RESUMEN

Oxidative stress and the activation of the nucleotide-binding domain, leucine-rich-containing family, pyrin domain containing 3 (NLRP3) inflammasome have been linked to insulin resistance in skeletal muscle. In immune cells, the exacerbated generation of reactive oxygen species (ROS) activates the NLRP3 inflammasome, by facilitating the interaction between thioredoxin interacting protein (TXNIP) and NLRP3. However, the precise role of ROS/TXNIP-dependent NLRP3 inflammasome activation in skeletal muscle during obesity-induced insulin resistance remains undefined. Here, we induced insulin resistance in C57BL/6J mice by feeding them for 8 weeks with a high-fat diet (HFD) and explored whether the ROS/TXNIP/NLRP3 pathway was involved in the induction of insulin resistance in skeletal muscle. Skeletal muscle fibers from insulin-resistant mice exhibited increased oxidative stress, as evidenced by elevated malondialdehyde levels, and altered peroxiredoxin 2 dimerization. Additionally, these fibers displayed augmented activation of the NLRP3 inflammasome, accompanied by heightened ROS-dependent proximity between TXNIP and NLRP3, which was abolished by the antioxidant N-acetylcysteine (NAC). Inhibition of the NLRP3 inflammasome with MCC950 or suppressing the ROS/TXNIP/NLRP3 pathway with NAC restored insulin-dependent glucose uptake in muscle fibers from insulin-resistant mice. These findings provide insights into the mechanistic link between oxidative stress, NLRP3 inflammasome activation, and obesity-induced insulin resistance in skeletal muscle.

Asunto(s)

Proteínas Portadoras , Dieta Alta en Grasa , Glucosa , Resistencia a la Insulina , Músculo Esquelético , Proteína con Dominio Pirina 3 de la Familia NLR , Obesidad , Estrés Oxidativo , Especies Reactivas de Oxígeno , Transducción de Señal , Tiorredoxinas , Animales , Masculino , Ratones , Proteínas Portadoras/metabolismo , Proteínas Portadoras/genética , Dieta Alta en Grasa/efectos adversos , Furanos/farmacología , Glucosa/metabolismo , Indenos/farmacología , Inflamasomas/metabolismo , Insulina/metabolismo , Ratones Endogámicos C57BL , Ratones Obesos , Músculo Esquelético/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Obesidad/metabolismo , Obesidad/patología , Especies Reactivas de Oxígeno/metabolismo , Sulfonamidas , Tiorredoxinas/metabolismo , Tiorredoxinas/genética

RESUMEN

Focal palmoplantar and gingival keratosis syndrome is a rare dominant inherited disease with an early onset in life. Clinically, the condition is characterized by pressure related thickening of the epidermis of the palms and soles, usually accompanied by pain and different levels of skin involvement and thickness between patients. Recently, we observed a 38-year-old woman with multiple non-removable, painless white plaques of variable size and thickness on the attached gingiva and a white plaque widespread across the hard palate. By further questioning, the patient comments that she has thick yellowish focal plaques in both soles of her feet. Histopathological analysis revealed a hyperplastic and hyperorthokeratinized stratified squamous epithelium with basal hyperplasia. The spinous, granular and stratum corneum showed dispersed basophilic keratohyalin granules. At higher magnification, the keratinocytes contained paranuclear bodies, seen as round eosinophilic condensation that indented the nuclei. Based on these findings the final diagnosis was rendered as focal palmoplantar and gingival keratosis. Key words:Genodermatoses, white plaque, dyskeratosis, gingiva.