Hippocampal neural stem cells and microglia response to experimental inflammatory bowel disease (IBD).

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a disease associated with dysbiosis, resulting in compromised intestinal epithelial barrier and chronic mucosal inflammation. Patients with IBD present with increased incidence of psychiatric disorders and cognitive impairment. Hippocampus is a brain region where adult neurogenesis occurs with functional implications in mood control and cognition. Using a well-established model of experimental colitis based on the administration of dextran sodium sulfate (DSS) in the drinking water, we sought to characterize the short and long-term effects of colitis on neurogenesis and glia responses in the hippocampus. We show that acute DSS colitis enhanced neurogenesis but with deficits in cell cycle kinetics of proliferating progenitors in the hippocampus. Chronic DSS colitis was characterized by normal levels of neurogenesis but with deficits in the migration and integration of newborn neurons in the functional circuitry of the DG. Notably, we found that acute DSS colitis-induced enhanced infiltration of the hippocampus with macrophages and inflammatory myeloid cells from the periphery, along with elevated frequencies of inflammatory M1-like microglia and increased release of pro-inflammatory cytokines. In contrast, increased percentages of tissue-repairing M2-like microglia, along with elevated levels of the anti-inflammatory cytokine, IL-10 were observed in the hippocampus during chronic DSS colitis. These findings uncover key effects of acute and chronic experimental colitis on adult hippocampal neurogenesis and innate immune cell responses, highlighting the potential mechanisms underlying cognitive and mood dysfunction in patients with IBD.

CRH Promotes the Neurogenic Activity of Neural Stem Cells in the Adult Hippocampus.

Local cues in the adult neurogenic niches dynamically regulate homeostasis in neural stem cells, whereas their identity and associated molecular mechanisms remain poorly understood. Here, we show that corticotropin-releasing hormone (CRH), the major mediator of mammalian stress response and a key neuromodulator in the adult brain, is necessary for hippocampal neural stem cell (hiNSC) activity under physiological conditions. In particular, we demonstrate functionality of the CRH/CRH receptor (CRHR) system in mouse hiNSCs and conserved expression in humans. Most important, we show that genetic deficiency of CRH impairs hippocampal neurogenesis, affects spatial memory, and compromises hiNSCs' responsiveness to environmental stimuli. These deficits have been partially restored by virus-mediated CRH expression. Additionally, we provide evidence that local disruption of the CRH/CRHR system reduces neurogenesis, while exposure of adult hiNSCs to CRH promotes neurogenic activity via BMP4 suppression. Our findings suggest a critical role of CRH in adult neurogenesis, independently of its stress-related systemic function.

Mapping metabolic changes by noninvasive, multiparametric, high-resolution imaging using endogenous contrast.

Monitoring subcellular functional and structural changes associated with metabolism is essential for understanding healthy tissue development and the progression of numerous diseases, including cancer, diabetes, and cardiovascular and neurodegenerative disorders. Unfortunately, established methods for this purpose either are destructive or require the use of exogenous agents. Recent work has highlighted the potential of endogenous two-photon excited fluorescence (TPEF) as a method to monitor subtle metabolic changes; however, mechanistic understanding of the connections between the detected optical signal and the underlying metabolic pathways has been lacking. We present a quantitative approach to detecting both functional and structural metabolic biomarkers noninvasively, relying on endogenous TPEF from two coenzymes, NADH (reduced form of nicotinamide adenine dinucleotide) and FAD (flavin adenine dinucleotide). We perform multiparametric analysis of three optical biomarkers within intact, living cells and three-dimensional tissues: cellular redox state, NADH fluorescence lifetime, and mitochondrial clustering. We monitor the biomarkers in cells and tissues subjected to metabolic perturbations that trigger changes in distinct metabolic processes, including glycolysis and glutaminolysis, extrinsic and intrinsic mitochondrial uncoupling, and fatty acid oxidation and synthesis. We demonstrate that these optical biomarkers provide complementary insights into the underlying biological mechanisms. Thus, when used in combination, these biomarkers can serve as a valuable tool for sensitive, label-free identification of changes in specific metabolic pathways and characterization of the heterogeneity of the elicited responses with single-cell resolution.

CD8+ T cells in beige adipogenesis and energy homeostasis.

Although accumulation of lymphocytes in the white adipose tissue (WAT) in obesity is linked to insulin resistance, it remains unclear whether lymphocytes also participate in the regulation of energy homeostasis in the WAT. Here, we demonstrate enhanced energy dissipation in Rag1-/- mice, increased catecholaminergic input to subcutaneous WAT, and significant beige adipogenesis. Adoptive transfer experiments demonstrated that CD8+ T cell deficiency accounts for the enhanced beige adipogenesis in Rag1-/- mice. Consistently, we identified that CD8-/- mice also presented with enhanced beige adipogenesis. The inhibitory effect of CD8+ T cells on beige adipogenesis was reversed by blockade of IFN-γ. All together, our findings identify an effect of CD8+ T cells in regulating energy dissipation in lean WAT, mediated by IFN-γ modulation of the abundance of resident immune cells and of local catecholaminergic activity. Our results provide a plausible explanation for the clinical signs of metabolic dysfunction in diseases characterized by altered CD8+ T cell abundance and suggest targeting of CD8+ T cells as a promising therapeutic approach for obesity and other diseases with altered energy homeostasis.

Strain-specific Differences in the Effects of Lymphocytes on the Development of Insulin Resistance and Obesity in Mice.

Obesity is characterized as a chronic, low-grade inflammatory disease owing to the infiltration of the adipose tissue by macrophages. Although the role of macrophages in this process is well established, the role of lymphocytes in the development of obesity and metabolism remains less well defined. In the current study, we fed WT and Rag1-/- male mice, of C57BL/6J and BALB/c backgrounds, high-fat diet (HFD) or normal diet for 15 wk. Compared with WT mice, Rag1-/- mice of either of the examined strains were found less prone to insulin resistance after HFD, had higher metabolic rates, and used lipids more efficiently, as shown by the increased expression of genes related to fatty acid oxidation in epidydimal white adipose tissue. Furthermore, Rag1-/- mice had increased Ucp1 protein expression and associated phenotypic characteristics indicative of beige adipose tissue in subcutaneous white adipose tissue and increased Ucp1 expression in brown adipose tissue. As with inflammatory and other physiologic responses previously reported, the responses of mice to HFD show strain-specific differences, with increased susceptibility of C57BL/6J as compared with BALB/c strain. Our findings unmask a crucial role for lymphocytes in the development of obesity and insulin resistance, in that lymphocytes inhibit efficient dissipation of energy by adipose tissue. These strain-associated differences highlight important metabolic factors that should be accommodated in disease modeling and drug testing.

A self-sustained loop of inflammation-driven inhibition of beige adipogenesis in obesity.

In obesity, inflammation of white adipose tissue (AT) is associated with diminished generation of beige adipocytes ('beige adipogenesis'), a thermogenic and energy-dissipating function mediated by beige adipocytes that express the uncoupling protein UCP1. Here we delineated an inflammation-driven inhibitory mechanism of beige adipogenesis in obesity that required direct adhesive interactions between macrophages and adipocytes mediated by the integrin α4 and its counter-receptor VCAM-1, respectively; expression of the latter was upregulated in obesity. This adhesive interaction reciprocally and concomitantly modulated inflammatory activation of macrophages and downregulation of UCP1 expression dependent on the kinase Erk in adipocytes. Genetic or pharmacological inactivation of the integrin α4 in mice resulted in elevated expression of UCP1 and beige adipogenesis of subcutaneous AT in obesity. Our findings, established in both mouse systems and human systems, reveal a self-sustained cycle of inflammation-driven impairment of beige adipogenesis in obesity.

Metformin protects against infection-induced myocardial dysfunction.

BACKGROUND AND PURPOSE: Metformin administration is associated with myocardial protection during ischemia and/or reperfusion, possibly via inhibition of inflammatory responses in the heart. Exposure to pathogens, in addition to the activation of the immune system and the associated metabolic dysfunction, often results in compromised myocardial function. We examined whether metformin administration could maintain the normal myocardial function in experimental moderate Gram negative infection, induced by lipopolysaccharide (LPS) administration. EXPERIMENTAL APPROACH: 129xC57BL/6 mice were divided into control groups that received either vehicle or a single intraperitoneal (i.p.) injection of low dose LPS (5mg/kg body wt), and metformin treated groups that received either daily metformin (4mg/kg/animal) i.p. injections for five days prior to LPS administration [Experiment 1], or a single metformin injection following same dose of LPS [Experiment 2]. KEY RESULTS: LPS alone caused cardiac dysfunction, as confirmed by echocardiography, whereas metformin administration, either before or after LPS, rescued myocardial function. LPS caused marked reduction of the cardiac metabolism-related genes tested, including Prkaa2, Cpt1b, Ppargc1a and Ppargc1b; reduction of fatty acid oxidation, as reflected by the regulation of Ppara, Acaca and Acacb; increased glucose transport, as shown by Slc2a4 levels; reduction of ATP synthesis; significant increase of inflammatory markers, in particular IL6; and reduction of autophagy. Pretreatment with metformin normalized the levels of all these factors. CONCLUSIONS AND IMPLICATIONS: We show for the first time that metformin protects the myocardium from LPS-associated myocardial dysfunction mainly by supporting its metabolic activity and allowing efficient energy utilization. Metformin can be a potential cardioprotective agent in individuals susceptible to exposure to pathogens.

Two-photon excited fluorescence of intrinsic fluorophores enables label-free assessment of adipose tissue function.

Current methods for evaluating adipose tissue function are destructive or have low spatial resolution. These limit our ability to assess dynamic changes and heterogeneous responses that occur in healthy or diseased subjects, or during treatment. Here, we demonstrate that intrinsic two-photon excited fluorescence enables functional imaging of adipocyte metabolism with subcellular resolution. Steady-state and time-resolved fluorescence from intracellular metabolic co-factors and lipid droplets can distinguish the functional states of excised white, brown, and cold-induced beige fat. Similar optical changes are identified when white and brown fat are assessed in vivo. Therefore, these studies establish the potential of non-invasive, high resolution, endogenous contrast, two-photon imaging to identify distinct adipose tissue types, monitor their functional state, and characterize heterogeneity of induced responses.

Identification of a novel interaction between corticotropin releasing hormone (Crh) and macroautophagy.

In inflammatory bowel disease (IBD), compromised restitution of the epithelial barrier contributes to disease severity. Owing to the complexity in the pathogenesis of IBD, a variety of factors have been implicated in its progress. In this study, we report a functional interaction between macroautophagy and Corticotropin Releasing Hormone (Crh) in the gut. For this purpose we used DSS colitis model on Crh -/- or wild-type (wt) with pharmacological inhibition of autophagy. We uncovered sustained basal autophagy in the gut of Crh -/- mice, which persisted over the course of DSS administration. Autophagy inhibition resulted in partial rescue of Crh -/- mice, while it increased the expression of Crh in the wt gut. Similarly, Crh deficiency was associated with sustained activation of base line autophagy. In vitro models of amino acid deprivation- and LPS-induced autophagy confirmed the in vivo findings. Our results indicate a novel role for Crh in the intestinal epithelium that involves regulation of autophagy, while suggesting the complementary action of the two pathways. These data suggest the intriguing possibility that targeting Crh stimulation in the intestine may provide a novel therapeutic approach to support the integrity of the epithelial barrier and to protect from chronic colitis.

Neural stem cells respond to stress hormones: distinguishing beneficial from detrimental stress.

Neural stem cells (NSCs), the progenitors of the nervous system, control distinct, position-specific functions and are critically involved in the maintenance of homeostasis in the brain. The responses of these cells to various stressful stimuli are shaped by genetic, epigenetic, and environmental factors via mechanisms that are age and developmental stage-dependent and still remain, to a great extent, elusive. Increasing evidence advocates for the beneficial impact of the stress response in various settings, complementing the extensive number of studies on the detrimental effects of stress, particularly in the developing brain. In this review, we discuss suggested mechanisms mediating both the beneficial and detrimental effects of stressors on NSC activity across the lifespan. We focus on the specific effects of secreted factors and we propose NSCs as a "sensor," capable of distinguishing among the different stressors and adapting its functions accordingly. All the above suggest the intriguing hypothesis that NSCs are an important part of the adaptive response to stressors via direct and indirect, specific mechanisms.

Dual role of B7 costimulation in obesity-related nonalcoholic steatohepatitis and metabolic dysregulation.

UNLABELLED: The low-grade inflammatory state present in obesity contributes to obesity-related metabolic dysregulation, including nonalcoholic steatohepatitis (NASH) and insulin resistance. Intercellular interactions between immune cells or between immune cells and hepatic parenchymal cells contribute to the exacerbation of liver inflammation and steatosis in obesity. The costimulatory molecules, B7.1 and B7.2, are important regulators of cell-cell interactions in several immune processes; however, the role of B7 costimulation in obesity-related liver inflammation is unknown. Here, diet-induced obesity (DIO) studies in mice with genetic inactivation of both B7.1 and B7.2 (double knockout; DKO) revealed aggravated obesity-related metabolic dysregulation, reduced insulin signalling in the liver and adipose tissue (AT), glucose intolerance, and enhanced progression to steatohepatitis resulting from B7.1/B7.2 double deficiency. The metabolic phenotype of B7.1/B7.2 double deficiency upon DIO was accompanied by increased hepatic and AT inflammation, associated with largely reduced numbers of regulatory T cells (Tregs) in these organs. In order to assess the role of B7 costimulation in DIO in a non-Treg-lacking environment, we performed antibody (Ab)-mediated inhibition of B7 molecules in wild-type mice in DIO. Antibody-blockade of both B7.1 and B7.2 improved the metabolic phenotype of DIO mice, which was linked to amelioration of hepatic steatosis and reduced inflammation in liver and AT. CONCLUSION: Our study demonstrates a dual role of B7 costimulation in the course of obesity-related sequelae, particularly NASH. The genetic inactivation of B7.1/B7.2 deteriorates obesity-related liver steatosis and metabolic dysregulation, likely a result of the intrinsic absence of Tregs in these mice, rendering DKO mice a novel murine model of NASH. In contrast, inhibition of B7 costimulation under conditions where Tregs are present may provide a novel therapeutic approach for obesity-related metabolic dysregulation and, especially, NASH.

The complement anaphylatoxin C5a receptor contributes to obese adipose tissue inflammation and insulin resistance.

Obese adipose tissue (AT) inflammation contributes critically to development of insulin resistance. The complement anaphylatoxin C5a receptor (C5aR) has been implicated in inflammatory processes and as regulator of macrophage activation and polarization. However, the role of C5aR in obesity and AT inflammation has not been addressed. We engaged the model of diet-induced obesity and found that expression of C5aR was significantly upregulated in the obese AT, compared with lean AT. In addition, C5a was present in obese AT in the proximity of macrophage-rich crownlike structures. C5aR-sufficient and -deficient mice were fed a high-fat diet (HFD) or a normal diet (ND). C5aR deficiency was associated with increased AT weight upon ND feeding in males, but not in females, and with increased adipocyte size upon ND and HFD conditions in males. However, obese C5aR(-/-) mice displayed improved systemic and AT insulin sensitivity. Improved AT insulin sensitivity in C5aR(-/-) mice was associated with reduced accumulation of total and proinflammatory M1 macrophages in the obese AT, increased expression of IL-10, and decreased AT fibrosis. In contrast, no difference in ß cell mass was observed owing to C5aR deficiency under an HFD. These results suggest that C5aR contributes to macrophage accumulation and M1 polarization in the obese AT and thereby to AT dysfunction and development of AT insulin resistance.

cGMP-dependent protein kinase contributes to hydrogen sulfide-stimulated vasorelaxation.

A growing body of evidence suggests that hydrogen sulfide (H2S) is a signaling molecule in mammalian cells. In the cardiovascular system, H2S enhances vasodilation and angiogenesis. H2S-induced vasodilation is hypothesized to occur through ATP-sensitive potassium channels (K(ATP)); however, we recently demonstrated that it also increases cGMP levels in tissues. Herein, we studied the involvement of cGMP-dependent protein kinase-I in H2S-induced vasorelaxation. The effect of H2S on vessel tone was studied in phenylephrine-contracted aortic rings with or without endothelium. cGMP levels were determined in cultured cells or isolated vessel by enzyme immunoassay. Pretreatment of aortic rings with sildenafil attenuated NaHS-induced relaxation, confirming previous findings that H2S is a phosphodiesterase inhibitor. In addition, vascular tissue levels of cGMP in cystathionine gamma lyase knockouts were lower than those in wild-type control mice. Treatment of aortic rings with NaHS, a fast releasing H2S donor, enhanced phosphorylation of vasodilator-stimulated phosphoprotein in a time-dependent manner, suggesting that cGMP-dependent protein kinase (PKG) is activated after exposure to H2S. Incubation of aortic rings with a PKG-I inhibitor (DT-2) attenuated NaHS-stimulated relaxation. Interestingly, vasodilatory responses to a slowly releasing H2S donor (GYY 4137) were unaffected by DT-2, suggesting that this donor dilates mouse aorta through PKG-independent pathways. Dilatory responses to NaHS and L-cysteine (a substrate for H2S production) were reduced in vessels of PKG-I knockout mice (PKG-I⁻/⁻). Moreover, glibenclamide inhibited NaHS-induced vasorelaxation in vessels from wild-type animals, but not PKG-I⁻/⁻, suggesting that there is a cross-talk between K(ATP) and PKG. Our results confirm the role of cGMP in the vascular responses to NaHS and demonstrate that genetic deletion of PKG-I attenuates NaHS and L-cysteine-stimulated vasodilation.

Modulation of pancreatic islets-stress axis by hypothalamic releasing hormones and 11beta-hydroxysteroid dehydrogenase.

Corticotropin-releasing hormone (CRH) and growth hormone-releasing hormone (GHRH), primarily characterized as neuroregulators of the hypothalamic-pituitary-adrenal axis, directly influence tissue-specific receptor-systems for CRH and GHRH in the endocrine pancreas. Here, we demonstrate the expression of mRNA for CRH and CRH-receptor type 1 (CRHR1) and of protein for CRHR1 in rat and human pancreatic islets and rat insulinoma cells. Activation of CRHR1 and GHRH-receptor significantly increased cell proliferation and reduced cell apoptosis. CRH stimulated both cellular content and release of insulin in rat islet and insulinoma cells. At the ultrastructural level, CRHR1 stimulation revealed a more active metabolic state with enlarged mitochondria. Moreover, glucocorticoids that promote glucose production are balanced by both 11b-hydroxysteroid dehydrogenase (11ß-HSD) isoforms; 11ß-HSD-type-1 and 11ß-HSD-type-2. We demonstrated expression of mRNA for 11ß-HSD-1 and 11ß-HSD-2 and protein for 11ß-HSD-1 in rat and human pancreatic islets and insulinoma cells. Quantitative real-time PCR revealed that stimulation of CRHR1 and GHRH-receptor affects the metabolism of insulinoma cells by down-regulating 11ß-HSD-1 and up-regulating 11ß-HSD-2. The 11ß-HSD enzyme activity was analyzed by measuring the production of cortisol from cortisone. Similarly, activation of CRHR1 resulted in reduced cortisol levels, indicating either decreased 11ß-HSD-1 enzyme activity or increased 11ß-HSD-2 enzyme activity; thus, activation of CRHR1 alters the glucocorticoid balance toward the inactive form. These data indicate that functional receptor systems for hypothalamic-releasing hormone agonists exist within the endocrine pancreas and influence synthesis of insulin and the pancreatic glucocorticoid shuttle. Agonists of CRHR1 and GHRH-receptor, therefore, may play an important role as novel therapeutic tools in the treatment of diabetes mellitus.

A novel role of peripheral corticotropin-releasing hormone (CRH) on dermal fibroblasts.

Corticotropin-releasing hormone, or factor, (CRH or CRF) exerts important biological effects in multiple peripheral tissues via paracrine/autocrine actions. The aim of our study was to assess the effects of endogenous CRH in the biology of mouse and human skin fibroblasts, the primary cell type involved in wound healing. We show expression of CRH and its receptors in primary fibroblasts, and we demonstrate the functionality of fibroblast CRH receptors by induction of cAMP. Fibroblasts genetically deficient in Crh (Crh-/-) had higher proliferation and migration rates and compromised production of IL-6 and TGF-ß1 compared to the wildtype (Crh+/+) cells. Human primary cultures of foreskin fibroblasts exposed to the CRF(1) antagonist antalarmin recapitulated the findings in the Crh-/- cells, exhibiting altered proliferative and migratory behavior and suppressed production of IL-6. In conclusion, our findings show an important role of fibroblast-expressed CRH in the proliferation, migration, and cytokine production of these cells, processes associated with the skin response to injury. Our data suggest that the immunomodulatory effects of CRH may include an important, albeit not explored yet, role in epidermal tissue remodeling and regeneration and maintenance of tissue homeostasis.

Corticotropin-releasing factor regulates TLR4 expression in the colon and protects mice from colitis.

BACKGROUND & AIMS: Defects in the colonic innate immune response have been associated with inflammatory bowel disease (IBD). Corticotropin-releasing hormone (CRH, or corticotropin-releasing factor [CRF]) is a neuropeptide that mediates the stress response in humans, is an immunomodulatory factor with proinflammatory effects, and regulates transcription of Toll-like receptors (TLR)-2 and TLR4. We investigated the role of CRF in an innate immunity-dependent mouse model of IBD. METHODS: Crh(-/-) and wild-type (Crh(+/+)) mice, which are glucocorticoid insufficient, were given dextran sodium sulfate in their drinking water to induce colitis; in some experiments, mice were also given glucocorticoids. Phenotypes of mice were compared; tissues were analyzed by histology and for expression of immune mediators. RESULTS: Crh(-/-) mice had more colonic inflammation than Crh(+/+) mice, characterized by reduced numbers of crypts and severe epithelial damage and ulcerations. Colonic tissue levels of the proinflammatory factors interleukin-12 and prostaglandin E(2) were increased in the Crh(-/-) mice. Colons of Crh(-/-) mice expressed lower levels of Tlr4 than wild-type mice before, but not after, colitis was induced. Administration of glucocorticoid at low levels did not prevent Crh(-/-) mice from developing severe colitis. Crh(-/-) mice were unable to recover from acute colitis, as indicated by their increased death rate. CONCLUSIONS: Mice deficient in CRF down-regulate TLR4 and are more susceptible to dextran sodium sulfate-induced colitis. CRF has anti-inflammatory effects in innate immunity-dependent colitis and its recovery phase; these are independent of glucocorticoid administration. CRF might therefore be developed as a therapeutic target for patients with IBD.

TNF-alpha and obesity.

Obesity, an epidemic of our times with rates rising to alarming levels, is associated with comorbidities including cardiovascular diseases, arthritis, certain cancers, and degenerative diseases of the brain and other organs. Importantly, obesity is a leading cause of insulin resistance and type 2 diabetes. As emerging evidence has shown over the last decade, inflammation is one of the critical processes associated with the development of insulin resistance, diabetes and related diseases, and obesity is now considered as a state of chronic low-grade inflammation. Adipose tissue, apart from its classical role as an energy storage depot, is also a major endocrine organ secreting many factors, whose local and circulating levels are affected by the degree of adiposity. Obesity leads to infiltration of the expanded adipose tissue by macrophages and increased levels in proinflammatory cytokines. The first indication for increased cytokine release in obesity was provided by the identification of increased expression of TNF-alpha, a proinflammatory cytokine, in the adipose tissue of obese mice in the early 1990s. TNF-alpha is expressed in and secreted by adipose tissue, its levels correlating with the degree of adiposity and the associated insulin resistance. Targeting TNF-alpha and/or its receptors has been suggested as a promising treatment for insulin resistance and type 2 diabetes. This review will summarize the available knowledge on the role of TNF-alpha in obesity and related processes and the potential implications of the above in the development of new therapeutic approaches for obesity and insulin resistance. Recent data from clinical studies will also be described together with late findings on the pathogenesis of obesity and insulin resistance.

Mechanisms of obesity and related pathology: linking immune responses to metabolic stress.

There is a tightly regulated interaction, which is well-conserved in evolution, between the metabolic and immune systems that is deranged in states of over- or under-nutrition. Obesity, an energy-rich condition, is characterized by the activation of an inflammatory process in metabolically active sites such as adipose tissue, liver and immune cells. The consequence of this response is a sharp increase in circulating levels of proinflammatory cytokines, adipokines and other inflammatory markers. Activation of the immune response in obesity is mediated by specific signaling pathways, with Jun N-terminal kinase and IkappaB kinase beta/nuclear factor kappa-light-chain-enhancer of activated B cells being the most well studied. It is known that the above events modify insulin signaling and result in the development of insulin resistance. The nutrient overload characterizing obesity is a metabolic stressor associated with intracellular organelle (e.g. the endoplasmic reticulum) stress. The exact characterization of the series of events and the mechanisms that integrate the inflammatory response with metabolic homeostasis at the cellular and systemic level is a very active research field. In this minireview, we discuss the signaling pathways and molecules associated with the development of obesity-induced inflammation, as well as the evidence that supports a critical role for the stress response in this process.

Activation of phosphatidylinositol 3-kinase/protein kinase B by corticotropin-releasing factor in human monocytes.

Corticotropin-releasing factor (CRF) exerts proinflammatory effects in peripheral tissues, whereas the intracellular pathways mediating these effects have not been completely characterized yet. We have previously shown that CRF induces nuclear factor-kappaB DNA-binding activity in mouse and human leukocytes. Here we demonstrate that in the human monocytic THP-1 cells, CRF activates the phosphatidylinositol 3-kinase (PI3K)/Akt and ERK1/2 pathways. These effects of CRF are mediated by corticotropin-releasing factor receptor 2 (CRF2), as suggested by their abolishment after treatment with the specific CRF2 antagonist, astressin 2B. The CRF-mediated PI3K/Akt activation induces cell survival as suggested by the stimulation of the antiapoptotic factor Bcl-2. ERK1/2 activation results in up-regulation of IL-8 expression, an effect inhibited by the CRF-induced activation of PI3K/Akt. These studies demonstrate novel effects of CRF in human monocytes mediated by the activation of PI3K/Akt. Moreover, they reveal pathway-specific effects of the CRF/CRF2 system in chemokine activation and cell survival that may be of importance for the development of novel therapeutics for inflammatory diseases.