A severe restriction of sodium chloride intake has been associated with insulin resistance and obesity. The molecular mechanisms by which the low salt diet (LS) can induce insulin resistance have not yet been established. The c-jun N-terminal kinase (JNK) activity has been involved in the pathophysiology of obesity and induces insulin resistance by increasing inhibitory IRS-1ser307 phosphorylation. In this study we have evaluated the regulation of insulin signaling, JNK activation and IRS-1ser307 phophorylation in liver, muscle and adipose tissue by immunoprecipitation and immunoblotting in rats fed with LS or normal salt diet (NS) during 9 weeks. LS increased body weight, visceral adiposity, blood glucose and plasma insulin levels, induced insulin resistance and did not change blood pressure. In LS rats a decrease in PI3-K/Akt was observed in liver and muscle and an increase in this pathway was seen in adipose tissue. JNK activity and IRS-1ser307 phosphorylation were higher in insulin-resistant tissues. In summary, the insulin resistance, induced by LS, is tissue-specific and is accompanied by activation of JNK and IRS-1ser307 phosphorylation. The impairment of the insulin signaling in these tissues, but not in adipose tissue, may lead to increased adiposity and insulin resistance in LS rats.
Patrícia Oliveira Prada, Michella Soares Coelho, Henrique Gottardello Zecchin, Miriam Sterman Dolnikoff, Alessandra Lia Gasparetti, Luzia Naôko Shinohara Furukawa, Mario José Abdalla Saad and Joel Claudio Heimann
Mariana Rosolen Tavares, Simone Ferreira Lemes, Thais de Fante, Cristina Saenz de Miera, Isadora Carolina Betim Pavan, Rosangela Maria Neves Bezerra, Patricia Oliveira Prada, Marcio Alberto Torsoni, Carol Fuzeti Elias and Fernando Moreira Simabuco
The mTOR/S6Ks signaling is one of the intracellular pathways important for metabolic control, acting both peripherally and centrally. In the hypothalamus, mTOR/S6Ks axis mediates the action of leptin and insulin and can modulate the expression of neuropeptides. We analyzed the role of different S6Ks isoforms in the hypothalamic regulation of metabolism. We observed decreased food intake and decreased expression of agouti-related peptide (AgRP) following intracerebroventricular (icv) injections of adenoviral-mediated overexpression of three different S6Ks isoforms. Moreover, mice overexpressing p70-S6K1 in undefined periventricular hypothalamic neurons presented changes in glucose metabolism, as an increase in gluconeogenesis. To further evaluate the hypothalamic role of a less-studied S6K isoform, p54-S6K2, we used a Cre-LoxP approach to specifically overexpress it in AgRP neurons. Our findings demonstrate the potential participation of S6K2 in AgRP neurons regulating feeding behavior.