Glucocorticoids and Thiazolidinediones Interfere with Adipocyte-mediated Macrophage Chemotaxis and Recruitment

The link between intra-abdominal adiposity and type II diabetes has been known for decades, and adipose tissue macrophage (ATM)-associated inflammation has recently been linked to insulin resistance. However, the mechanisms associated with ATM recruitment remain ill defined. Herein, we describe in vitro chemotaxis studies, in which adipocyte conditioned medium was used to stimulate macrophage migration. We demonstrate that tumor necrosis factor α and free fatty acids, key inflammatory stimuli involved in obesity-associated autocrine/paracrine inflammatory signaling, stimulate adipocyte expression and secretion of macrophage chemoattractants. Pharmacological studies showed that peroxisome proliferator-activated receptor γ agonists and glucocorticoids potently inhibit adipocyte- induced recruitment of macrophages. This latter effect was mediated by the glucocorticoid receptor, which led to decreased chemokine secretion and expression. In vivo results were quite comparable; treatment of high fat diet-fed mice with dexamethasone prevented ATM accumulation in epididymal fat. This decrease in ATM was most pronounced for the proinflammatory F4/80⁺, CD11b⁺, CD11c⁺ M-1-like ATM subset. Overall, our results elucidate a beneficial function of peroxisome proliferator-activated receptor γ activation and glucocorticoid receptor/glucocorticoids in adipose tissue and indicate that pharmacologic prevention of ATM accumulation could be beneficial.     

MiR-690, an exosomal-derived miRNA from M2-polarized macrophages,improves insulin sensitivity in obese mice

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Separate intracellular pathways for insulin receptor recycling and insulin degradation in isolated rat adipocytes

To gain insight into the sequence of events that follow endocytotic uptake of insulin receptor complexes, we have examined the interrelationship between the degradative pathway of the insulin ligand and the recycling pathway of the insulin receptor. Tris(hydroxymethyl)aminomethane and other nonamphoteric amines were found to selectively impair insulin receptor recycling while leaving the insulin-degradative pathway intact. In contrast, low concentrations of the lysosomotropic agent chloroquine markedly inhibited intracellular insulin degradation but had little or no affect on the recycling of internalized receptors. Thus, we conclude: (1) that insulin dissociates from its receptor after endocytotic uptake and both receptor and ligand follow a separate intracellular pathway; and (2) that receptor recycling and insulin degradation can be selectively inhibited by Tris and chloroquine, respectively, highlighting the potential usefulness of these agents as intracellular probes in the study of receptor-ligand metabolism.     

Comparison of the effects of insulin and insulin-like agents on different aspects of adipocyte metabolism.

The effect of insulin, spermine, cysteine, and diamide on glucose transport, glucose oxidation, and lipolysis were compared using isolated rat adipocytes. Each agent exerted insulin-like effects on glucose transport and glucose oxidation, whereas spermine and cysteine, but not diamide, inhibited lipolysis. Furthermore, the relative potencies of these agents on the various insulin responsive processes were markedly different. Thus, although these agents have much in common with insulin, the differences in relative potencies suggest that at least some of the insulin-like properties of these compounds may not be exerted through the same mechanisms as insulin.