Chronic unpredictable stress regulates visceral adipocyte-mediated glucose metabolism and inflammatory circuits in male rats

Chronic psychological stress is a prominent risk factor involved in the pathogenesis of many complex diseases, including major depression, obesity, and type II diabetes. Visceral adipose tissue is a key endocrine organ involved in the regulation of insulin action and an important component in the development of insulin resistance. Here, we examined for the first time the changes on visceral adipose tissue physiology and on adipocyte-associated insulin sensitivity and function after chronic unpredictable stress in rats. Male rats were subjected to chronic unpredictable stress for 35 days. Total body and visceral fat was measured. Cytokines and activated intracellular kinase levels were determined using high-throughput multiplex assays. Adipocyte function was assessed via tritiated glucose uptake assay. Stressed rats showed no weight gain, and their fat/lean mass ratio increased dramatically compared to control animals. Stressed rats had significantly higher mesenteric fat content and epididymal fat pad weight and demonstrated reduced serum glucose clearing capacity following glucose challenge. Alterations in fat depot size were mainly due to changes in adipocyte numbers and not size. High-throughput molecular screening in adipocytes isolated from stressed rats revealed activation of intracellular inflammatory, glucose metabolism, and MAPK networks compared to controls, as well as significantly reduced glucose uptake capacity in response to insulin stimulation. Our study identifies the adipocyte as a key regulator of the effects of chronic stress on insulin resistance, and glucose metabolism, with important ramifications in the pathophysiology of several stress-related disease states

Calcium Homeostasis and Organelle Function in the Pathogenesis of Obesity and Diabetes

A number of chronic metabolic pathologies, including obesity, diabetes, cardiovascular disease, asthma, and cancer, cluster together to present the greatest threat to human health. As research in this field has advanced, it has become clear that unresolved metabolic inflammation, organelle dysfunction, and other cellular and metabolic stresses underlie the development of these chronic metabolic diseases. However, the relationship between these systems and pathological mechanisms is poorly understood. Here we discuss the role of cellular Ca2+ homeostasis as a critical mechanism integrating the myriad of cellular and subcellular dysfunctional networks found in metabolic tissues such as liver and adipose tissue in the context of metabolic disease, particularly in obesity and diabetes

Aberrant islet unfolded protein response in type 2 diabetes

The endoplasmic reticulum adapts to fluctuations in demand and copes with stress through an adaptive signaling cascade called the unfolded protein response (UPR). Accumulating evidence indicates that the canonical UPR is critical to the survival and function of insulin-producing pancreatic β-cells, and alterations in the UPR may contribute to the pathogenesis of type 2 diabetes. However, the dynamic regulation of UPR molecules in the islets of animal models and humans with type 2 diabetes remains to be elucidated. Here, we analyzed the expression of activating factor 6 (ATF6α) and spliced X-box binding protein 1 (sXBP1), and phosphorylation of eukaryotic initiation factor 2 (eIF2α), to evaluate the three distinct branches of the UPR in the pancreatic islets of mice with diet- or genetic-induced obesity and insulin resistance. ATF6 and sXBP1 expression was predominantly found in the β-cells, where hyperglycemia coincided with a decline in expression in both experimental models and in humans with type 2 diabetes. These data suggest alterations in the expression of UPR mediators may contribute to the decline in islet function in type 2 diabetes in mice and humans

Defective Hepatic Autophagy in Obesity Promotes ER Stress and Causes Insulin Resistance

SummaryAutophagy is a homeostatic process involved in the bulk degradation of cytoplasmic components, including damaged organelles and proteins. In both genetic and dietary models of obesity, we observed a severe downregulation of autophagy, particularly in Atg7 expression levels in liver. Suppression of Atg7 both in vitro and in vivo resulted in defective insulin signaling and elevated ER stress. In contrast, restoration of the Atg7 expression in liver resulted in dampened ER stress, enhanced hepatic insulin action, and systemic glucose tolerance in obese mice. The beneficial action of Atg7 restoration in obese mice could be completely prevented by blocking a downstream mediator, Atg5, supporting its dependence on autophagy in regulating insulin action. Our data demonstrate that autophagy is an important regulator of organelle function and insulin signaling and that loss of autophagy is a critical component of defective insulin action seen in obesity

The inflammatory changes of adipose tissue in late pregnant mice

The infiltration of classically activated macrophages (M1) and alternatively activated macrophages (M2) in subcutaneous adipose tissue (SAT) and parametrial adipose tissue (PAT) was analyzed to investigate whether local inflammatory change in adipose tissue occurs in late pregnancy. C57BL/6N female mice at 6 weeks of age were fed a normal chow diet for 4 weeks prior to mating at 10 weeks of age and were sampled on day 17 of pregnancy. The serum levels of adipokines and biochemical markers were measured using ELISA and enzymatic methods. The identification of M1 and M2 was analyzed by double immunofluorescence with anti-F4/80 and anti-CD11c antibodies. The gene expression of adipokines in adipose tissues was analyzed by quantitative RT-PCR. The pregnant group showed adipocyte hypertrophy, higher macrophage infiltration, and higher M1/M2 in both SAT and PAT compared with the non-pregnant (NP) group. Serum levels of free fatty acids, tumor necrosis factor α (TNFα), interleukin 6 (IL6), and IL10 were higher, and serum levels of adiponectin were lower in the pregnant group than those in the NP group. The gene expressions of CD68, Itgax, CCR2, TNFα, and PAI1 in SAT during pregnancy were significantly higher than those in the NP group, as were the gene expressions of CD68, Emrl, Itgax, MCP1, TNFα, IL6, PAI1, adiponectin, and IL10 in PAT. These results suggest that the low-grade inflammation of adipose tissue indicated by increased macrophage infiltration occurs in late normal pregnancy

Palmitoleic acid prevents palmitic acid-induced macrophage activation and consequent p38 MAPK-mediated-skeletal muscle insulin resistance

Obesity and saturated fatty acid (SFA) treatment are both associated with skeletal muscle insulin resistance (IR) and increased macrophage infiltration. However, the relative effects of SFA and unsaturated fatty acid (UFA)-activated macrophages on muscle are unknown. Here, macrophages were treated with palmitic acid, palmitoleic acid or both and the effects of the conditioned medium (CM) on C2C12 myotubes investigated. CM from palmitic acid-treated J774s (palm-mac-CM) impaired insulin signalling and insulin-stimulated glycogen synthesis, reduced Inhibitor κBα and increased phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase in myotubes. p38 MAPK inhibition or siRNA partially ameliorated these defects, as did addition of tumour necrosis factor-α blocking antibody to the CM. Macrophages incubated with both FAs generated CM that did not induce IR, while palmitoleic acid-mac-CM alone was insulin sensitising. Thus UFAs may improve muscle insulin sensitivity and counteract SFA-mediated IR through an effect on macrophage activation

Tumor Necrosis Factor-α Antagonism Improves Vasodilation During Hyperinsulinemia in Metabolic Syndrome

OBJECTIVE—Obesity is associated with chronic inflammation due to overproduction of proinflammatory cytokines, including tumor necrosis factor (TNF)-α. We assessed the effects of TNF-α neutralization by infliximab on vascular reactivity during hyperinsulinemia in obesity-related metabolic syndrome

Fractalkine: A Cellular Link Between Adipose Tissue Inflammation and Vascular Pathologies

It is hard to imagine, given the wealth of new datareported over the recent past, that adipose tissue atone time was primarily considered as a passive res-ervoir for energy deposition and storage. However, research beginning in the early 1990s on the role of tumor necrosis factor (TNF)-a ushered in a new era of inves-tigation, and since that time, there has been an incredibly rapid and substantive increase in our understanding of underlying physiologic systems and molecular pathways linking obesity, inflammation, and insulin action (1,2). Spe-cifically, our understanding of the link between obesity and carbohydrate metabolism has been significantly enhanced with the elucidation of key regulators of energy balance and cellular insulin signaling that are complex and highly in-tegrated (3–6). We now readily accept adipose tissue as a key endocrine organ regulating processes throughout the body with its significant number of adipocyte secre-tions. What now appears to be emerging is the elucidatio