Activation of hypothalamic S6 kinase mediates diet-induced hepatic insulin resistance in rats

Abstract

Prolonged activation of p70 S6 kinase (S6K) by insulin and nutrients leads to inhibition of insulin signaling via negative feedback input to the signaling factor IRS-1. Systemic deletion of S6K protects against diet-induced obesity and enhances insulin sensitivity in mice. Herein, we present evidence suggesting that hypothalamic S6K activation is involved in the pathogenesis of diet-induced hepatic insulin resistance. Extending previous findings that insulin suppresses hepatic glucose production (HGP) partly via its effect in the hypothalamus, we report that this effect was blunted by short-term high-fat diet (HFD) feeding, with concomitant suppression of insulin signaling and activation of S6K in the mediobasal hypothalamus (MBH). Constitutive activation of S6K in the MBH mimicked the effect of the HFD in normal chow-fed animals, while suppression of S6K by overexpression of dominant-negative S6K or dominant-negative raptor in the MBH restored the ability of MBH insulin to suppress HGP after HFD feeding. These results suggest that activation of hypothalamic S6K contributes to hepatic insulin resistance in response to short-term nutrient excess.

Short-Term High-Fat-and-Fructose Feeding Produces Insulin Signaling Alterations Accompanied by Neurite and Synaptic Reduction and Astroglial Activation in the Rat Hippocampus

“…Phosphorylation of serine residues of IRS-1 mediated by kinases such as S6K, JNK and PKC, among others, prevents IRS-1 from recognizing the phosphorylated insulin receptor, and therefore gives rise to InsRes in HFFD-fed animals. 27,29,30 In line with this, we found an increase in S6K kinase activation, which might in turn phosphorylate IRS-1 in serine residues and therefore blunt insulin signaling in the HFFD-fed rats. mTOR/S6K signaling can be activated by insulin, some growth factors and nutrients.…”

“…Since insulin signaling is downregulated in our model, we believe that S6K High-fat diet decreases hippocampal insulin signaling E Calvo-Ochoa et al activation is caused by signaling pathways activated by the increase in saturated fatty acids, as has been found in the hypothalamus and the amygdala. 29,30 Another interesting finding was a significant decrease in Akt Ser473 phosphorylation, which is indicative that hippocampal insulin signaling can be compromised at different levels after consumption of an HFFD. High-fat diet decreases hippocampal insulin signaling E Calvo-Ochoa et al…”

“…Earlier experiments in rats have shown that HFFD feeding activates the mTOR/S6K pathway in muscle, liver, and mediobasal hypothalamus. 29,30 Therefore, we analyzed whether HFFD also induces the activation of S6K in the hippocampus. As shown in Figure 2D, we found an enhanced S6K phosphorylation of threonine 389 after 7 days of HFFD feeding (71.9%, Po0.001).…”

Modulation of AgRP-neuronal function by SOCS3 as an initiating event in diet-induced hypothalamic leptin resistance

“…Upon acute exposure to a high-fat diet, SOCS3 is up-regulated in AgRP neurons and this is followed by wide-spread SOCS3 up-regulation in a broader hypothalamic area after prolonged high-fat feeding. Transgenic up-regulation of SOCS3 in AgRP neurons causes several key phenotypes reminiscent of those observed after short-term consumption of fat-rich diets; this includes hyperphagia, elevation of energy expenditure, development of insulin resistance, and increased hepatic lipid content without significant changes in body adiposity (12)(13)(14)(15)(16)(17). This result suggests that modulation of SOCS3 expression may play a dynamic role in metabolic fine tuning in response to short-term changes of nutritional status.…”

“…Short-term consumption of a high-fat diet leads to increased feeding and caloric intake, but at the same time results in elevation of energy expenditure, which likely serves as an adaptive response to restore energy balance (12-15). Concurrent to that, however, is the rapid induction of insulin resistance and hepatic steatosis, even in the absence of an apparent weight change (16,17). Consumption of a fat-rich diet, when allowed to persist, ultimately leads to obesity.…”