Blocking iNOS and endoplasmic reticulum stress synergistically improves insulin resistance in mice

Abstract

ObjectiveRecent data show that iNOS has an essential role in ER stress in obesity. However, whether iNOS is sufficient to account for obesity-induced ER stress and Unfolded Protein Response (UPR) has not yet been investigated. In the present study, we used iNOS knockout mice to investigate whether high-fat diet (HFD) can still induce residual ER stress-associated insulin resistance.MethodsFor this purpose, we used the intraperitoneal glucose tolerance test (GTT), euglycemic-hyperinsulinemic clamp, western blotting and qPCR in liver, muscle, and adipose tissue of iNOS KO and control mice on HFD.ResultsThe results of the present study demonstrated that, in HFD fed mice, iNOS-induced alteration in insulin signaling is an essential mechanism of insulin resistance in muscle, suggesting that iNOS may represent an important target that could be blocked in order to improve insulin sensitivity in this tissue. However, in liver and adipose tissue, the insulin resistance induced by HFD was only partially dependent on iNOS, and, even in the presence of genetic or pharmacological blockade of iNOS, a clear ER stress associated with altered insulin signaling remained evident in these tissues. When this ER stress was blocked pharmacologically, insulin signaling was improved, and a complete recovery of glucose tolerance was achieved.ConclusionsTaken together, these results reinforce the tissue-specific regulation of insulin signaling in obesity, with iNOS being sufficient to account for insulin resistance in muscle, but in liver and adipose tissue ER stress and insulin resistance can be induced by both iNOS-dependent and iNOS-independent mechanisms.

Inducible nitric oxide synthase‐derived nitric oxide reduces vagal satiety signalling in obese mice

“…iNOS contributes J Physiol 597.6 to obesity-related insulin resistance by reducing insulin receptor substrate-1 expression (Sugita et al 2005). Consistently, iNOS knockout mice on a high-fat diet are protected from insulin resistance (Noronha et al 2005;Zanotto et al 2017). The present study clarified the involvement of iNOS in the pathogenesis of obesity in terms of modulation of satiety signalling conveyed by vagal afferents.…”

“…; Zanotto et al . ). The present study clarified the involvement of iNOS in the pathogenesis of obesity in terms of modulation of satiety signalling conveyed by vagal afferents.…”

Growth hormone enhances the recovery of hypoglycemia via ventromedial hypothalamic neurons

“…After 4 h without food, adult mice were subjected to a glucose tolerance test (GTT; 2 g glucose/kg body weight, i.p.). The hyperinsulinemic‐euglycemic clamp was done as previously described by Zanotto et al (25), after being unfed overnight (8–12 h). Briefly, anesthetized animals received a continuous insulin infusion at a fixed rate of 3 mU/kg/min through an inserted catheter in the jugular vein.…”

Endoplasmic Reticulum Stress in Metabolic Disorders

“…Some studies have aimed at evaluating the respective roles of ER stress and oxidative stress in insulin resistance. Blockade of ER stress, but not inducible nitric oxide synthase (iNOS), restores insulin sensitivity in mouse liver and adipose tissue, whereas disruption of iNOS alone is sufficient to confer glucose tolerance in muscle [90]. The effect of ER stress on insulin signaling has been deciphered in a model of Lipopolysaccharide (LPS)-induced ER stress.…”

“…One of the well-known oxidative stress response genes is nitric oxide synthase, especially its inducible isoform iNOS, which is capable of producing large amounts of NO as a defense mechanism, but it also induces inflammation. In liver, contrary to ER stress response, iNOS alone was not sufficient to account for the insulin resistance as iNOS blockade did not improve glucose metabolism whereas ER stress pharmacological blockade restored glucose tolerance and insulin sensitivity of the liver [90]. A key regulator of cellular resistance to oxidative stress is the transcription factor NRF2 which controls both basal and regulated expression of an array of antioxidant response element-dependent genes to regulate the physiological and pathophysiological outcomes of oxidant exposure [119].…”