contributed to improved insulin sensitivity, as assessed by the homeostasis model assessment of insulin resistance and intraperitoneal insulin tolerance test. Furthermore, gemigliptin reduced WD-induced hepatic triglyceride accumulation via inhibition of de novo lipogenesis and activation of fatty acid oxidation, which was accompanied by AMP-dependent protein kinase activation. Gemigliptin ameliorated WD-induced hepatic inflammation and fibrosis through suppression of oxidative stress. These results suggest that DPP-4 inhibitors may represent promising therapeutic agents for metabolic syndrome beyond their current role as antihyperglycemic agents.


Assuntos
Dieta Ocidental/efeitos adversos , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/etiologia , Piperidonas/farmacologia , Piperidonas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Adipócitos/patologia , Animais , Fígado Gorduroso/tratamento farmacológico , Fibrose/tratamento farmacológico , Hipercolesterolemia/prevenção & controle , Hipertrofia/tratamento farmacológico , Inflamação/tratamento farmacológico , Resistência à Insulina , Fígado/patologia , Masculino , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Camundongos , Gordura Subcutânea/metabolismo , Proteína Desacopladora 1/biossíntese , Ganho de Peso/efeitos dos fármacos
17.
Tissue Cell ; 48(5): 452-60, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27561621

RESUMO

Brown adipose tissue (BAT) is mainly composed of adipocytes, it is highly vascularized and innervated, and can be activated in adult humans. Brown adipocytes are responsible for performing non-shivering thermogenesis, which is exclusively mediated by uncoupling protein (UCP) -1 (a protein found in the inner mitochondrial membrane), the hallmark of BAT, responsible for the uncoupling of the proton leakage from the ATP production, therefore, generating heat (i.e. thermogenesis). Besides UCP1, other compounds are essential not only to thermogenesis, but also to the proliferation and differentiation of BAT, including peroxisome proliferator-activated receptor (PPAR) family, PPARgamma coactivator 1 (PGC1)-alpha, and PRD1-BF-1-RIZ1 homologous domain protein containing protein (PRDM) -16. The sympathetic nervous system centrally regulates thermogenesis through norepinephrine, which acts on the adrenergic receptors of BAT. This bound leads to the initialization of the many pathways that may activate thermogenesis in acute and/or chronic ways. In summary, this mini-review aims to demonstrate the latest advances in the knowledge of BAT.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo Marrom/crescimento & desenvolvimento , Diferenciação Celular/genética , Termogênese/genética , Trifosfato de Adenosina/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Proliferação de Células/genética , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Humanos , Camundongos , Norepinefrina/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/biossíntese , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética , Proteína Desacopladora 1/biossíntese , Proteína Desacopladora 1/genética
18.
PLoS One ; 11(7): e0159399, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27438137

RESUMO

The discovery of active brown adipose tissue (BAT) in adult humans and the fact that it is reduced in obese and diabetic patients have put a spotlight on this tissue as a key player in obesity-induced metabolic disorders. BAT regulates energy expenditure through thermogenesis; therefore, harnessing its thermogenic fat-burning power is an attractive therapeutic approach. We aimed to enhance BAT thermogenesis by increasing its fatty acid oxidation (FAO) rate. Thus, we expressed carnitine palmitoyltransferase 1AM (CPT1AM), a permanently active mutant form of CPT1A (the rate-limiting enzyme in FAO), in a rat brown adipocyte (rBA) cell line through adenoviral infection. We found that CPT1AM-expressing rBA have increased FAO, lipolysis, UCP1 protein levels and mitochondrial activity. Additionally, enhanced FAO reduced the palmitate-induced increase in triglyceride content and the expression of obese and inflammatory markers. Thus, CPT1AM-expressing rBA had enhanced fat-burning capacity and improved lipid-induced derangements. This indicates that CPT1AM-mediated increase in brown adipocytes FAO may be a new approach to the treatment of obesity-induced disorders.


Assuntos
Carnitina O-Palmitoiltransferase/genética , Metabolismo Energético/genética , Mitocôndrias/metabolismo , Obesidade/genética , Proteína Desacopladora 1/genética , Adipócitos Marrons/metabolismo , Adipócitos Marrons/patologia , Animais , Carnitina O-Palmitoiltransferase/biossíntese , Diferenciação Celular/genética , Regulação Enzimológica da Expressão Gênica , Humanos , Metabolismo dos Lipídeos/genética , Lipídeos/genética , Lipólise/genética , Mitocôndrias/patologia , Obesidade/metabolismo , Obesidade/patologia , Ratos , Termogênese/genética , Proteína Desacopladora 1/biossíntese
19.
Am J Physiol Regul Integr Comp Physiol ; 311(1): R79-88, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27097660

RESUMO

Adipose tissue PKA has roles in adipogenesis, lipolysis, and mitochondrial function. PKA transduces the cAMP signal downstream of G protein-coupled receptors, which are being explored for therapeutic manipulation to reduce obesity and improve metabolic health. This study aimed to determine the overall physiological consequences of PKA activation in adipose tissue. Mice expressing an activated PKA catalytic subunit in adipose tissue (Adipoq-caPKA mice) showed increased PKA activity in subcutaneous, epididymal, and mesenteric white adipose tissue (WAT) depots and brown adipose tissue (BAT) compared with controls. Adipoq-caPKA mice weaned onto a high-fat diet (HFD) or switched to the HFD at 26 wk of age were protected from diet-induced weight gain. Metabolic health was improved, with enhanced insulin sensitivity, glucose tolerance, and ß-cell function. Adipose tissue health was improved, with smaller adipocyte size and reduced macrophage engulfment of adipocytes. Using metabolic cages, we found that Adipoq-caPKA mice were shown to have increased energy expenditure, but no difference to littermate controls in physical activity or food consumption. Immunoblotting of adipose tissue showed increased expression of uncoupling protein-1 (UCP1) in BAT and dramatic UCP1 induction in subcutaneous WAT, but no induction in the visceral depots. Feeding a HFD increased PKA activity in epididymal WAT of wild-type mice compared with chow, but did not change PKA activity in subcutaneous WAT or BAT. This was associated with changes in PKA regulatory subunit expression. This study shows that adipose tissue PKA activity is sufficient to increase energy expenditure and indicates that PKA is a beneficial target in metabolic health.


Assuntos
Tecido Adiposo/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/farmacologia , Metabolismo Energético/fisiologia , Proteína Desacopladora 1/biossíntese , Adiponectina/genética , Adiponectina/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Adiposidade , Animais , Proteínas Quinases Dependentes de AMP Cíclico/genética , Dieta Hiperlipídica , Intolerância à Glucose , Nível de Saúde , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteína Desacopladora 1/efeitos dos fármacos , Ganho de Peso
20.
J Clin Invest ; 126(5): 1704-16, 2016 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-27018708

RESUMO

A classic metabolic concept posits that insulin promotes energy storage and adipose expansion, while catecholamines stimulate release of adipose energy stores by hydrolysis of triglycerides through ß-adrenergic receptor (ßARs) and protein kinase A (PKA) signaling. Here, we have shown that a key hub in the insulin signaling pathway, activation of p70 ribosomal S6 kinase (S6K1) through mTORC1, is also triggered by PKA activation in both mouse and human adipocytes. Mice with mTORC1 impairment, either through adipocyte-specific deletion of Raptor or pharmacologic rapamycin treatment, were refractory to the well-known ßAR-dependent increase of uncoupling protein UCP1 expression and expansion of beige/brite adipocytes (so-called browning) in white adipose tissue (WAT). Mechanistically, PKA directly phosphorylated mTOR and RAPTOR on unique serine residues, an effect that was independent of insulin/AKT signaling. Abrogation of the PKA site within RAPTOR disrupted ßAR/mTORC1 activation of S6K1 without affecting mTORC1 activation by insulin. Conversely, a phosphomimetic RAPTOR augmented S6K1 activity. Together, these studies reveal a signaling pathway from ßARs and PKA through mTORC1 that is required for adipose browning by catecholamines and provides potential therapeutic strategies to enhance energy expenditure and combat metabolic disease.


Assuntos
Tecido Adiposo Marrom/metabolismo , Complexos Multiproteicos/metabolismo , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Células 3T3-L1 , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Tecido Adiposo Marrom/citologia , Tecido Adiposo Branco/citologia , Tecido Adiposo Branco/metabolismo , Animais , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Células HEK293 , Humanos , Insulina/genética , Insulina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Knockout , Complexos Multiproteicos/genética , Receptores Adrenérgicos beta/genética , Proteína Regulatória Associada a mTOR , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Serina-Treonina Quinases TOR/genética , Proteína Desacopladora 1/biossíntese , Proteína Desacopladora 1/genética
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