Insulin resistance is a pathological condition that arises when insulin signaling is impaired, forcing β-cells to produce more insulin in order to cope with body demands and to maintain glucose homeostasis. When the pancreas is no more able to support an appropriate insulin secretion, insulin resistance becomes decompensated and hyperglycemia is detected. One of the mechanisms leading to insulin resistance is low-grade inflammation that involves a number of protagonists such as inflammatory cytokines, lipids and their metabolites, reactive oxygen species (ROS), hypoxia and endoplasmic reticulum stress, and changes in gut microbiota profiles. We review here the molecular aspects of metabolic inflammation converging to insulin resistance and secondarily to type 2 diabetes. We also discuss the place of high-sensitivity C-reactive protein (hsCRP) in the assessment of metabolic inflammation and potential therapeutic interventions aimed to impede inflammation and therefore prevent insulin resistance.

https://www.tandfonline.com/doi/pdf/10.3109/07853890.2012.705015

Metabolic inflammation: Connecting obesity and insulin resistance

Sprague-Dawley rats were fed either a control diet (7 g/100 g soybean oil) or a conjugated linoleic acid (CLA) diet (6.5 g/100 g soybean oil and 0.5 g/100 g CLA) beginning on d 7 of gestation to determine whether pre- and postnatal CLA affects short- and long-term growth and adiposity. At weaning (d 21), progeny were assigned control or CLA diet and fed until 11 wk of age. At birth, litter size and weight were not different between treatments. There were age- and sex-dependent changes in inguinal adipose fatty acid composition at birth and weaning, whereas there were no differences in lipid accretion or adipocyte proliferation. At weaning, CLA did not alter inguinal adipocyte proliferation but increased (P < 0.01) CCAAT/enhancer binding protein alpha expression in inguinal adipose tissue from females, whereas there was no difference in expression in males. Significant differences in size distribution of inguinal adipocytes at weaning and retroperitoneal adipocytes at 11 wk of age were observed. In general, CLA increased the proportion of smaller cells and decreased the proportion of larger cells. The main long-term effect of the dams' diet was the significantly heavier gastrocnemius and soleus muscles, and significantly longer tail lengths, an indication of skeletal growth, of male pups whose dams were fed CLA. Postweaning diet reduced fat pad weights in female but not male pups fed CLA. This response was due to differences in cell size rather than number. Response to CLA treatment may depend on the sex and age of the animal as well as duration of feeding.

/pdf/pre-and-postnatal-dietary-conjugated-linoleic-acid-alters-1vn2v4ltsh.pdf

Pre- and Postnatal Dietary Conjugated Linoleic Acid Alters Adipose Development, Body Weight Gain and Body Composition in Sprague-Dawley Rats

Adipose tissue has the largest capacity to store energy in the body and provides energy through the release of free fatty acids during times of energy need. Different types of immune cells are recruited to adipose tissue under various physiological conditions, indicating that these cells contribute to the regulation of adipose tissue. One major pathway influenced by a number of immune cells is the release of free fatty acids through lipolysis during both physiological (e.g., cold stress) and pathophysiological processes (e.g., obesity, type 2 diabetes). Adipose tissue expansion during obesity leads to immune cell infiltration and adipose tissue remodeling, a homeostatic process that promotes inflammation in adipose tissue. The release of proinflammatory cytokines stimulates lipolysis and causes insulin resistance, leading to adipose tissue dysfunction and systemic disruptions of metabolism. This review focuses on the interactions of cytokines and other inflammatory molecules that regulate adipose tissue lipolysis during physiological and pathophysiological states.

/pdf/fat-in-flames-influence-of-cytokines-and-pattern-recognition-4hw5lij7sx.pdf

Fat in flames: influence of cytokines and pattern recognition receptors on adipocyte lipolysis.

Osmotic shock and insulin stimulate GLUT4 translocation and glucose transport via mechanisms that are for the most part distinct yet convergent. In this article, we investigated the effect of osmotic shock and insulin on the activation of the mitogen-activated protein kinase (MAPK) cascades in differentiated 3T3-L1 adipocytes. The MAPKs are activated by phosphorylation on conserved tyrosine and threonine residues. Both sorbitol and insulin strongly stimulated extracellular regulated kinase (ERK) 1 and 2 phosphorylation (8- and 18-fold, respectively). In contrast, c-jun-NH2-terminal kinase (JNK)/stress-activated protein kinase (SAPK) phosphorylation was stimulated only by sorbitol (sevenfold) and not by insulin. Phosphorylation of p38 MAPK was stimulated strongly by sorbitol (22-fold) but weakly by insulin (2.7-fold). Measurement of intrinsic JNK and p38 MAPK activity confirmed the phosphorylation studies. JNK and p38 MAPK were activated only significantly by sorbitol. The MAPKs are phosphorylated by dual-specificity kinases (mitogen-activated ERK-activating kinase [MEK] or MAPK kinase [MKK]). As expected, sorbitol and insulin both stimulated MEK phosphorylation. MKK4 was phosphorylated only in response to sorbitol, and neither of the stimuli caused phosphorylation of MKK3 or 6. To determine the functional significance of the observed activation of p38 MAPK in response to insulin and osmotic shock, we used three pyridinyl imidazole p38 MAPK inhibitors, SB203580, SB202190, and PD169316. Insulin and osmotic shock-stimulated glucose transport was not inhibited by any inhibitor at concentrations that were shown to block p38 MAPK activity. Furthermore, activation of the p38 MAPK pathway by treatment of cells with anisomycin did not stimulate glucose transport. These results suggest that activation of the p38 MAPK pathway is not involved in the stimulation of glucose transport.

https://diabetes.diabetesjournals.org/content/diabetes/49/11/1783.full.pdf

Stimulation of MAPK cascades by insulin and osmotic shock: lack of an involvement of p38 mitogen-activated protein kinase in glucose transport in 3T3-L1 adipocytes.

cope
Saturated-free fatty acids, such as palmitate, are associated with insulin resistance. This study aimed to establish if an aspalathin-enriched green rooibos extract (GRE) and, its major flavanoid, aspalathin (ASP) could contribute significantly to the amelioration of experimentally induced insulin resistance in 3T3-L1 adipocytes.

Methods and results
3T3-L1 adipocytes were cultured in DMEM containing 0.75 mM palmitate for 16 h to induce insulin resistance before treatment for 3 h with GRE (10 μg/mL) or ASP (10 μM). GRE and ASP reversed the palmitate-induced insulin resistance. At a protein level GRE and ASP suppressed nuclear factor kappa beta (NF-κB), insulin receptor substrate one (serine 307) (IRS1 (Ser 307)) and AMP-activated protein kinase phosphorylation and increased serine/threonine kinase AKT (AKT) activation, while only GRE increased glucose transporter four (Glut4) protein expression. Peroxisome proliferator-activated receptor alpha and gamma (PPARα and γ), and carnitine palmitoyltransferase one (CPT1) expression were increased by ASP alone.

Conclusion
Together these effects offer a plausible explanation for the ameliorative effect of GRE and ASP on insulin-resistance, an underlying cause for obesity and type 2 diabetes.

Aspalathin improves glucose and lipid metabolism in 3T3-L1 adipocytes exposed to palmitate

Proinflammatory cytokines are well-known to inhibit insulin signaling to result in insulin resistance. IL-1alpha is also one of the proinflammatory cytokines, but the mechanism of how IL-1alpha induces insulin resistance remains unclear. We have now examined the effects of IL-1alpha on insulin signaling in 3T3-L1 adipocytes. Prolonged IL-1alpha treatment for 12 to 24 hours partially decreased the protein levels as well as the insulin-stimulated tyrosine phosphorylation of IRS-1 and Akt phosphorylation. mRNA for SOCS3, an endogenous inhibitor of insulin signaling, was dramatically augmented 4 hours after IL-1alpha treatment. Concomitantly, the level of IL-6 in the medium and STAT3 phosphorylation were increased by the prolonged IL-1alpha treatment. Addition of anti-IL-6 neutralizing antibody to the medium or overexpression of dominant-negative STAT3 decreased the IL-1alpha-stimulated STAT3 activation and SOCS3 induction, and ameliorated insulin signaling. These results suggest that the IL-1alpha-mediated deterioration of insulin signaling is largely due to the IL-6 production and SOCS3 induction in 3T3-L1 adipocytes.

Long-term Interleukin-1α Treatment Inhibits Insulin Signaling via IL-6 Production and SOCS3 Expression in 3T3-L1 Adipocytes

Non-esterified fatty acids are thought to be one of the causes for insulin resistance. However, the molecular mechanism of fatty acid-induced insulin resistance is not clearly known. In this study, we first examined the effect of palmitate on insulin signaling in 3T3-L1 adipocytes. We found that 1h treatment with 1 mmol/l palmitate had no effect on insulin binding, tyrosine phosphorylation of insulin receptors, 185 kDa proteins and Shc, and PI3 kinase activity in 3T3-L1 adipocytes. Then, the effects of palmitate on MAP kinase activity and glucose uptake in fully differentiated 3T3-L1 adipocytes were compared with those in poorly differentiated 3T3-L1 cells and in HIRc-B cells. Palmitate treatment had no effect on MAP kinase activity in fully differentiated 3T3-L1 adipocytes, while it inhibited MAP kinase in poorly differentiated 3T3-L1 cells and HIRc-B cells. Glucose transport in 3T3-L1 adipocytes treated with palmitate for 1 h, 4 h and 16 h was higher than that in control cells, but palmitate treatment caused a rightward shift of the insulin-dose responsive curve for glucose uptake in HIRc-B cells. Palmitate treatment did not significantly affect basal and insulin-stimulated GLUT4 translocation. When the cells were treated with PD98059, a specific MEK inhibitor, insulin-stimulated glucose uptake was not affected in 3T3-L1 adipocytes, while it was almost completely inhibited in HIRc-B cells. These results suggest the primary effect of palmitate on adipocytes may not involve insulin resistance of adipocytes themselves.

Differential effects of palmitate on glucose uptake in rat-1 fibroblasts and 3T3-L1 adipocytes.

Osmotic shock induces GLUT4 translocation and glucose uptake through a mechanism independent of PI 3-kinase, but dependent on tyrosine phosphorylation of cellular proteins. To identify the tyrosine phosphorylated proteins required for osmotic shock-stimulated glucose uptake, we examined tyrosine phosphorylation of candidate proteins, and found that the 60-80kDa species including paxillin and the 120-130kDa species including p130Cas, PYK2, FAK and Gab1 were tyrosine-phosphorylated in response to osmotic shock. Inhibition of actin polymerization by cytochalasin D significantly decreased the tyrosine phosphorylation of paxillin, p130Cas, PYK2 and FAK but not Gab1, but had no effect on 2-deoxyglucose (DOG) uptake, suggesting a role for Gab1 in osmotic shock-induced glucose transport. Also, we found that osmotic shock increases the association of phospholipase C-gamma (PLC-gamma) with Gab1 and stimulates tyrosine phosphorylation of PLC-gamma itself. The PLC inhibitor, U73122, inhibited osmotic shock-induced 2-DOG uptake. These results suggest that tyrosine phosphorylation of Gab1 and subsequent recruitment and activation of PLC-gamma may play a role in osmotic shock-induced glucose transport.

Potential role of Gab1 and phospholipase C-gamma in osmotic shock-induced glucose uptake in 3T3-L1 adipocytes.

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Long-term Interleukin-1α Treatment Inhibits Insulin Signaling via IL-6 Production and SOCS3 Expression in 3T3-L1 Adipocytes

Differential effects of palmitate on glucose uptake in rat-1 fibroblasts and 3T3-L1 adipocytes.

Potential role of Gab1 and phospholipase C-gamma in osmotic shock-induced glucose uptake in 3T3-L1 adipocytes.