The fat cell senescence hypothesis: a mechanism responsible for abrogating the resolution of inflammation in chronic disease.

PURPOSE OF REVIEW: Obesity is a chronic inflammatory disease in which the physiological resolution of inflammation is attenuated, leading to low-grade inflammation throughout the body. However, the heat shock response, which is a key component of the physiological response to resolve inflammation, is seriously hampered in adipose tissue and other metabolic organs (e.g. skeletal muscle, liver, pancreatic ß-cells) in metabolic diseases. In this review, we hypothesize that adipocyte metabolic stress triggers the onset of fat cell senescence, and companion senescence-associated secretory phenotype (SASP), and that such a scenario is responsible for attenuating the resolution of inflammation. RECENT FINDINGS: We shall discuss the role of the heat shock response in the context of the resolution of inflammation and the relevance of heat shock response blockade in chronic inflammatory diseases. Sirtuin-1 is responsible for the induction of heat shock transcription factor-1 mRNA expression and for the stabilization of heat shock transcription factor-1 in a high-profile activity state. However, adipose tissue-emanated SASP depress sirtuin-1 expression, leading adipocytes to a perpetual state of unresolved inflammation, due to a dampening of the heat shock response. SUMMARY: The advance of inflammasome-mediated SASP from adipose to other tissues promotes cellular senescence in many other cells of the organism, aggravating obesity-dependent chronic inflammation. Inducers of heat shock response (e.g. heat shock itself, physical exercise and calorie restriction) may efficiently interrupt this vicious cycle and are envisaged as the best and also the most economical treatment for obesity-related chronic diseases.

L-arginine is essential for pancreatic ß-cell functional integrity, metabolism and defense from inflammatory challenge.

In this work, our aim was to determine whether L-arginine (a known insulinotropic amino acid) can promote a shift of ß-cell intermediary metabolism favoring glutathione (GSH) and glutathione disulfide (GSSG) antioxidant responses, stimulus-secretion coupling and functional integrity. Clonal BRIN-BD11 ß-cells and mouse islets were cultured for 24 h at various L-arginine concentrations (0-1.15  mmol/l) in the absence or presence of a proinflammatory cytokine cocktail (interleukin 1ß, tumour necrosis factor α and interferon γ). Cells were assessed for viability, insulin secretion, GSH, GSSG, glutamate, nitric oxide (NO), superoxide, urea, lactate and for the consumption of glucose and glutamine. Protein levels of NO synthase-2, AMP-activated protein kinase (AMPK) and the heat shock protein 72 (HSP72) were also evaluated. We found that L-arginine at 1.15  mmol/l attenuated the loss of ß-cell viability observed in the presence of proinflammatory cytokines. L-arginine increased total cellular GSH and glutamate levels but reduced the GSSG/GSH ratio and glutamate release. The amino acid stimulated glucose consumption in the presence of cytokines while also stimulating AMPK phosphorylation and HSP72 expression. Proinflammatory cytokines reduced, by at least 50%, chronic (24 h) insulin secretion, an effect partially attenuated by L-arginine. Acute insulin secretion was robustly stimulated by L-arginine but this effect was abolished in the presence of cytokines. We conclude that L-arginine can stimulate ß-cell insulin secretion, antioxidant and protective responses, enabling increased functional integrity of ß-cells and islets in the presence of proinflammatory cytokines. Glucose consumption and intermediary metabolism were increased by L-arginine. These results highlight the importance of L-arginine availability for ß-cells during inflammatory challenge.

HSP70 expression: does it a novel fatigue signalling factor from immune system to the brain?

Integrative physiology studies have shown that immune system and central nervous system interplay very closely towards behavioural modulation. Since the 70-kDa heat shock proteins (HSP70s), whose heavy expression during exercise is well documented in the skeletal muscle and other tissues, is also extremely well conserved in nature during all evolutionary periods of species, it is conceivable that HSP70s might participate of physiologic responses such as fatigue induced by some types of physical exercise. In this way, increased circulating levels of extracellular HSP70 (eHSP70) could be envisaged as an immunomodulatory mechanism induced by exercise, besides other chemical messengers (e.g. cytokines) released during an exercise effort, that are able to binding a number of receptors in neural cells. Studies from this laboratory led us to believe that increased levels of eHSP70 in the plasma during exercise and the huge release of eHSP70 from lymphocytes during high-load exercise bouts may participate in the fatigue sensation, also acting as a danger signal from the immune system.

Acute exercise stimulates macrophage function: possible role of NF-kappaB pathways.

Moderate physical activity when performed on a regular basis presents a number of benefits to the whole organism, especially regarding immune system function, such as augmenting resistance to infections and to cancer growth. Although glutamine production by active muscle cells as well as neuroendocrine alterations mediated by the chronic adaptation to exercise may play a role, the entire mechanism by which exercise makes the immune system aware of challenges remains mostly uncovered. This is particularly true for the effects of an acute exercise session on immune function. In this work, circulating monocytes/macrophages from sedentary rats submitted to an acute (1 h) swimming session were tested for the ability of phagocytosing zymosan particles, phorbol myristate acetate (PMA)-induced hydrogen peroxide production, nitric oxide (NO) release (assessed by nitrate and nitrite production) and the expression of NO synthases (NOS-1, NOS-2 and NOS-3). The results showed that an exercise bout induced a 2.4-fold rise in macrophage phagocytic capacity (p = 0.0041), a 9.6-fold elevation in PMA-induced hydrogen peroxide release into the incubation media (1-h, p = 0.0022) and a 95.5%-augmentation in nitrite basal production (1-h incubation; p = 0.0220), which was associated with a marked expression of NOS-2 (the inducible NOS isoform; p = 0.0319), but not in other NOS gene products. Although NOS-2 expression is nuclear factor-kappaB (NF-kappaB)-dependent, no systemic oxidative stress was found, as inferred from the data of plasma TBARS and glutathione disulphide (GSSG) to glutathione (GSH) ratio in circulating blood erythrocytes which remained constant after the acute exercise. Also, no stressful situation seemed to be faced by monocytes/macrophages, since the expression of the 70-kDa heat shock protein (HSP70) remained unchanged. We conclude that NF-kappaB-dependent induction of NOS-2 and macrophage activation must be related to local factor(s) produced in the surroundings of monocytes/macrophages.

MRP1/GS-X pump ATPase expression: is this the explanation for the cytoprotection of the heart against oxidative stress-induced redox imbalance in comparison to skeletal muscle cells?

Striated muscle activity is always accompanied by oxidative stress (OxStress): the more intense muscle work and/or its duration, the more a redox imbalance may be attained. In spite of cardiac muscle functioning continuously, it is well known that the heart does not suffer from OxStress-induced damage over a broad physiological range. Although the expression of antioxidant enzymes may be of importance in defending heart muscle against OxStress, a series of combined antioxidant therapeutic approaches have proved to be mostly ineffective in avoiding cellular injury. Hence, additional mechanisms may be involved in heart cytoprotection other than antioxidant enzyme activities. The strong cardiotoxic effect of doxorubicin-induced cancer chemotherapy shed light on the possible role for multidrug resistance-associated proteins (MRP) in this context. Muscle activity-induced 'physiological' OxStress enhances the production of glutathione disulfide (GSSG) thus increasing the ratio of GSSG to glutathione (GSH) content inside the cells, which, in turn, leads to redox imbalance. Since MRP1 gene product (a GS-X pump ATPase) is a physiological GSSG transporter, adult Wistar rats were tested for MRP1 expression and activity in the heart and skeletal muscle (gastrocnemius), in as much as the latter is known to be extremely sensitive to muscle activity-induced OxS. MRP1 expression was completely absent in skeletal muscle. In contrast, the heart showed an exercise training-dependent induction of MRP1 protein expression which was further augmented (2.4-fold) as trained rats were challenged with a session of acute exercise. On the other hand, inducible expression of the 70-kDa heat shock protein (HSP70), a universal marker of cellular stress, was completely absent in the heart of sedentary and acutely exercised rats, whereas skeletal muscle showed a conspicuous exercise-dependent HSP70 expression, which decreased by 45% with exercise training. This effect was paralleled by a 58% decrease in GSH content in skeletal muscle which was even higher (an 80%-fall) after training thus leading to a marked redox imbalance ([GSSG]/[GSH] raised up to 38-fold). In the heart, GSH contents and [GSSG]/[GSH] ratio remained virtually unchanged even after exercise challenges, while GS-X pump activity was found to be 20% higher in the heart related to skeletal muscle. These findings suggest that an intrinsic higher capacity to express the MRP1/GS-X pump may dictate the redox status in the heart muscle thus protecting myocardium by preventing GSSG accumulation in cardiomyocytes as compared to skeletal muscle fibres.