RESUMEN
Circulating free fatty acids (FFAs) are elevated in obesity and cause insulin resistance. The objective of the current study was to determine whether the antioxidant N-acetyl-l-cysteine (NAC) prevented hepatic and peripheral insulin resistance caused by prolonged elevation of plasma FFAs. Chronically cannulated Wistar rats received saline (SAL), Intralipid plus heparin (IH), IH plus NAC, or NAC i.v. infusion for 48âh. Insulin sensitivity was determined using the hyperinsulinemic-euglycemic clamp with tritiated glucose tracer. IH induced hepatic and peripheral insulin resistance (P<0.05). NAC co-infusion did not prevent insulin resistance in the liver, although it was able to prevent peripheral insulin resistance. Prolonged IH infusion did not appear to induce oxidative stress in the liver because hepatic content of protein carbonyl, malondialdehyde, and reduced to oxidized glutathione ratio did not differ across treatment groups. In alignment with our insulin sensitivity results, IH augmented skeletal muscle protein carbonyl content and this was prevented by NAC co-infusion. Taken together, our results indicate that oxidative stress mediates peripheral, but not hepatic, insulin resistance resulting from prolonged plasma FFA elevation. Thus, in states of chronic plasma FFA elevation, such as obesity, antioxidants may protect against peripheral but not hepatic insulin resistance.
Asunto(s)
Acetilcisteína/farmacología , Ácidos Grasos no Esterificados/sangre , Resistencia a la Insulina/fisiología , Fosfolípidos/administración & dosificación , Aceite de Soja/administración & dosificación , Animales , Biomarcadores , Glucemia , Emulsiones/administración & dosificación , Femenino , Depuradores de Radicales Libres/farmacología , Glucosa/metabolismo , Heparina/administración & dosificación , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Ratas , Ratas WistarRESUMEN
The bipartite transcription factor beta-catenin/TCF (cat/TCF) has been recognized as the major effector of the Wnt signaling pathway for more than a decade, and its over-activation has been associated with malignancy such as colon and breast cancer. Extensive examination in different cell lineages has shown that the activity of cat/TCF can be stimulated by mechanisms other than via the Wnt glycoproteins, including the stimulation of beta-cat nuclear translocation and enhanced binding of cat/TCF to the Wnt target gene promoters by insulin and insulin-like growth factor-1 (IGF-1). In addition, the heterotrimeric G proteins of the G(12) subfamily can interact with the cytoplasmic domain of cadherins, resulting in the release of the transcriptional activator beta-cat. Furthermore, certain peptide hormones may stimulate cat/TCF-mediated gene transcription via activation of their corresponding G-protein coupled receptors. Recently, the serine/threonine kinase GSK-3 has been recognized to coordinate with AMP activated protein kinase (AMPK) in phosphorylation and activation of TSC2, the major component of the tumor suppressor complex TSC1/2. Thus, Wnt activation can stimulate protein translation via GSK-3 and TSC1/2 inactivation, followed by mTOR activation. Finally, beta-cat also functions as a pivotal molecule in defense against oxidative stress via serving as a partner of forkhead box O (FOXO) transcription factors. Thus, FOXO proteins, which mainly mediate aging and stress signaling, and TCF factors, which mainly mediate developmental and proliferation signaling, compete for a limited pool of free beta-cat. Insulin and growth factors, on the other hand, control the balance between TCF- and FOXO-mediated gene transcription via phosphorylation and nuclear exclusion of FOXO proteins. These observations provide new insight to understand how Wnt, insulin/growth factors, and FOXOs are involved in versatile physiological events and the development and progression of various human diseases.