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Background: Inflammation is the most relevant mechanism linking obesity with insulin-resistance and metabolic disease. It impacts the structure and function of tissues and organs involved in metabolism, such as the liver, pancreatic islets and the hypothalamus. Brown adipose tissue has emerged as an important component of whole body energy homeostasis, controlling caloric expenditure through the regulation of non-shivering thermogenesis. However, little is known about the impact of systemic inflammation on the structure and function of brown adipose tissue., Methods: The relations between IL10 and mitochondria structure/function and also with thermogenesis were evaluated by bioinformatics using human and rodent data. Real-time PCR, immunoblot, fluorescence and transmission electron microscopy were employed to determine the effect of IL10 in the brown adipose tissue of wild type and IL10 knockout mice., Findings: IL10 knockout mice, a model of systemic inflammation, present severe structural abnormalities of brown adipose tissue mitochondria, which are round-shaped with loss of cristae structure and increased fragmentation. IL10 deficiency leads to newborn cold intolerance and impaired UCP1-dependent brown adipose tissue mitochondrial respiration. The reduction of systemic inflammation with an anti-TNFα monoclonal antibody partially rescued the structural but not the functional abnormalities of brown adipose tissue mitochondria. Using bioinformatics analyses we show that in both humans and mice, IL10 transcripts correlate with mitochondrial lipid metabolism and caspase gene expression., Interpretation: IL10 and systemic inflammation play a central role in the regulation of brown adipose tissue by controlling mitochondrial structure and function. FUND: Sao Paulo Research Foundation grant 2013/07607-8., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The consumption of large amounts of dietary fats induces hypothalamic inflammation and impairs the function of the melanocortin system, leading to a defective regulation of caloric intake and whole-body energy expenditure. In mice fed a high-fat diet (HFD), TGF-β1 expression was increased and NF-κB signaling was activated in proopiomelanocortin neurons, which plays an important role in the obesity-associated hypothalamic inflammation scenario. However, whether excessive hypothalamic TGF-β1 impairs energy homeostasis remains unclear., Objectives: We aimed to investigate the role of diet-induced hypothalamic TGF-β1 on inflammation and whole-body energy homeostasis., Methods: A TGF-β1 inhibitory lentiviral shRNA particle was stereotaxically injected bilaterally in the arcuate nucleus (ARC) of C57BL/6 mice fed a HFD. We assessed changes in body mass and adiposity, food intake, inflammatory markers, and the function of energy and glucose metabolism., Results: TGF-β1 down-regulation in the ARC-attenuated body-mass gain, reduced fat-mass accumulation, decreased hypothalamic inflammatory markers, and protected against HFD-induced lipohypertrophy of brown adipose tissue. In addition, the inhibition of hypothalamic TGF-β1 increased the locomotor activity and improved whole-body lipid metabolism, which attenuated hepatic fat accumulation and serum triglyceride levels. No changes were observed in food intake and glucose homeostasis., Conclusion: Hypothalamic TGF-β1 down-regulation attenuates hypothalamic inflammation and improves energy metabolism, resulting in lower body-mass gain and lower fat-mass accumulation, which protects mice from the development of obesity. Our data suggest that modulation of hypothalamic TGF-β1 expression might be an effective strategy to treat obesity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the effects of intensity of exercise on insulin resistance and the expression of inflammatory proteins in the skeletal muscle of diet-induced obese (DIO) rats after a single bout of exercise., Methods: In the first exercise protocol, the rats swam for two 3-h bouts, separated by a 45-min rest period (with 6 h in duration--O + EXE), and in the second protocol, the rats were exercised with 45 min of swimming at 70% of the maximal lactate steady state--SS (DIO + MLSS)., Results: Our data demonstrated that both protocols of exercise increased insulin sensitivity and increased insulin-stimulated tyrosine phosphorylation of insulin receptor and insulin receptor substrate 1 and serine phosphorylation of protein kinase B in the muscle of DIO rats by the same magnitude. In parallel, both exercise protocols also reduced protein tyrosine phosphatase 1B activity and insulin receptor substrate 1 serine phosphorylation, with concomitant reduction in c-jun N-terminal kinase and IJB kinase activities in the muscle of DIO rats in a similar fashion., Conclusions: Thus, our data demonstrate that either exercise protocols with low intensity and high volume or exercise with moderate intensity and low volume represents different strategies to restore insulin sensitivity with the same efficacy.

Obesity is one of the most prevalent diseases in the modern world. It results from the progressive loss of balance between food intake and whole body energy expenditure. Recent studies have shown that consumption of fat-rich diets induces hypothalamic inflammation and dysfunction which is characterized by defective response to anorexygenic and thermogenic hormones, such as leptin and insulin, leading to anomalous neurotransmitter production and favoring body mass gain. In this chapter, we present the main recent advances in this rapidly evolving field, focusing on the role of hypothalamic inflammation on the genesis of obesity., (Copyright 2010 Elsevier Inc. All rights reserved.)

Infiltrating macrophages play an important role in the production of inflammatory mediators by the adipose tissue of obese subjects. To reach the adipose tissue, peripheral monocytes are recruited by locally produced chemoattractants. However, little is known about the activation of monocytes in the peripheral blood of obese subjects. The objective of this study was to determine reactive oxygen species and endoplasmic reticulum stress as early markers of monocytic commitment with an inflammatory phenotype in the peripheral blood of nondiabetic obese patients. Patients were recruited from an academic general hospital; controls were voluntary students. Seven lean controls and 6 nondiabetic obese patients were included in the study. Monocytes were prepared from peripheral blood. Immunoblot, flow cytometry, and polymerase chain reaction were used to determine reactive oxygen species and endoplasmic reticulum stress. Increased reactive oxygen species and activation of endoplasmic reticulum stress were detected in the monocytes from obese patients. Reducing endoplasmic reticulum stress with a chemical chaperone reversed monocytic activation, as determined by the reduction of reactive oxygen species production. Thus, monocytes from nondiabetic obese patients are already committed with an inflammatory phenotype in peripheral blood; and reducing endoplasmic reticulum stress negatively modulates their activation.

Obesity has reached epidemic proportions in several regions of the world. General changes in lifestyle, including consumption of fat-rich food, are among the most important factors leading to an unprecedented increase in the prevalence of this disease. Weight gain results from an imbalance between caloric intake and energy expenditure. Both of these parameters are under the tight control of specialized neurons of the hypothalamus that respond to peripheral anorexigenic and adipostatic signals carried by leptin and insulin. Here we show, by macroarray analysis, that high-fat feeding [hyperlipidic diet (HL)] induces the expression of several proinflammatory cytokines and inflammatory responsive proteins in hypothalamus. This phenomenon is accompanied by increased activation of c-Jun N-terminal kinase and nuclear factor-kappaB. In addition, HL feeding leads to impaired functional and molecular activation of the insulin-signaling pathway, which is paralleled by increased serine phosphorylation of the insulin receptor and insulin receptor substrate-2. Intracerebroventricular treatment of HL rats with a specific inhibitor of c-Jun N-terminal kinase (SP600125) restores insulin signaling and leads to a reduced caloric intake and weight loss. We conclude that HL feeding induces a local proinflammatory status in the hypothalamus, which results in impaired anorexigenic insulin signaling.

Chronic/abnormal activation of endoplasmic reticulum (ER) stress is linked to the exacerbation of the inflammatory process and has been recently linked to Crohn’s disease (CD) pathophysiology. We investigated the intestinal mucosa and the mesenteric adipose tissue (MAT) collected from CD patients with active disease (CD group) and from non-IBD patients (CTR group) to study ER stress activation and to address tissue-specific modulation in CD. The intestinal mucosa of CD patients showed an upregulation in the expression of ER stress related genes, including ATF3, DNAJC3, STC2, DDIT3, CALR, HSPA5 and HSP90B1. Results showed that EIF2AK3 gene was upregulated, along with increased protein expression of p-eIF2α and p-eIF2α/eIF2α ratio. Additionally, ERN1 gene expression was upregulated, along with an increased spliced/activated form sXBP1 protein. Despite the upregulation of ATF6 gene expression in the intestinal mucosa of CD patients, no differences were found in ATF6 protein expression. Lastly, the analysis of MAT revealed unchanged levels of ER stress markers along with no differences in the activation of UPR. However, chaperone gene expression was modulated in the MAT of CD patients. To conclude, our results address tissue-specific differences in UPR activation in CD and point the ER stress as an important pro-inflammatory mechanism in CD, specifically in the intestinal mucosa. [ABSTRACT FROM AUTHOR]

Interleukin-6 (IL-6) is a unique cytokine that can play both pro- and anti-inflammatory roles depending on the anatomical site and conditions under which it has been induced. Specific neurons of the hypothalamus provide important signals to control food intake and energy expenditure. In individuals with obesity, a microglia-dependent inflammatory response damages the neural circuits responsible for maintaining whole-body energy homeostasis, resulting in a positive energy balance. However, little is known about the role of IL-6 in the regulation of hypothalamic microglia. In this systematic review, we asked what types of conditions and stimuli could modulate microglial IL-6 expression in murine model. We searched the PubMed and Web of Science databases and analyzed 13 articles that evaluated diverse contexts and study models focused on IL-6 expression and microglia activation, including the effects of stress, hypoxia, infection, neonatal overfeeding and nicotine exposure, lipopolysaccharide stimulus, hormones, exercise protocols, and aging. The results presented in this review emphasized the role of "injury-like" stimuli, under which IL-6 acts as a proinflammatory cytokine, concomitant with marked microglial activation, which drive hypothalamic neuroinflammation. Emerging evidence indicates an important correlation of basal IL-6 levels and microglial function with the maintenance of hypothalamic homeostasis. Advances in our understanding of these different contexts will lead to the development of more specific pharmacological approaches for the management of acute and chronic conditions, like obesity and metabolic diseases, without disturbing the homeostatic functions of IL-6 and microglia in the hypothalamus. [ABSTRACT FROM AUTHOR]

Emerging data demonstrate that microglia activation plays a pivotal role in the development of hypothalamic inflammation in obesity. Early after the introduction of a high-fat diet, hypothalamic microglia undergo morphological, and functional changes in response to excessive dietary saturated fats. Initially the resident microglia are affected; however, as diet-induced obesity persists, bone marrow-derived myeloid cells gradually replace resident microglia. Genetic and pharmacological approaches aimed at dampening the inflammatory activity in the hypothalamus of experimental models of obesity have proven beneficial to correct the obese phenotype and improve metabolic abnormalities commonly associated with obesity. These approaches provide an experimental proof-of-concept that hypothalamic inflammation is central to the pathophysiology of obesity; understanding the details of the roles played by microglia in this process may help the development of preventive and therapeutic advances in the field. In this review, we discuss the potential mechanisms underlying hypothalamic microglial activation in high-fat induced obesity. [ABSTRACT FROM AUTHOR]

In animal models of diet-induced obesity, the activation of an inflammatory response in the hypothalamus produces molecular and functional resistance to the anorexigenic hormones insulin and leptin. The primary events triggered by dietary fats that ultimately lead to hypothalamic cytokine expression and inflammatory signaling are unknown. Here, we test the hypothesis that dietary fats act through the activation of toll-like receptors 2/4 and endoplasmic reticulum stress to induce cytokine expression in the hypothalamus of rodents. According to our results, long-chain saturated fatty acids activate predominantly toll-like receptor 4 signaling, which determines not only the induction of local cytokine expression but also promotes endoplasmic reticulum stress. Rats fed on a monounsaturated fat-rich diet do not develop hypothalamic leptin resistance, whereas toll-like receptor 4 loss-of-function mutation and immunopharmacological inhibition of toll-like receptor 4 protects mice from diet-induced obesity. Thus, toll-like receptor 4 acts as a predominant molecular target for saturated fatty acids in the hypothalamus, triggering the intracellular signaling network that induces an inflammatory response, and determines the resistance to anorexigenic signals. [ABSTRACT FROM AUTHOR]

Abstract: Uncoupling protein 2 (UCP2) is highly expressed in the hypothalamus; however, little is known about the functions it exerts in this part of the brain. Here, we hypothesized that UCP2 protects hypothalamic cells from oxidative and pro-apoptotic damage generated by inflammatory stimuli. Intracerebroventricular injection of tumor necrosis factor alpha (TNF-α)-induced an increase of UCP2 expression in the hypothalamus, which was accompanied by increased expression of markers of oxidative stress and pro-apoptotic proteins. The inhibition of UCP2 expression by an antisense oligonucleotide enhanced the damaging effects of TNF-α. Conversely, increasing the hypothalamic expression of UCP2 by cold exposure reversed most of the effects of the cytokine. Thus, UCP2 acts as a protective factor against cellular damage induced by an inflammatory stimulus in the hypothalamus. [Copyright &y& Elsevier]

Most phenolic compounds and dietary fiber reach intact to the colon. We hypothesized that grape peel powder (GPP), a rich source of these bioactive compounds, modulates inflammatory and oxidative pathways collaborating to attenuate colonic damage in experimental colitis. To determine which bioactive fraction would be responsible for this effect, the aim of this study was to evaluate the effect of dietary supplementation with whole GPP or the isolated bioactive-rich fractions from GPP (extractable polyphenols [EP], dietary fiber and fiber-bound polyphenols [NEP-F], and dietary fiber) in rats with experimental colitis. Colitis was induced by intrarectal injection of 2,4,6-trinitrobenzene sulfonic acid (TNBS) after 15 days of dietary supplementation. EP diet did not reverse the decrease in feed intake and indeed worsened colon shortening and increased spleen weight; however, these effects were not observed for the GPP group, which had polyphenols associated to the matrix besides the extractable ones. Colitis impaired the activity of colonic antioxidant enzymes and increased lipid peroxidation, protein oxidation, nitric oxide (NO) levels, and proinflammatory cytokines in serum and in the colon tissue. GPP restored the activity of antioxidant enzymes and decreased colon oxidation and NO levels. All grape peel fractions reduced the protein expression of the inhibitor of kappa kinase beta and NO levels in colon tissue, but only NEP-F reduced the expression of phosphorylated nuclear factor kappa B and myeloperoxidase activity. Results demonstrated that GPP attenuates inflammatory and oxidative response in TNBS–induced colitis by downregulating the nuclear factor kappa B pathway and upregulating antioxidant enzymes, with NEP-F being the fraction most likely associated to these protective effects. [ABSTRACT FROM AUTHOR]

Inflammatory bowel diseases are characterized by impaired intestinal barrier function. This study aimed to evaluate the effects of grape peel powder (GPP) and its bioactive rich-fractions on the barrier function and colonic injury in a model of colitis induced by 2,4,6 trinitrobenzene sulfonic acid (TNBS). Wistar rats received diets supplemented with either GPP (8%), extractable polyphenols (EP), non-extractable polyphenols-rich fraction (NEP-F), or polyphenols-poor, fiber-rich fraction (F) from grapes at amounts equivalent to the GPP group during 15 days before and for 7 days after colitis induction. NEP-F has decreased the extension of colonic lesion but the other grape peel bioactive fractions did not protect against macroscopic or microscopic colonic damage, EP diet increased macroscopic colonic damage. GPP, EP, and NEP-F reduced claudin-2 mRNA expression, whereas GPP and F fraction increased occludin and ZO-1 mRNA expression. All experimental diets reduced the colitis-triggered increase of MMP-9 mRNA expression. Colitis reduced by 30% the production of cecal short-chain fatty acids (SCFA). GPP and NEP-F completely protected against this effect, whereas F fraction was ineffective. Only GPP and NEP-F were able to decrease the upregulation of GRP94 mRNA triggered by colitis. Dietary fiber seems to reestablish the intestinal barrier function, whereas fiber-bound phenolics were able to restore cecal metabolism to produce beneficial metabolites like SCFA and to reduce the activation of the unfolded protein response. Unlabelled Image • Extractable polyphenols (EP) from grape peel worsened TNBS-induced colonic damage. • Fraction rich in non-extractable polyphenols and fiber (NEP-F) had protective effects. • NEP-F was as effective as mesalamine to decrease the area of colonic lesion. • Fiber-rich fraction (F) of grape peel improved the colonic barrier permeability. • NEP-F but not F fraction enhanced the cecal production of short chain fatty acids. [ABSTRACT FROM AUTHOR]

Highlights • HDF increased HIF-1 protein in hypothalamus through increasing its stabilization. • ARC HIF-1 downregulation potentiates an obese phenotype. • ARC HIF-1 downregulation induces hypothalamic inflammation and gliosis. • Obesity-associated metabolic diseases may be potentiated with ARC HIF-1 downregulation. Abstract Hypothalamic hypoxia-inducible factor-1 (HIF-1) can regulate whole-body energy homeostasis in response to changes in blood glucose, suggesting that it acts as a sensor for systemic energy stores. Here, we hypothesized that hypothalamic HIF-1 could be affected by diet-induced obesity (DIO). We used eight-week old, male C57Bl6 mice, fed normal chow diet or with high fat diet for 1, 3, 7, 14 and 28 days. The expression of HIF-1alpha and HIF-1beta was measured by PCR and western blotting and its hypothalamic distribution was evaluated by fluorescence microscopy. Inhibition of HIF-1beta in arcuate nucleus of hypothalamus was performed using stereotaxic injection of shRNA lentiviral particles and animals were grouped under normal chow diet or high fat diet for 14 days. Using bioinformatics, we show that in humans, the levels of HIF-1 transcripts are directly correlated with those of hypothalamic transcripts for proteins involved in inflammation, regulation of apoptosis, autophagy, and the ubiquitin/proteasome system; furthermore, in rodents, hypothalamic HIF-1 expression is directly correlated with the phenotype of increased energy expenditure. In mice, DIO was accompanied by increased HIF-1 expression. The inhibition of hypothalamic HIF-1 by injection of an shRNA resulted in a further increase in body mass, a decreased basal metabolic rate, increased hypothalamic inflammation, and glucose intolerance. Thus, hypothalamic HIF-1 is increased during DIO, and its inhibition worsens the obesity-associated metabolic phenotype. Thus, hypothalamic HIF-1 emerges as a target for therapeutic intervention against obesity. [ABSTRACT FROM AUTHOR]

To investigate the effect of voluntary physical activity (VPA) on inflammatory profile and the progression of experimental periodontal disease (PD) in mice. Male C57BL/6 mice were randomly distributed into Control; VPA; PD and PD/VPA groups. We registered VPA (total volume of revolutions) and average speed (revolutions/minute) in a free running wheel for 30 days. On the 15th day, animals from the PD and PD/VPA groups received ligatures on the upper second molars bilaterally. On the 30th day animals were euthanized, and PD progression was assessed by measuring alveolar bone loss (ABL - the linear distance between the cemento-enamel junction and the alveolar bone crest on the teeth buccal surface). Gene expression of RANKL (kappa nuclear factor B receptor) OPG (osteoprotegerin), IL-1β (interleukin 1 beta), IL-6 (interleukin 6) and TNF-α (tumor necrosis factor alpha) were evaluated by real-time PCR (quantitative Polymerase Chain Reaction - relative gene expression). The total volume of physical activity and the activity speed decreased along the seven days after ligature-placement (p < 0.05), returning to a similar pattern in relation to VPA group. Ligature placement produced significant bone resorption, and increased RANKL, IL-1β, IL-6 and TNF-α expression. VPA reduced ABL (p < 0,05) and the expression of TNF-α and IL-1β, whereas increased OPG expression. Animals induced to PD with access to the VPA wheel presented both lower gingival inflammation and less alveolar bone resorption in comparison to animals without access to the wheel. [ABSTRACT FROM AUTHOR]

Abstract: Acting in the hypothalamus, tumor necrosis factor-α (TNF-α) produces a potent anorexigenic effect. However, the molecular mechanisms involved in this phenomenon are poorly characterized. In this study, we investigate the capacity of TNF-α to activate signal transduction in the hypothalamus through elements of the pathways employed by the anorexigenic hormones insulin and leptin. High dose TNF-α promotes a reduction of 25% in 12h food intake, which is an inhibitory effect that is marginally inferior to that produced by insulin and leptin. In addition, high dose TNF-α increases body temperature and respiratory quotient, effects not reproduced by insulin or leptin. TNF-α, predominantly at the high dose, is also capable of activating canonical pro-inflammatory signal transduction in the hypothalamus, inducing JNK, p38, and NFκB, which results in the transcription of early responsive genes and expression of proteins of the SOCS family. Also, TNF-α activates signal transduction through JAK-2 and STAT-3, but does not activate signal transduction through early and intermediary elements of the insulin/leptin signaling pathways such as IRS-2, Akt, ERK and FOXO1. When co-injected with insulin or leptin, TNF-α, at both high and low doses, partially impairs signal transduction through IRS-2, Akt, ERK and FOXO1 but not through JAK-2 and STAT-3. This effect is accompanied by the partial inhibition of the anorexigenic effects of insulin and leptin, when the low, but not the high dose of TNF-α is employed. In conclusion, TNF-α, on a dose-dependent way, modulates insulin and leptin signaling and action in the hypothalamus. [Copyright &y& Elsevier]

Abstract: Fatty-acid-induced endoplasmic reticulum stress has been recently described as a novel mechanism involved in the genesis of atherosclerosis. Here we show that statins, a class of drug widely employed in the clinical management of hypercholesterolemia, reduces lipid-induced macrophage endoplasmic reticulum stress in an isolated cell system and in LDL receptor knockout mice. Given the importance of endoplasmic reticulum stress as an inducer of inflammation, we suspect that the novel mechanism of action herein described for statins may play a major role on its beneficial effects in the prevention of cardiovascular disease. [ABSTRACT FROM AUTHOR]