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1.
Biomed Pharmacother ; 143: 112188, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34563947

RESUMEN

An extract from Artemisia dracunculus L. (termed PMI-5011) improves glucose homeostasis by enhancing insulin action and reducing ectopic lipid accumulation, while increasing fat oxidation in skeletal muscle tissue in obese insulin resistant male mice. A chalcone, DMC-2, in PMI-5011 is the major bioactive that enhances insulin signaling and activation of AKT. However, the mechanism by which PMI-5011 improves lipid metabolism is unknown. AMPK is the cellular energy and metabolic sensor and a key regulator of lipid metabolism in muscle. This study examined PMI-5011 activation of AMPK signaling using murine C2C12 muscle cell culture and skeletal muscle tissue. Findings show that PMI-5011 increases Thr172-phosphorylation of AMPK in muscle cells and skeletal muscle tissue, while hepatic AMPK activation by PMI-5011 was not observed. Increased AMPK activity by PMI-5011 affects downstream signaling of AMPK, resulting in inhibition of ACC and increased SIRT1 protein levels. Selective deletion of DMC-2 from PMI-5011 demonstrates that compounds other than DMC-2 in a "DMC-2 knock out extract" (KOE) are responsible for AMPK activation and its downstream effects. Compared to 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) and metformin, the phytochemical mixture characterizing the KOE appears to more efficiently activate AMPK in muscle cells. KOE-mediated AMPK activation was LKB-1 independent, suggesting KOE does not activate AMPK via LKB-1 stimulation. Through AMPK activation, compounds in PMI-5011 may regulate lipid metabolism in skeletal muscle. Thus, the AMPK-activating potential of the KOE adds therapeutic value to PMI-5011 and its constituents in treating insulin resistance or type 2 diabetes.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Artemisia , Activadores de Enzimas/farmacología , Hipoglucemiantes/farmacología , Resistencia a la Insulina , Músculo Esquelético/efectos de los fármacos , Fitoquímicos/farmacología , Extractos Vegetales/farmacología , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacología , Animales , Artemisia/química , Línea Celular , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Activación Enzimática , Activadores de Enzimas/aislamiento & purificación , Hipoglucemiantes/aislamiento & purificación , Masculino , Metformina/farmacología , Ratones Endogámicos C57BL , Músculo Esquelético/enzimología , Mioblastos Esqueléticos/efectos de los fármacos , Mioblastos Esqueléticos/enzimología , Fosforilación , Fitoquímicos/aislamiento & purificación , Extractos Vegetales/aislamiento & purificación , Ribonucleótidos/farmacología , Transducción de Señal/efectos de los fármacos
2.
Obes Rev ; 10 Suppl 2: 46-51, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19849801

RESUMEN

As the obesity pandemic has accelerated, investigators have begun to explore alternative mechanisms linking circadian biology and sleep to adipose tissue metabolism and obesity. This manuscript reviews recent findings in murine and human models demonstrating the oscillatory expression of the mRNAs encoding the core circadian regulatory proteins in adipose tissue. Comparative transcriptomic analyses of circadian oscillating genes have been used to identify the 'delta sleep-inducing peptide immunoreactor', also known as 'glucocorticoid-induced leucine zipper (GILZ)', as a potential link in this chain. The GILZ gene has been found to differentially regulate stromal stem cell adipogenic and osteogenic differentiation in a reciprocal manner. In adipose and other metabolically active tissues, the circadian oscillation of GILZ expression is subject to entrainment by external stimuli. Together, these observations suggest that GILZ is an attractive candidate for future studies evaluating the role of circadian mechanisms in adipose tissue physiology and pathology.


Asunto(s)
Adipogénesis/fisiología , Tejido Adiposo/metabolismo , Ritmo Circadiano/fisiología , Péptido Inductor del Sueño Delta/metabolismo , Leucina Zippers/fisiología , Osteogénesis/fisiología , Animales , Diferenciación Celular/fisiología , Péptido Inductor del Sueño Delta/genética , Regulación de la Expresión Génica , Glucocorticoides/farmacología , Humanos , Leucina Zippers/efectos de los fármacos , Leucina Zippers/genética , Ratones , Obesidad/etiología , Obesidad/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factores de Transcripción
3.
J Biol Chem ; 276(25): 22468-75, 2001 Jun 22.
Artículo en Inglés | MEDLINE | ID: mdl-11309375

RESUMEN

Many short-lived nuclear proteins are targeted for degradation by the ubiquitin-proteasome pathway. The role of the nucleus in regulating the turnover of these proteins is not well defined, although many components of the ubiquitin-proteasome system are localized in the nucleus. We have used nucleoplasm from highly purified HeLa nuclei to examine the degradation of a physiological substrate of the ubiquitin-proteasome system (MyoD). In vitro studies using inhibitors of the system demonstrate MyoD is degraded via the ubiquitin-proteasome pathway in HeLa nucleoplasm. Purified nucleoplasm in vitro also supports the generation of high molecular mass MyoD-ubiquitin adducts. In addition, in vivo studies, using leptomycin B to inhibit nuclear export, demonstrate that MyoD is degraded in HeLa cells by the nuclear ubiquitin-proteasome system.


Asunto(s)
Núcleo Celular/metabolismo , Cisteína Endopeptidasas/metabolismo , Complejos Multienzimáticos/metabolismo , Proteína MioD/metabolismo , Ubiquitinas/metabolismo , Adenosina Trifosfato/metabolismo , Núcleo Celular/efectos de los fármacos , Ácidos Grasos Insaturados/farmacología , Células HeLa , Humanos , Hidrólisis , Complejo de la Endopetidasa Proteasomal
4.
J Biol Chem ; 276(10): 7062-8, 2001 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-11106650

RESUMEN

Interferon-gamma (IFN-gamma) is known primarily for its roles in immunological responses but also has been shown to affect fat metabolism and adipocyte gene expression. To further investigate the effects of IFN-gamma on fat cells, we examined the effects of this cytokine on the expression of adipocyte transcription factors in 3T3-L1 adipocytes. Although IFN-gamma regulated the expression of several adipocyte transcription factors, IFN-gamma treatment resulted in a rapid reduction of both peroxisome proliferator-activated receptor (PPAR) protein and mRNA. A 48-h exposure to IFN-gamma also resulted in a decrease of both CCAAT/enhancer-binding alpha and sterol regulatory element binding protein (SREBP-1) expression. The short half-life of both the PPARgamma mRNA and protein likely contributed to the rapid decline of both cytosolic and nuclear PPARgamma in the presence of IFN-gamma. Our studies clearly demonstrated that the IFN-gamma-induced loss of PPARgamma protein is partially inhibited in the presence of two distinct proteasome inhibitors. Moreover, IFN-gamma also inhibited the transcription of PPARgamma, which was accompanied by a decrease in PPARgamma mRNA accumulation. In addition, exposure to IFN-gamma resulted in a substantial increase in STAT 1 expression and a small increase in STAT 3 expression. IFN-gamma treatment of 3T3-L1 adipocytes (48-96 h) resulted in a substantial inhibition of insulin-sensitive glucose uptake. These data clearly demonstrate that IFN-gamma treatment results in the development of insulin resistance, which is accompanied by the regulation of various adipocyte transcription factors, in particular the synthesis and degradation of PPARgamma.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , Interferón gamma/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Transactivadores/metabolismo , Factores de Transcripción/metabolismo , Adipocitos/metabolismo , Animales , Transporte Biológico , Proteína alfa Potenciadora de Unión a CCAAT/metabolismo , Proteínas Potenciadoras de Unión a CCAAT/biosíntesis , Núcleo Celular/metabolismo , Células Cultivadas , Citosol/metabolismo , Proteínas de Unión al ADN/biosíntesis , Dactinomicina/farmacología , Desoxiglucosa/metabolismo , Relación Dosis-Respuesta a Droga , Electroforesis en Gel de Poliacrilamida , Regulación Enzimológica de la Expresión Génica , Immunoblotting , Insulina/metabolismo , Resistencia a la Insulina , Ligandos , Ratones , Regiones Promotoras Genéticas , ARN Mensajero/metabolismo , Factor de Transcripción STAT1 , Factor de Transcripción STAT3 , Proteína 1 de Unión a los Elementos Reguladores de Esteroles , Factores de Tiempo , Transcripción Genética
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