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2.
J Biol Chem ; 296: 100332, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33508319

RESUMO

Traditionally, lipolysis has been regarded as an enzymatic activity that liberates fatty acids as metabolic fuel. However, recent work has shown that novel substrates, including a variety of lipid compounds such as fatty acids and their derivatives, release lipolysis products that act as signaling molecules and transcriptional modulators. While these studies have expanded the role of lipolysis, the mechanisms underpinning lipolysis signaling are not fully defined. Here, we uncover a new mechanism regulating glucose uptake, whereby activation of lipolysis, in response to elevated cAMP, leads to the stimulation of thioredoxin-interacting protein (TXNIP) degradation. This, in turn, selectively induces glucose transporter 1 surface localization and glucose uptake in 3T3-L1 adipocytes and increases lactate production. Interestingly, cAMP-induced glucose uptake via degradation of TXNIP is largely dependent upon adipose triglyceride lipase (ATGL) and not hormone-sensitive lipase or monoacylglycerol lipase. Pharmacological inhibition or knockdown of ATGL alone prevents cAMP-dependent TXNIP degradation and thus significantly decreases glucose uptake and lactate secretion. Conversely, overexpression of ATGL amplifies the cAMP response, yielding increased glucose uptake and lactate production. Similarly, knockdown of TXNIP elicits enhanced basal glucose uptake and lactate secretion, and increased cAMP further amplifies this phenotype. Overexpression of TXNIP reduces basal and cAMP-stimulated glucose uptake and lactate secretion. As a proof of concept, we replicated these findings in human primary adipocytes and observed TXNIP degradation and increased glucose uptake and lactate secretion upon elevated cAMP signaling. Taken together, our results suggest a crosstalk between ATGL-mediated lipolysis and glucose uptake.


Assuntos
Proteínas de Transporte/genética , Transportador de Glucose Tipo 1/genética , Glucose/metabolismo , Lipase/genética , Lipólise/genética , Tiorredoxinas/genética , Células 3T3-L1 , Adipócitos/enzimologia , Adipócitos/metabolismo , Animais , AMP Cíclico/metabolismo , AMP Cíclico/farmacologia , Glucose/genética , Humanos , Ácido Láctico/biossíntese , Ácido Láctico/metabolismo , Camundongos , Proteólise/efeitos dos fármacos , Esterol Esterase/genética
3.
Nature ; 566(7743): 279-283, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30700909

RESUMO

Adaptation to the environment and extraction of energy are essential for survival. Some species have found niches and specialized in using a particular source of energy, whereas others-including humans and several other mammals-have developed a high degree of flexibility1. A lot is known about the general metabolic fates of different substrates but we still lack a detailed mechanistic understanding of how cells adapt in their use of basic nutrients2. Here we show that the closely related fasting/starvation-induced forkhead transcription factors FOXK1 and FOXK2 induce aerobic glycolysis by upregulating the enzymatic machinery required for this (for example, hexokinase-2, phosphofructokinase, pyruvate kinase, and lactate dehydrogenase), while at the same time suppressing further oxidation of pyruvate in the mitochondria by increasing the activity of pyruvate dehydrogenase kinases 1 and 4. Together with suppression of the catalytic subunit of pyruvate dehydrogenase phosphatase 1 this leads to increased phosphorylation of the E1α regulatory subunit of the pyruvate dehydrogenase complex, which in turn inhibits further oxidation of pyruvate in the mitochondria-instead, pyruvate is reduced to lactate. Suppression of FOXK1 and FOXK2 induce the opposite phenotype. Both in vitro and in vivo experiments, including studies of primary human cells, show how FOXK1 and/or FOXK2 are likely to act as important regulators that reprogram cellular metabolism to induce aerobic glycolysis.


Assuntos
Aerobiose , Fatores de Transcrição Forkhead/metabolismo , Glicólise , Células 3T3 , Animais , Células Cultivadas , Feminino , Fatores de Transcrição Forkhead/deficiência , Fatores de Transcrição Forkhead/genética , Humanos , Ácido Láctico/biossíntese , Ácido Láctico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/enzimologia , Mitocôndrias/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Oxirredução , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Piruvato Desidrogenase (Lipoamida)-Fosfatase/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil , Complexo Piruvato Desidrogenase/química , Complexo Piruvato Desidrogenase/metabolismo , Ácido Pirúvico/metabolismo
4.
J Endocrinol ; 239(1): 1­17, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30307150

RESUMO

miRNA has been known to regulate diverse cellular and molecular functions. In the earlier study, we have reported that adipocytes differentiated from human mesenchymal stem cells (hMSC) on 72-h chronic insulin (CI) treatment exhibit insulin resistance (IR). Present study has further explored above model to investigate the role of early expressed miRNAs within human adipocytes to modulate differential adipokine expression as observed during IR. Our results highlight that miR-876-3p regulate glucose homeostasis and its dysregulation leads to IR. We found that miR-876-3p level is a critical determinant of adiponectin expression by virtue of its target within adiponectin 3'UTR. Regulatory effect of miR-876-3p impacts crosstalk between adiponectin and insulin signaling. Rosiglitazone treatment in CI-induced IR adipocytes drastically reduced miR-876-3p expression and increased adiponectin level. In line with this, lentiviral-mediated inhibition of miR-876-3p expression ameliorated CI and high-fat diet (HFD)-induced IR in adipocytes differentiated from hMSC and C57BL/6 mice, respectively. Our findings thus suggest that modulating miR-876-3p expression could provide novel opportunities for therapeutic intervention of obesity-associated metabolic syndrome.


Assuntos
Adipócitos/metabolismo , Adiponectina/metabolismo , Resistência à Insulina , MicroRNAs/metabolismo , Tecido Adiposo/metabolismo , Animais , Células Cultivadas , Glucose/metabolismo , Homeostase , Humanos , Insulina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Transcriptoma
6.
J Mol Med (Berl) ; 96(3-4): 315-331, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29455245

RESUMO

Defect in insulin signaling leads to the development of insulin resistance followed by type 2 diabetes. Exploiting our previously developed physiological chronic hyperinsulinemia (CI)-mediated insulin resistance (IR) model, we wanted to understand how miRNAs contribute to the development of IR. Amongst the identified and validate miRNAs, the expression of miR-27b was found to be highly upregulated during CI-induced IR in 3T3-L1 adipocytes. We also validated the expression of miR-27b in CI-induced IR in human mesenchymal stem cell (hMSC)-derived adipocytes and in vivo high fat diet (HFD)-induced IR mice model. Bioinformatics target prediction softwares and luciferase reporter assay identified insulin receptor (INSR) as one of a prime target of miR-27b. Lentiviral mediated overexpression of miR-27b impairs insulin signaling by modulating INSR expression that in turn led to decreased glucose uptake in both 3T3-L1 and hMSC-derived adipocytes. Conversely, inhibition of miR-27b reversed CI-mediated suppression of target protein INSR and improved phosphorylation of Akt, a nodal protein of insulin signaling that is impaired by CI treatment. Lentiviral mediated overexpression of miR-27b in in vivo C57BL/6 mice impaired whole body glucose tolerance and adipose tissue insulin sensitivity. Furthermore, inhibition of miR-27b in HFD-induced insulin resistance mice model improved glucose tolerance and adipose tissue insulin sensitivity by increasing the expression of its target gene INSR in eWAT. Thus, our results indicate that miR-27b functions as a prime modulator of CI-induced IR via regulating the expression of INSR. KEY MESSAGES: miR-27b is upregulated in different in vitro and in vivo models of insulin resistance. miR-27b directly suppresses the expression of INSR by targeting 3'UTR of INSR. Modulation of miR-27b expression regulates insulin sensitivity by targeting INSR.


Assuntos
Adipócitos/metabolismo , Hiperinsulinismo/genética , Resistência à Insulina/genética , MicroRNAs , Receptor de Insulina/metabolismo , Células 3T3-L1 , Tecido Adiposo Branco/metabolismo , Animais , Dieta Hiperlipídica , Glucose/metabolismo , Humanos , Hiperinsulinismo/metabolismo , Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
7.
Metabolism ; 73: 109-124, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28732567

RESUMO

BACKGROUND: Adipocyte dysfunction, obesity and associated metabolic disorders are of prime healthcare concern worldwide. Among available medications, natural products and inspired molecules hold 40% space in clinically prescribed medicines. In queue, this study overcomes the drawback of curcumin's low bioavailability with potent anti-adipogenic and anti-dyslipidemic activity. METHODS: To evaluate the role of CDPP on adipocyte differentiation, 3T3-L1 adipocytes were used as an in-vitro model. Flow cytometry was performed for cell cycle analysis. Syrian golden hamsters were used to study pharmacokinetic profile and dyslipidemic activity exhibited by CDPP. RESULT: CDPP was found to be a potent inhibitor of adipogenesis in-vitro. It blocked mitotic clonal expansion by causing cell cycle arrest. CDPP showed marked improvement in gastrointestinal stability and bioavailability in-vivo as compared to curcumin. Administration of CDPP (100mg/kg) significantly improved HFD induced dyslipidemic profile in hamsters and activated reverse cholesterol transport machinery. CONCLUSION: CDPP could be used as a potential drug candidate against adipogenesis and dyslipidemia with enhanced gastrointestinal stability and bioavailability.


Assuntos
Adipogenia/efeitos dos fármacos , Colesterol/metabolismo , Curcumina/análogos & derivados , Curcumina/farmacologia , Dislipidemias/tratamento farmacológico , Pirazóis/farmacologia , Células 3T3 , Animais , Disponibilidade Biológica , Transporte Biológico Ativo/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Cricetinae , Curcumina/farmacocinética , Curcumina/uso terapêutico , Mesocricetus , Camundongos , Pirazóis/farmacocinética , Pirazóis/uso terapêutico
8.
Free Radic Biol Med ; 112: 93-108, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28739528

RESUMO

Leptin, following its discovery, has developed a formidable interest in the scientific community to delineate its contribution towards overall metabolic homeostasis. Contradictory reports have been published on leptin administration effects on whole body insulin sensitivity. Following late reports, we surveyed human serum leptin levels along with other metabolic parameters including BMI and HOMA-IR. We found a positive correlation between leptin levels and insulin resistance parameters. Considering the presence of the long form of leptin receptor on adipocytes, we explored the effects of chronic physiological hyper-leptinemic exposure on adipocyte insulin sensitivity. Chronic leptin (50ng/ml) treatment in 3T3-L1 adipocytes decreased insulin-induced phosphorylation of nodal insulin signaling proteins along with reduced glucose uptake. Metabolic flux studies indicated mitochondrial dysfunction and reduced oxygen consumption rate. Leptin treatment also increased both cellular and mitochondrial superoxide levels concomitant to increased expression of nitric oxide synthase-2 (NOS2). Further, pharmacological depletion of NOS2 reversed leptin mediated effects on insulin signaling. In-vivo implantation of leptin osmotic pumps in C57BL/6 mice also decreased insulin responsiveness. Interestingly, these effects were lacking in NOS2 knockout strain. In conclusion, our studies put forward a potential link between leptin and adipocyte insulin responsiveness in an NOS2 dependent manner.


Assuntos
Resistência à Insulina , Leptina/farmacologia , Mitocôndrias/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/genética , Transdução de Sinais , Células 3T3-L1 , Adolescente , Adulto , Animais , Feminino , Expressão Gênica , Glucose/metabolismo , Humanos , Bombas de Infusão Implantáveis , Insulina/metabolismo , Insulina/farmacologia , Leptina/genética , Leptina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Óxido Nítrico Sintase Tipo II/deficiência , Consumo de Oxigênio/efeitos dos fármacos , Fosforilação/efeitos dos fármacos
9.
Elife ; 62017 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-28589878

RESUMO

Insulin, downstream of Akt activation, promotes glucose uptake into fat and muscle cells to lower postprandial blood glucose, an enforced change in cellular metabolism to maintain glucose homeostasis. This effect is mediated by the Glut4 glucose transporter. Growth factors also enhance glucose uptake to fuel an anabolic metabolism required for tissue growth and repair. This activity is predominantly mediated by the Glut1. Akt is activated by phosphorylation of its kinase and hydrophobic motif (HM) domains. We show that insulin-stimulated Glut4-mediated glucose uptake requires PDPK1 phosphorylation of the kinase domain but not mTORC2 phosphorylation of the HM domain. Nonetheless, an intact HM domain is required for Glut4-mediated glucose uptake. Whereas, Glut1-mediated glucose uptake also requires mTORC2 phosphorylation of the HM domain, demonstrating both phosphorylation-dependent and independent roles of the HM domain in regulating glucose uptake. Thus, mTORC2 links Akt to the distinct physiologic programs related to Glut4 and Glut1-mediated glucose uptake.


Assuntos
Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Glucose/metabolismo , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases Dependentes de 3-Fosfoinositídeo/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Fosforilação
10.
Cell Rep ; 17(11): 2966-2978, 2016 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-27974210

RESUMO

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone involved in nutrient homeostasis. GIP receptor (GIPR) is constitutively internalized and returned to the plasma membrane, atypical behavior for a G-protein-coupled receptor (GPCR). GIP promotes GIPR downregulation from the plasma membrane by inhibiting recycling without affecting internalization. This transient desensitization is achieved by altered intracellular trafficking of activated GIPR. GIP stimulation induces a switch in GIPR recycling from a rapid endosomal to a slow trans-Golgi network (TGN) pathway. GPCR kinases and ß-arrestin2 are required for this switch in recycling. A coding sequence variant of GIPR, which has been associated with metabolic alterations, has altered post-activation trafficking characterized by enhanced downregulation and prolonged desensitization. Downregulation of the variant requires ß-arrestin2 targeting to the TGN but is independent of GPCR kinases. The single amino acid substitution in the variant biases the receptor to promote GIP-stimulated ß-arrestin2 recruitment without receptor phosphorylation, thereby enhancing downregulation.


Assuntos
Polipeptídeo Inibidor Gástrico/genética , Receptores Acoplados a Proteínas G/genética , Receptores dos Hormônios Gastrointestinais/genética , beta-Arrestina 2/genética , Células 3T3-L1 , Animais , Endossomos/metabolismo , Polipeptídeo Inibidor Gástrico/metabolismo , Humanos , Incretinas/genética , Camundongos , Transporte Proteico/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores dos Hormônios Gastrointestinais/metabolismo , beta-Arrestina 2/metabolismo , Rede trans-Golgi/genética , Rede trans-Golgi/metabolismo
11.
Mol Cell Endocrinol ; 437: 97-107, 2016 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-27521959

RESUMO

Insulin resistance is associated with deregulation of insulin signaling owing to the chronic exposure of insulin (hyperinsulinemia) to the tissues. Phosphorylation and dephosphorylation events in insulin signaling pathway play an essential role in signal transduction and glucose uptake. Amongst all, Akt protein is considered to be central to the overall insulin signaling proteins. In glucose responsive tissues like adipose and muscles, activation of Akt is responsible for triggering GLUT4 translocation and glucose transport. Several phosphatases such as PTEN, PP2A have been reported to be involved in dephosphorylation and inactivation of Akt protein. We have identified increased PP2A activity during state of chronic hyperinsulinemia exposure along-with development of adipocyte insulin resistance. This increased phosphatase activity leads activation of cAMP/PKA axis, which in turn increased cAMP levels in insulin resistant (IR) adipocytes. Okadaic acid, an inhibitor of PP2A restored and increased insulin stimulated glucose uptake in insulin resistant (IR) and insulin sensitive (IS) adipocytes respectively. In IS adipocyte, chemical activation of PP2A through MG132 and FTY720 showed decreased insulin sensitivity corroborated with decreased Akt phosphorylation and glucose uptake. We also observed an increased expression of PP2A-B (regulatory) subunit in IR adipocytes. We found PPP2R5B, a regulatory subunit of PP2A is responsible for the dephosphorylation and inactivation of Akt protein. Increased expression of PPP2R5B was also confirmed in white adipose tissue of high fat diet induced IR mice model. Overexpression and suppression strategies confirmed the role of PPP2R5B in regulating insulin signaling. Thus, we conclude that PPP2R5B, a B subunit of PP2A is a negative regulator of Akt phosphorylation contributing partly to the chronic hyperinsulinemia induced insulin resistance in adipocytes.


Assuntos
Adipócitos/metabolismo , Adipócitos/patologia , Resistência à Insulina , Proteína Fosfatase 2/metabolismo , Subunidades Proteicas/metabolismo , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Fosfatase Alcalina/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Dieta Hiperlipídica , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Glucose/metabolismo , Células HEK293 , Humanos , Insulina/efeitos adversos , Lentivirus/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas/genética , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
12.
J Endocrinol ; 230(3): 275-90, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27340034

RESUMO

The growing pandemics of diabetes have become a real threat to world economy. Hyperinsulinemia and insulin resistance are closely associated with the pathophysiology of type 2 diabetes. In pretext of brown adipocytes being considered as the therapeutic strategy for the treatment of obesity and insulin resistance, we have tried to understand the effect of hyperinsulinemia on brown adipocyte function. We here with for the first time report that hyperinsulinemia-induced insulin resistance in brown adipocyte is also accompanied with reduced insulin sensitivity and brown adipocyte characteristics. CI treatment decreased expression of brown adipocyte-specific markers (such as PRDM16, PGC1α, and UCP1) and mitochondrial content as well as activity. CI-treated brown adipocytes showed drastic decrease in oxygen consumption rate (OCR) and spare respiratory capacity. Morphological study indicates increased accumulation of lipid droplets in CI-treated brown adipocytes. We have further validated these findings in vivo in C57BL/6 mice implanted with mini-osmotic insulin pump for 8weeks. CI treatment in mice leads to increased body weight gain, fat mass and impaired glucose intolerance with reduced energy expenditure and insulin sensitivity. CI-treated mice showed decreased BAT characteristics and function. We also observed increased inflammation and ER stress markers in BAT of CI-treated animals. The above results conclude that hyperinsulinemia has deleterious effect on brown adipocyte function, making it susceptible to insulin resistance. Thus, the above findings have greater implication in designing approaches for the treatment of insulin resistance and diabetes via recruitment of brown adipocytes.


Assuntos
Adipócitos Marrons/metabolismo , Hiperinsulinismo/metabolismo , Resistência à Insulina/fisiologia , Animais , Composição Corporal/fisiologia , Peso Corporal/fisiologia , Diferenciação Celular , Teste de Tolerância a Glucose , Humanos , Hiperinsulinismo/induzido quimicamente , Espectroscopia de Ressonância Magnética , Masculino , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Transcrição/metabolismo , Aumento de Peso/fisiologia
13.
Diabetes ; 65(6): 1577-89, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27207531

RESUMO

Insulin controls glucose uptake into adipose and muscle cells by regulating the amount of GLUT4 in the plasma membrane. The effect of insulin is to promote the translocation of intracellular GLUT4 to the plasma membrane. The small Rab GTPase, Rab10, is required for insulin-stimulated GLUT4 translocation in cultured 3T3-L1 adipocytes. Here we demonstrate that both insulin-stimulated glucose uptake and GLUT4 translocation to the plasma membrane are reduced by about half in adipocytes from adipose-specific Rab10 knockout (KO) mice. These data demonstrate that the full effect of insulin on adipose glucose uptake is the integrated effect of Rab10-dependent and Rab10-independent pathways, establishing a divergence in insulin signal transduction to the regulation of GLUT4 trafficking. In adipose-specific Rab10 KO female mice, the partial inhibition of stimulated glucose uptake in adipocytes induces insulin resistance independent of diet challenge. During euglycemic-hyperinsulinemic clamp, there is no suppression of hepatic glucose production despite normal insulin suppression of plasma free fatty acids. The impact of incomplete disruption of stimulated adipocyte GLUT4 translocation on whole-body glucose homeostasis is driven by a near complete failure of insulin to suppress hepatic glucose production rather than a significant inhibition in muscle glucose uptake. These data underscore the physiological significance of the precise control of insulin-regulated trafficking in adipocytes.


Assuntos
Adipócitos/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Resistência à Insulina , Insulina/metabolismo , Fígado/metabolismo , Proteínas rab de Ligação ao GTP/deficiência , Células 3T3-L1 , Animais , Membrana Celular/metabolismo , Feminino , Glucose/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Esquelético/metabolismo , Transporte Proteico , Transdução de Sinais
14.
Pharmacogn Mag ; 11(Suppl 4): S501-10, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27013786

RESUMO

BACKGROUND: Cucumis melo ssp. agrestis var. agrestis (CMA) is a wild variety of C. melo. This study aimed to explore anti-dyslipidemic and anti-adipogenic potential of CMA. MATERIALS AND METHODS: For initial anti-dyslipidemic and antihyperglycemic potential of CMA fruit extract (CMFE), male Syrian golden hamsters were fed a chow or high-fat diet with or without CMFE (100 mg/kg). Further, we did fractionation of this CMFE into two fractions namely; CMA water fraction (CMWF) and CMA hexane fraction (CMHF). Phytochemical screening was done with liquid chromatography-mass spectrometry LC- (MS)/MS and direct analysis in real time-MS to detect active compounds in the fractions. Further, high-fat diet fed dyslipidemic hamsters were treated with CMWF and CMHF at 50 mg/kg for 7 days. RESULTS: Oral administration of CMFE and both fractions (CMWF and CMHF) reduced the total cholesterol, triglycerides, low-density lipoprotein cholesterol, and very low-density lipoprotein-cholesterol levels in high fat diet-fed dyslipidemic hamsters. CMHF also modulated expression of genes involved in lipogenesis, lipid metabolism, and reverse cholesterol transport. Standard biochemical diagnostic tests suggested that neither of fractions causes any toxicity to hamster liver or kidneys. CMFE and CMHF also decreased oil-red-O accumulation in 3T3-L1 adipocytes. CONCLUSION: Based on these results, it is concluded that CMA possesses anti-dyslipidemic and anti-hyperglycemic activity along with the anti-adipogenic activity. SUMMARY: The oral administration of Cucumis melo agrestis fruit extract (CMFE) and its fractions (CMWF and CMHF) improved serum lipid profile in HFD fed dyslipidemic hamsters.CMFE, CMWF and CMHF significantly attenuated body weight gain and eWAT hypertrophy.The CMHF decreased lipogenesis in both liver and adipose tissue.CMFE and CMHF also inhibited adipogenesis in 3T3-L1 adipocytes. Abbreviation used: CMA: Cucumis melo ssp. agrestis var. agrestis, CMFE: CMA fruit extract, CMWF: CMA water fraction, CMHF: CMA hexane fraction, FAS: Fatty acid synthase, SREBP1c: Sterol regulatory element binding protein 1c, ACC: Acetyl CoA carboxylase, LXR α: Liver X receptor α.

15.
Mol Cell Endocrinol ; 399: 373-85, 2015 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-25450865

RESUMO

A clerodane diterpene, 16α-Hydroxycleroda-3, 13 (14) Z-dien-15, 16-olide (compound 1) isolated from Polyalthia longifolia had previously been reported as a new structural class of HMG-CoA reductase inhibitor apart from statins. Statins are known to be anti-adipogenic in nature. The distant structural similarity between compound 1 and lovastatin (polyketide class of compound) prompted us to investigate effects of diterpene compound 1 on adipogenesis and thereby obesity. High content microscopy proved diterpene compound 1 exhibits better anti-adipogenic activity and less toxicity in differentiating adipocytes. Moreover, it reduced expression levels of PPARγ, C/EBPα and GLUT4 during differentiation in a time and concentration dependent manner. Diterpene compound 1 during early differentiation reduced MDI induced-Akt/mTOR phosphorylation and expression of cell cycle proteins, and thereby halted mitotic clonal expansion, the decisive factor in early adipogenesis. Further, its anti-adipogenic activity was validated in murine mesenchymal cell-line C3H10T1/2 and human mesenchymal stem cell models of adipogenic differentiation. When compound 1 was administered along with HFD, for another 8 weeks in 2 month HFD fed overweight mice (with BMI > 30 and impaired glucose tolerance), it attenuated weight gain and epididymal fat accumulation. It improved body glucose tolerance, reduced HFD induced increase in total cholesterol and leptin/adiponectin ratio. All these effects were comparable with standard anti-obesity drug Orlistat with added edge of potently decreasing circulating triglyceride levels comparable with normal chow fed group. Histological analysis shows that compound 1 inhibit adipocyte hypertrophy and decreased steatosis in hepatocytes. Both in vivo and in vitro results demonstrate a potential value of compound 1 as a novel anti-adipogenic and anti-obesity agent.


Assuntos
Adipogenia/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Diterpenos Clerodânicos/farmacologia , Obesidade/tratamento farmacológico , Animais , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Linhagem Celular , Diterpenos Clerodânicos/química , Diterpenos Clerodânicos/isolamento & purificação , Transportador de Glucose Tipo 4/metabolismo , Humanos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Obesidade/metabolismo , Obesidade/patologia , PPAR gama/metabolismo
16.
Eur J Med Chem ; 86: 570-7, 2014 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-25216379

RESUMO

In our efforts to develop safe and active chemical entities from nature, we first identified poliothrysoside (1), a phytoconstituent isolated from Flacourtia indica, possessing antidiabetic potential. Subsequently, fifteen derivatives (2-16) were synthesized to assess the activity profile of this class. All the compounds were analyzed for their glucose uptake potency in chronic insulin-induced insulin resistant 3T3-L1 adipocytes. Interestingly, compound 2 exhibited strong ability to increase the insulin sensitivity, primarily activating the AMPK signaling pathway and also inhibited the adipogenesis in 3T3-L1 adipocytes, in concentration dependent manner. Overall, these studies suggest the potential of poliothrysoside and its derivatives as promising leads for non-insulin dependent type 2 diabetes (T2D).


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adipogenia/efeitos dos fármacos , Benzoatos/farmacologia , Glucosídeos/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Animais , Benzoatos/síntese química , Benzoatos/química , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Glucosídeos/síntese química , Glucosídeos/química , Hipoglicemiantes/síntese química , Resistência à Insulina , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade
17.
Differentiation ; 87(5): 183-92, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25130315

RESUMO

According to the World Health Organization obesity is defined as the excessive accumulation of fat, which increases risk of other metabolic disorders such as insulin resistance, dyslipidemia, hypertension, cardiovascular diseases, etc. There are two types of adipose tissue, white and brown adipose tissue (BAT) and the latter has recently gathered interest of the scientific community. Discovery of BAT has opened avenues for a new therapeutic strategy for the treatment of obesity and related metabolic syndrome. BAT utilizes accumulated fatty acids for energy expenditure; hence it is seen as one of the possible alternates to the current treatment. Moreover, browning of white adipocyte on exposure to cold, as well as with some of the pharmacological agents presents exciting outcomes and indicates the feasibility of transdifferentiation. A better understanding of molecular pathways and differentiation factors, those that play a key role in transdifferentiation are of extreme importance in designing novel strategies for the treatment of obesity and associated metabolic disorders.


Assuntos
Adipócitos Brancos/metabolismo , Tecido Adiposo Marrom/metabolismo , Transdiferenciação Celular/genética , Obesidade/genética , Adipócitos Brancos/citologia , Tecido Adiposo Marrom/citologia , Diferenciação Celular/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Humanos , Obesidade/metabolismo , Obesidade/patologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Transdução de Sinais , Termogênese , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
18.
Microbes Infect ; 16(7): 571-80, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24819214

RESUMO

The adipocytes are one of the non-professional phagocytes postulated to be a haven for Mycobacterium tuberculosis during persistence in the human host. The adipocyte - M. tuberculosis interaction data available to date are ex vivo. The present study was primarily aimed to investigate M. tuberculosis infection of adipocytes in course of infection of mouse model. Using primary murine adipocytes, the study first confirmed the infection and immunomodulation of natural adipocytes by M. tuberculosis. The bacilli could be isolated form visceral, subcutaneous, peri renal and mesenteric adipose depots of immunocompetent mice infected with M. tuberculosis intravenously. The bacilli could be isolated from adipocytes and the stromal vascular fraction, even though the numbers were significantly higher in the latter. The bacterial burden in the adipose depots was comparable to those in lungs in the early phase of infection. But with time, the burden in the adipose depots was either decreased or kept under control, despite the increasing burden in the lungs. Infected mice treated with standard anti tubercular drugs, despite effective elimination of bacterial loads in the lungs, continued to harbour M. tuberculosis in adipose depots at loads similar to untreated mice in the late infection phase.


Assuntos
Adipócitos/imunologia , Adipócitos/microbiologia , Antituberculosos/uso terapêutico , Mycobacterium tuberculosis/crescimento & desenvolvimento , Tuberculose/microbiologia , Adipócitos/química , Adipocinas/análise , Tecido Adiposo/microbiologia , Animais , Antituberculosos/farmacologia , Células Cultivadas , Citocinas/análise , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno/imunologia , Gotículas Lipídicas , Camundongos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Tuberculose/tratamento farmacológico
19.
J Lipid Res ; 55(6): 1019-32, 2014 06.
Artigo em Inglês | MEDLINE | ID: mdl-24646949

RESUMO

We developed a common feature pharmacophore model using known antiadipogenic compounds (CFPMA). We identified rohitukine, a reported chromone anticancer alkaloid as a potential hit through in silico mapping of the in-house natural product library on CFPMA. Studies were designed to assess the antiadipogenic potential of rohitukine. Rohitukine was isolated from Dysoxylum binacteriferum Hook. to ⬧95% purity. As predicted by CFPMA, rohitukine was indeed found to be an antiadipogenic molecule. Rohitukine inhibited lipid accumulation and adipogenic differentiation in a concentration- and exposure-time-dependent manner in 3T3-L1 and C3H10T1/2 cells. Rohitukine downregulated expression of PPARγ, CCAAT/enhancer binding protein α, adipocyte protein 2 (aP2), FAS, and glucose transporter 4. It also suppressed mRNA expression of LPL, sterol-regulatory element binding protein (SREBP) 1c, FAS, and aP2, the downstream targets of PPARγ. Rohitukine arrests cells in S phase during mitotic clonal expansion. Rohitukine was bioavailable, and 25.7% of orally administered compound reached systemic circulation. We evaluated the effect of rohitukine on dyslipidemia induced by high-fat diet in the hamster model. Rohitukine increased hepatic expression of liver X receptor α and decreased expression of SREBP-2 and associated targets. Rohitukine decreased hepatic and gonadal lipid accumulation and ameliorated dyslipidemia significantly. In summary, our strategy to identify a novel antiadipogenic molecule using CFPMA successfully resulted in identification of rohitukine, which confirmed antiadipogenic activity and also exhibited in vivo antidyslipidemic activity.


Assuntos
Adipogenia/efeitos dos fármacos , Cromonas/farmacologia , Dislipidemias/tratamento farmacológico , Mitose/efeitos dos fármacos , Piperidinas/farmacologia , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Células 3T3-L1 , Animais , Cromonas/química , Dislipidemias/metabolismo , Dislipidemias/patologia , Feminino , Masculino , Mesocricetus , Camundongos , Piperidinas/química
20.
Phytomedicine ; 21(4): 406-14, 2014 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-24252344

RESUMO

Obesity is a result of adipocyte hypertrophy followed by hyperplasia. It is a risk factor for several metabolic disorders such as dyslipidemia, type-2 diabetes, hypertension, and cardiovascular diseases. Coagulanolides, particularly coagulin-L isolated from W. coagulan has earlier been reported for anti-hyperglycemic activity. In this study, we investigated the effect of coagulin-L on in vitro models of adipocyte differentiation including 3T3-L1 pre-adipocyte, mouse stromal mesenchymal C3H10T1/2 cells and bone marrow derived human mesenchymal stem cells (hMSCs). Our results showed that, coagulin-L reduces the expressions of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), the major transcription factors orchestrating adipocyte differentiation. Detailed analysis further proved that early exposure of coagulin-L is sufficient to cause significant inhibition during adipogenesis. Coagulin-L inhibited mitotic clonal expansion (MCE) by delayed entry in G1 to S phase transition and S-phase arrest. This MCE blockade was caused apparently by decreased phosphorylation of C/EBPß, modulation in expression of cell cycle regulatory proteins, and upregulation of Wnt/ß-catenin pathway, the early stage regulatory proteins of adipogenic induction. Taken together all evidences, a known anti-hyperglycemic agent coagulin-L has shown potential to inhibit adipogenesis significantly, which can be therapeutically exploited for treatment of obesity and metabolic syndrome.


Assuntos
Adipogenia/efeitos dos fármacos , Proteína alfa Estimuladora de Ligação a CCAAT/antagonistas & inibidores , Serina-Treonina Quinases TOR/antagonistas & inibidores , Withania , Vitanolídeos/farmacologia , Células 3T3-L1 , Animais , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Humanos , Camundongos , Mitose/efeitos dos fármacos , Obesidade/tratamento farmacológico , PPAR gama/antagonistas & inibidores , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Células-Tronco/efeitos dos fármacos , Vitanolídeos/uso terapêutico , Proteínas Wnt/metabolismo , beta Catenina/metabolismo
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