Obese mice lacking inducible nitric oxide synthase are sensitized to the metabolic actions of peroxisome proliferator-activated receptor-gamma agonism.

Objective: Synthetic ligands for peroxisome proliferator-activated receptor-gamma (PPAR-gamma) improve insulin sensitivity in obesity, but it is still unclear whether inflammatory signals modulate their metabolic actions. In this study, we tested whether targeted disruption of inducible nitric oxide (NO) synthase (iNOS), a key inflammatory mediator in obesity, modulates the metabolic effects of rosiglitazone in obese mice.

Research Design And Methods: iNOS(-/-) and iNOS(+/+) were subjected to a high-fat diet or standard diet for 18 weeks and were then treated with rosiglitazone for 2 weeks.

Visceral obesity and the heart.

Obesity and particularly its deleterious form, visceral adiposity, has reached a high prevalence in the industrialized world owing to the lack of exercise and the widely available energy-dense diet. As a consequence, cardiovascular diseases and metabolic disorders are afflicting an unprecedented number of individuals at a world-wide scale. Over the last decades, investigations have established firm links between visceral obesity and the development of cardiovascular diseases.

AMPK activation with AICAR provokes an acute fall in plasma [K+].

AMP-activated protein kinase (AMPK), activated by an increase in intracellular AMP-to-ATP ratio, stimulates pathways that can restore ATP levels. We tested the hypothesis that AMPK activation influences extracellular fluid (ECF) K(+) homeostasis. In conscious rats, AMPK was activated with 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) infusion: 38.

Identification of IRS-1 Ser-1101 as a target of S6K1 in nutrient- and obesity-induced insulin resistance.

S6K1 has emerged as a critical signaling component in the development of insulin resistance through phosphorylation and inhibition of IRS-1 function. This effect can be triggered directly by nutrients such as amino acids or by insulin through a homeostatic negative-feedback loop. However, the role of S6K1 in mediating IRS-1 phosphorylation in a physiological setting of nutrient overload is unresolved.

Role of dietary proteins and amino acids in the pathogenesis of insulin resistance.

Dietary proteins and amino acids are important modulators of glucose metabolism and insulin sensitivity. Although high intake of dietary proteins has positive effects on energy homeostasis by inducing satiety and possibly increasing energy expenditure, it has detrimental effects on glucose homeostasis by promoting insulin resistance and increasing gluconeogenesis. Varying the quality rather than the quantity of proteins has been shown to modulate insulin resistance induced by Western diets and has revealed that proteins derived from fish might have the most desirable effects on insulin sensitivity.

Long-chain omega-3 fatty acids regulate bovine whole-body protein metabolism by promoting muscle insulin signalling to the Akt-mTOR-S6K1 pathway and insulin sensitivity.

The ability of the skeletal musculature to use amino acids to build or renew constitutive proteins is gradually lost with age and this is partly due to a decline in skeletal muscle insulin sensitivity. Since long-chain omega-3 polyunsaturated fatty acids (LCn-3PUFA) from fish oil are known to improve insulin-mediated glucose metabolism in insulin-resistant states, their potential role in regulating insulin-mediated protein metabolism was investigated in this study. Experimental data are based on a switchback design composed of three 5 week experimental periods using six growing steers to compare the effect of a continuous abomasal infusion of LCn-3PUFA-rich menhaden oil with an iso-energetic control oil mixture.

Altered glucose homeostasis in mice lacking the receptor protein tyrosine phosphatase sigma.

Several protein tyrosine phosphatases (PTPs) expressed in insulin sensitive-tissues are proposed to attenuate insulin action and could act as key regulators of the insulin receptor (IR) signaling pathway. Among these PTPs, RPTPsigma is expressed in relatively high levels in insulin-target tissues. We show that RPTPsigma-/- knockout mice have reduced plasma glucose and insulin concentrations in the fasted state compared with their wild-type siblings.

Overproduction of intestinal lipoprotein containing apolipoprotein B-48 in Psammomys obesus: impact of dietary n-3 fatty acids.

Aims/hypothesis: Emerging evidence underscores the important role of the small intestine in the pathogenesis of dyslipidaemia in insulin resistance and type 2 diabetes. We therefore tested the hypothesis that n-3 fatty acids improve the various events governing intra-enterocyte lipid transport in Psammomys obesus gerbils, a model of nutritionally induced metabolic syndrome.

Materials And Methods: Experiments were carried out on Psammomys obesus gerbils that were assigned to an isocaloric control diet and a diet rich in fish oil for 6 weeks.

The SHP-1 protein tyrosine phosphatase negatively modulates glucose homeostasis.

The protein tyrosine phosphatase SHP-1 is a well-known inhibitor of activation-promoting signaling cascades in hematopoietic cells but its potential role in insulin target tissues is unknown. Here we show that Ptpn6(me-v/me-v) (also known as viable motheaten) mice bearing a functionally deficient SHP-1 protein are markedly glucose tolerant and insulin sensitive as compared to wild-type littermates, as a result of enhanced insulin receptor signaling to IRS-PI3K-Akt in liver and muscle. Downregulation of SHP-1 activity in liver of normal mice by adenoviral expression of a catalytically inert mutant of SHP-1, or after small hairpin RNA-mediated SHP-1 silencing, further confirmed this phenotype.

Overexpression of Rad in muscle worsens diet-induced insulin resistance and glucose intolerance and lowers plasma triglyceride level.

Rad is a low molecular weight GTPase that is overexpressed in skeletal muscle of some patients with type 2 diabetes mellitus and/or obesity. Overexpression of Rad in adipocytes and muscle cells in culture results in diminished insulin-stimulated glucose uptake. To further elucidate the potential role of Rad in vivo, we have generated transgenic (tg) mice that overexpress Rad in muscle using the muscle creatine kinase (MCK) promoter-enhancer.

Fatty acid-induced changes in vascular reactivity in healthy adult rats.

Dietary fatty acids (FAs) are known to modulate endothelial dysfunction, which is the first stage of atherosclerosis. However, their exact role in this initial phase is still unclear. The effects of isolated or combined (by 2) purified FAs from the main FA families were studied on the vascular response of isolated thoracic aorta in healthy rats to get a better understanding of the mechanisms of action of dietary FAs in regulating vascular endothelial function.

Overactivation of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availability.

To examine the molecular mechanisms by which plasma amino acid elevation impairs insulin action, we studied seven healthy men twice in random order during infusion of an amino acid mixture or saline (total plasma amino acid approximately 6 vs. approximately 2 mmol/l). Somatostatin-insulin-glucose clamps created conditions of low peripheral hyperinsulinemia ( approximately 100 pmol/l, 0-180 min) and prandial-like peripheral hyperinsulinemia ( approximately 430 pmol/l, 180-360 min).

NF-kappa B-mediated MyoD decay during muscle wasting requires nitric oxide synthase mRNA stabilization, HuR protein, and nitric oxide release.

Muscle wasting (cachexia) is a consequence of chronic diseases, such as cancer, and is associated with degradation of muscle proteins such as MyoD. The cytokines tumor necrosis factor alpha and gamma interferon induce muscle degeneration by activating the transcription factor NF-kappaB and its target genes. Here, we show that a downstream target of NF-kappaB is the nitric oxide (NO) synthase gene (iNos) and suggest that NO production stimulates MyoD mRNA loss.

Redox modulation of insulin signaling and endothelial function.

Reactive oxygen and nitrogen species (ROS and RNS) recently emerged as critical signaling molecules in cardiovascular research. Several studies over the past decade have shown that physiological effects of vasoactive factors are mediated by these reactive species and, conversely, that altered redox mechanisms are implicated in the occurrence of metabolic and cardiovascular diseases. Oxidant stress occurs when ROS and/or RNS production exceeds the cell natural antioxidant systems, and pathological events ensue.

Modulation of insulin action by dietary proteins and amino acids: role of the mammalian target of rapamycin nutrient sensing pathway.

Purpose Of Review: An increasing number of studies point towards an important role of dietary proteins and amino acids in the modulation of insulin action in peripheral tissues. The purpose of this review is to discuss how these nutrients affect insulin sensitivity and the potential mechanism by which they exert their action.

Recent Findings: Increased plasma amino acid availability in both animals and humans has been shown to cause enhanced translation initiation and protein synthesis and the inhibition of insulin-stimulated glucose transport in skeletal muscle.

Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: possible involvement in obesity-linked insulin resistance.

The mammalian target of rapamycin (mTOR) pathway integrates insulin and nutrient signaling in numerous cell types. Recent studies also suggest that this pathway negatively modulates insulin signaling to phosphatidylinositol 3-kinase/Akt in adipose and muscle cells. However, it is still unclear whether activation of the mTOR pathway is increased in obesity and if it could be involved in the promotion of insulin resistance.

Activation of the mammalian target of rapamycin pathway acutely inhibits insulin signaling to Akt and glucose transport in 3T3-L1 and human adipocytes.

The mammalian target of rapamycin (mTOR) pathway has recently emerged as a chronic modulator of insulin-mediated glucose metabolism. In this study, we evaluated the involvement of this pathway in the acute regulation of insulin action in both 3T3-L1 and human adipocytes. Insulin rapidly (t(1/2) = 5 min) stimulated the mTOR pathway, as reflected by a 10-fold stimulation of 70-kDa ribosomal S6 kinase 1 (S6K1) activity in 3T3-L1 adipocytes.

Inducible nitric oxide synthase modulates lipolysis in adipocytes.

The role of inducible nitric oxide synthase (iNOS) in the modulation of adipocyte lipolysis was investigated. Treatment of white and brown adipose cell lines and mouse adipose explants with a mixture of tumor necrosis factor-alpha, interferon-gamma, and lipopolysaccharide (LPS) doubled the lipolytic rate, and this was associated with marked induction of iNOS expression and nitric oxide (NO) production. iNOS inhibition by 1400W, aminoguanidine, or L-NIL pretreatment further increased the cytokine/LPS-mediated lipolysis by 30% (P < 0.

Inhibition of inducible nitric-oxide synthase by activators of AMP-activated protein kinase: a new mechanism of action of insulin-sensitizing drugs.

AMP-activated protein kinase (AMPK), an energy-sensing enzyme that is activated in response to cellular stress, is a critical signaling molecule for the regulation of multiple metabolic processes. AMPK has recently emerged as an attractive novel target for the treatment of obesity and type 2 diabetes because its activation increases fatty acid oxidation and improves glucose homeostasis. Here we show that pharmacological activation of AMPK by insulin-sensitizing drugs markedly inhibits inducible nitric-oxide synthase (iNOS), a proinflammatory mediator in endotoxic shock and in chronic inflammatory states including obesity-linked diabetes.

Reduction of endothelial NOS and bradykinin-induced extravasation of macromolecules in skeletal muscle of the fructose-fed rat model.

Objective: Reduced capillary permeability of the skeletal muscle vascular bed has been suggested to play a role in fructose-fed rats, corroborating a long held view that insulin resistance might partially be explained by the lack of access of insulin and glucose to its target organs, mainly skeletal muscles. The goal of this study was to explore mechanisms underlying this vascular abnormality, and more specifically the role of bradykinin and nitric oxide (NO) on skeletal muscle microcirculation and the extravasation of macromolecules.

Methods: For that purpose, Sprague-Dawley rats were fed with either a fructose-enriched (F) or a normal chow (N) diet and extravasation of macromolecules was assessed at 4 weeks by measuring in vivo the extravasation of Evans Blue (EB) dye in the quadriceps muscles of both groups after the intravenous injection of the potent vasodilator bradykinin (150 microg/kg).

The AMP-activated protein kinase activator AICAR does not induce GLUT4 translocation to transverse tubules but stimulates glucose uptake and p38 mitogen-activated protein kinases alpha and beta in skeletal muscle.

The AMP-activated protein kinase (AMPK) pathway participates in the metabolic effects of contraction on muscle glucose uptake. We have shown that contraction increases both GLUT4 translocation to the cell surface and p38 mitogen-activated protein kinase (p38 MAPK) activity. The latter pathway may be involved in the activation of GLUT4.