Exercise training induces alteration of clock genes and myokines expression in tumor-bearing mice.

To investigate the impact of different exercise training schedules (following a fixed schedule or at random times of the day) on clock genes and myokine expression patterns in the skeletal muscle of tumor-bearing mice. Mice were divided into three groups: tumor (LLC), tumor + exercise training (LLC + T) always performed at the same time of the day (ZT2) and exercise training at random times of the day (ZTAlt). Mice were inoculated subcutaneously with Lewis lung carcinoma cells. The gastrocnemius muscle was dissected and the clock gene expression (Clock/Per1/Per2/Per3/Rev-Erbα/GAPDH) was investigated by quantitative reverse transcription polymerase chain reaction with SYBR® Green. Myokine content in muscle (tumour necrosis factor alpha/IL-10/IL-4) was assessed by enzyme-linked immunosorbent assay. At the end of the protocol, the trained groups showed a reduction in total weight, when compared to Lewis lung carcinoma. Tumor weight was lower in the LLC + T (ZTAlt), when compared to LLC. Clock gene mRNA expression showed a significant increase for ZT20 in the groups that performed physical exercise at LLC + T (ZTAlt), when compared with LLC. The Per family showed increased mRNA expression in ZT4 in both trained mice groups, when compared with LLC. LLC + T (ZTAlt) presented reduction of the expression of anti-inflammatory myokines (Il-10/IL-4) during the night, compared with LLC + T(ZT2). Exercise training is able to induce marked modification of clock gene expression and of the production of myokines, in a way that is dependent on schedule exercise training strategy. Taken together, the results show that exercise is a potent Zeitgeber and may thus contribute to change clock genes expression and myokines that are able to reduce the tumor weight.

Aerobic training improves NAFLD markers and insulin resistance through AMPK-PPAR-α signaling in obese mice.

Liver steatosis is one of the main drivers for the development of whole-body insulin resistance. Conversely, aerobic training (AT) has been suggested as non-pharmacological tool to improve liver steatosis, however, the underlying molecular mechanism remains unclear. Therefore, the aim of this study was to analyze the effect of 8-weeks AT in non-alcoholic liver disease (NAFLD) outcomes in obese mice. Male C57BL/6 J wild type (WT) were fed with standard (SD) or high-fat diet (HFD) for 12-weeks. Another group fed with HFD underwent 8-weeks of AT (60% of maximum velocity), initiated at the 5th week of experimental protocol. We measured metabolic, body composition parameters, protein and gene expression inflammatory and metabolic mediators. We found that AT attenuates the weight gain, but not body fat accumulation. AT improved triacylglycerol and non-esterified fatty acid plasma concentrations, and also whole-body insulin resistance. Regarding NAFLD, AT decreased the progression of macrovesicular steatosis and inflammation through the upregulation of AMPK Thr172 phosphorylation and PPAR-α protein expression. Moreover, although no effects of intervention in PPAR-γ protein concentration were observed, we found increased levels of its target genes Cd36 and Scd1 in exercised group, demonstrating augmented transcriptional activity. AT reduced liver cytokines concentrations, such as TNF-α, IL-10, MCP-1 and IL-6, regardless of increased Ser536 NF-κB phosphorylation. In fact, none of the interventions regulated NF-κB target genes Il1b and Cccl2, demonstrating its low transcriptional activity. Therefore, we conclude that AT attenuates the progression of liver macrovesicular steatosis and inflammation through AMPK-PPAR-α signaling and PPAR-γ activation, respectively, improving insulin resistance in obese mice.

Exercise Reduces the Resumption of Tumor Growth and Proteolytic Pathways in the Skeletal Muscle of Mice Following Chemotherapy.

The pathogenesis of muscle atrophy plays a central role in cancer cachexia, and chemotherapy contributes to this condition. Therefore, the present study aimed to evaluate the effects of endurance exercise on time-dependent muscle atrophy caused by doxorubicin. For this, C57 BL/6 mice were subcutaneously inoculated with Lewis lung carcinoma cells (LLC group). One week after the tumor establishment, a group of these animals initiated the doxorubicin chemotherapy alone (LLC + DOX group) or combined with endurance exercise (LLC + DOX + EXER group). One group of animals was euthanized after the chemotherapy cycle, whereas the remaining animals were euthanized one week after the last administration of doxorubicin. The practice of exercise combined with chemotherapy showed beneficial effects such as a decrease in tumor growth rate after chemotherapy interruption and amelioration of premature death due to doxorubicin toxicity. Moreover, the protein degradation levels in mice undergoing exercise returned to basal levels after chemotherapy; in contrast, the mice treated with doxorubicin alone experienced an increase in the mRNA expression levels of the proteolytic pathways in gastrocnemius muscle (Trim63, Fbxo32, Myostatin, FoxO). Collectively, our results suggest that endurance exercise could be utilized during and after chemotherapy for mitigating muscle atrophy promoted by doxorubicin and avoid the resumption of tumor growth.

Palmitoleic acid reduces high fat diet-induced liver inflammation by promoting PPAR-γ-independent M2a polarization of myeloid cells.

Palmitoleic acid (POA, 16:1n-7) is a lipokine that has potential nutraceutical use to treat non-alcoholic fatty liver disease. We tested the effects of POA supplementation (daily oral gavage, 300 mg/Kg, 15 days) on murine liver inflammation induced by a high fat diet (HFD, 59% fat, 12 weeks). In HFD-fed mice, POA supplementation reduced serum insulin and improved insulin tolerance compared with oleic acid (OA, 300 mg/Kg). The livers of POA-treated mice exhibited less steatosis and inflammation than those of OA-treated mice with lower inflammatory cytokine levels and reduced toll-like receptor 4 protein content. The anti-inflammatory effects of POA in the liver were accompanied by a reduction in liver macrophages (LM, CD11c+; F4/80+; CD86+), an effect that could be triggered by peroxisome proliferator activated receptor (PPAR)-γ, a lipogenic transcription factor upregulated in livers of POA-treated mice. We also used HFD-fed mice with selective deletion of PPAR-γ in myeloid cells (PPAR-γ KOLyzCre+) to test whether the beneficial anti-inflammatory effects of POA are dependent on macrophages PPAR-γ. POA-mediated improvement of insulin tolerance was tightly dependent on myeloid PPAR-γ, while POA anti-inflammatory actions including the reduction in liver inflammatory cytokines were preserved in mice bearing myeloid cells deficient in PPAR-γ. This overlapped with increased CD206+ (M2a) cells and downregulation of CD86+ and CD11c+ liver macrophages. Moreover, POA supplementation increased hepatic AMPK activity and decreased expression of the fatty acid binding scavenger receptor, CD36. We conclude that POA controls liver inflammation triggered by fat accumulation through induction of M2a macrophages independently of myeloid cell PPAR-γ.

Macrophage immunophenotype but not anti-inflammatory profile is modulated by peroxisome proliferator-activated receptor gamma (PPARγ) in exercised obese mice.

Moderate aerobic training may be therapeutic for chronic low-grade inflammatory diseases due to the associated anti-inflammatory response that is mediated by immune cells. The peroxisome proliferator-activated receptor gamma (PPARγ) regulates the M1 (pro-inflammatory) and M2 (anti-inflammatory) polarization, as well as the immunometabolic response of macrophages. Against this background, the present study seeks to clarify whether the conditional deletion of PPARγ in macrophages would have any effect on the anti-inflammatory role of moderate aerobic training. To test this hypothesis, two mice strains were used: PPARγ LyzCre+/+ (KO) and littermates control animals (WT). Each genotype was divided into 1) sedentary high-fat diet (HF) and 2) high-fat diet and moderate aerobic training (HFT) (n = 5-8 per group). The experimental protocol lasted for 12 weeks, comprising 4 weeks of HF diet only and 8 weeks of HF diet and aerobic training (5 times/week, 50-60 minutes/day at 60% of maximum speed). Metabolic analyses were carried out on the serum glucose homeostase, adipose tissue morphology and cytokine content, and macrophage cytokine production.Immunophenotyping and gene expression were also performed. KO male mice were more prone to hypertrophy in the subcutaneous adipose tissue, though only the IL-1ß (p = 0.0049) was higher compared to the values observed in WT animals. Peritoneal macrophages from KO animals exhibited a marked inflammatory environment with an increase in TNF-α (p = 0.0008), IL- 1ß (p = 0.0017), and IL-6 (p < 0.0001) after lipopolysaccharide stimulation. The moderate aerobic training protected both genotypes from weight gain and reduced the caloric intake in the KO animals. Despite the attenuation of the M2 marker CD206 (p < 0.001) in the absence of PPAR-γ, the aerobic training modulated cytokine production in LPS stimulated peritoneal macrophages from both genotypes, reducing proinflammatory cytokines such as TNF-α (p = 0.0002) and IL-6 (p < 0.0001). Overall, our findings demonstrate the essential role of PPARγ in macrophage immunophenotypes. However, the deletion of PPARγ did not inhibit the exercise-mediated anti-inflammatory effect, underscoring the important role of exercise in modulating inflammation.

The Relevance of Thimet Oligopeptidase in the Regulation of Energy Metabolism and Diet-Induced Obesity.

Thimet oligopeptidase (EC 3.4.24.15; EP24.15; THOP1) is a potential therapeutic target, as it plays key biological functions in processing biologically functional peptides. The structural conformation of THOP1 provides a unique restriction regarding substrate size, in that it only hydrolyzes peptides (optimally, those ranging from eight to 12 amino acids) and not proteins. The proteasome activity of hydrolyzing proteins releases a large number of intracellular peptides, providing THOP1 substrates within cells. The present study aimed to investigate the possible function of THOP1 in the development of diet-induced obesity (DIO) and insulin resistance by utilizing a murine model of hyperlipidic DIO with both C57BL6 wild-type (WT) and THOP1 null (THOP1-/-) mice. After 24 weeks of being fed a hyperlipidic diet (HD), THOP1-/- and WT mice ingested similar chow and calories; however, the THOP1-/- mice gained 75% less body weight and showed neither insulin resistance nor non-alcoholic fatty liver steatosis when compared to WT mice. THOP1-/- mice had increased adrenergic-stimulated adipose tissue lipolysis as well as a balanced level of expression of genes and microRNAs associated with energy metabolism, adipogenesis, or inflammation. Altogether, these differences converge to a healthy phenotype of THOP1-/- fed a HD. The molecular mechanism that links THOP1 to energy metabolism is suggested herein to involve intracellular peptides, of which the relative levels were identified to change in the adipose tissue of WT and THOP1-/- mice. Intracellular peptides were observed by molecular modeling to interact with both pre-miR-143 and pre-miR-222, suggesting a possible novel regulatory mechanism for gene expression. Therefore, we successfully demonstrated the previously unanticipated relevance of THOP1 in energy metabolism regulation. It was suggested that intracellular peptides were responsible for mediating the phenotypic differences that are described herein by a yet unknown mechanism of action.

Pharmacological Strategies for Insulin Sensitivity in Obesity and Cancer: Thiazolidinediones and Metformin.

BACKGROUND: Chronic diseases, such as obesity and cancer, have high prevalence rates. Both diseases have hyperinsulinemia, hyperglycemia, high levels of IGF-1 and inflammatory cytokines in common. Therefore, these can be considered triggers for cancer development and growth. In addition, low-grade inflammation that modulates the activation of immune cells, cellular metabolism, and production of cytokines and chemokines are common in obesity, cancer, and insulin resistance. Pharmacological strategies are necessary when a change in lifestyle does not improve glycemic homeostasis. In this regard, thiazolidinediones (TZD) possess multiple molecular targets and regulate PPARγ in obesity and cancer related to insulin resistance, while metformin acts through the AMPK pathway. OBJECTIVE: The aim of this study was to review TZD and metformin as pharmacological treatments for insulin resistance associated with obesity and cancer. CONCLUSION: Thiazolidinediones restored adiponectin secretion and leptin sensitivity, reduced lipid droplets in hepatocytes and orexigen peptides in the hypothalamus. In cancer cells, TZD reduced proliferation, production of reactive oxygen species, and inflammation by acting through the mTOR and NFκB pathways. Metformin has similar effects, though these are AMPK-dependent. In addition, both drugs can be efficient against certain side effects caused by chemotherapy.

Doxorubicin modulated clock genes and cytokines in macrophages extracted from tumor-bearing mice.

Circadian rhythm is essential for cellular regulation of physiological, metabolic, and immune functions. Perturbations of circadian rhythms have been correlated with increased susceptibility to cancer and poor prognosis in the cancer treatment. Our aim is to investigate the role of doxorubicin (DOX) treatment on clock genes expression and inflammation in intraperitoneal macrophages and the antitumoral response. METHODS: Macrophages were extracted from intraperitoneal cavity of mice without or with Lewis lung carcinoma (LLC) and treated with DOX totaling four groups (CTL, LLC, LLC+DOX and DOX) and analyzes of clock genes in six time points (ZT02, ZT06, ZT10, ZT14, ZT18 AND ZT22). Intraperitoneal macrophages cell culture was stimulated with LPS and DOX and clock genes and inflammatory profile were analyzed. In tumor were analyzed macrophages markers. RESULTS: The expression of F4/80 (ZT22) and CD11c (ZT06) tumor tissue was significantly differed between LLC and LCC+DOX groups. In the intraperitoneal macrophages, DOX increased Clock (ZT10), Rev-Erbα (ZT18 and ZT22) and Per2 expressions (ZT18); in the LLC+DOX group was increased Bmal1 (ZT10), Per2 (ZT18) and NF-kB (ZT22) expressions; IL-6 expression increased in the LCC group (ZT02). In intraperitoneal macrophages cell culture stimulated with DOX and LPS after 24 h decreased Clock and Per1. DOX causes depression after 6 and 24 h in TNF-α content and Per2 gene expression after 24 h IL-1ß expression was reduced also. CONCLUSION: DOX treatment in vivo disrupted cytokine and clock genes expression in intraperitoneal macrophages suppressing immune response. Moreover, macrophages cultured with DOX had decreased expression of LPS-stimulated inflammatory cytokines.

Nutrients, immune system, and exercise: Where will it take us?

The immune system plays a key role in controlling infections, repairing injuries, and restoring homeostasis. Immune cells are bioenergetically expensive during activation, which requires a tightly regulated control of the metabolic pathways, which is mostly regulated by two cellular energy sensors: Adenosine monophosphate-activated protein kinase and mammalian target of rapamycin. The activation and inhibition of this pathways can change cell subtype differentiation. Exercise intensity and duration and nutrient availability (especially glucose and glutamine) tightly regulate immune cell differentiation and function through Adenosine monophosphate-activated protein kinase and mammalian target of rapamycin signaling. Herein, we discuss the innate and adaptive immune-cell metabolism and how they can be affected by exercise and nutrients.

Tributyrin in Inflammation: Does White Adipose Tissue Affect Colorectal Cancer?

Colorectal cancer affects the large intestine, leading to loss of white adipose tissue (WAT) and alterations in adipokine secretion. Lower incidence of colorectal cancer is associated with increased fibre intake. Fructooligosaccharides (FOS) are fibres that increase production of butyrate by the intestinal microbiota. Tributyrin, a prodrug of butyric acid, exerts beneficial anti-inflammatory effects on colorectal cancer. Our aim was to characterise the effects of diets rich in FOS and tributyrin within the context of a colon carcinogenesis model, and characterise possible support of tumorigenesis by WAT. C57/BL6 male mice were divided into four groups: a control group (CT) fed with chow diet and three colon carcinogenesis-induced groups fed either with chow diet (CA), tributyrin-supplemented diet (BUT), or with FOS-supplemented diet. Colon carcinogenesis decreased adipose mass in subcutaneous, epididymal, and retroperitoneal tissues, while also reducing serum glucose and leptin concentrations. However, it did not alter the concentrations of adiponectin, interleukin (IL)-6, IL-10, and tumour necrosis factor alpha (TNF)-α in WAT. Additionally, the supplements did not revert the colon cancer affected parameters. The BUT group exhibited even higher glucose tolerance and levels of IL-6, VEGF, and TNF-α in WAT. To conclude our study, FOS and butyrate supplements were not beneficial. In addition, butyrate worsened adipose tissue inflammation.

Metformin Mitigates Fibrosis and Glucose Intolerance Induced by Doxorubicin in Subcutaneous Adipose Tissue.

Doxorubicin (DX) is a chemotherapeutic drug that is used in clinical practice that promotes deleterious side effects in non-tumor tissues such as adipose tissue. We showed that DX leads to extensive damage in adipose tissue via a disruption in 5'-adenosine monophosphate-activated protein kinase (AMPK) and PPAR-gamma signaling. Thus, we investigated whether co-treatment with the biguanide drug metformin (MET) could prevent the side effects of DX through the activation of AMPK in adipose tissue. The goal of the present study was to verify the effects of DX and adjuvant MET treatment in subcutaneous adipose tissue (SAT) and to determine whether MET could protect against chemotherapy-induced side effects. C57/BL6 mice received DX hydrochloride (2.5 mg/kg) intraperitoneally 2 times per week for 2 weeks (DX), concomitantly or not, with MET administration (300 mg/kg oral daily) (DX + MET). The control group (CTRL) was pair-fed according to the food consumption of the DX group. After euthanasia, adipose tissue fat pads were collected, and SAT was extracted so that adipocytes could be isolated. Glucose uptake was then measured, and histological, gene, and protein analyses were performed. One-way analysis of variance was also performed, and significance was set to 5%. DX reduced retroperitoneal fat mass and epididymal pads and decreased glycemia. In cultured primary subcutaneous adipocytes, mice in the DX group had lower glucose uptake when stimulated with insulin compared with mice in the CTRL group. Adipocytes in the DX group exhibited a reduced area, perimeter, and diameter; decreased adiponectin secretion; and decreased fatty acid synthase gene expression. SAT from MET-treated mice also showed a reduction in collagen deposition. Treatment with MET prevented fibrosis and restored glucose uptake in SAT after insulin stimulation, yet the drug was unable to prevent other side effects of DX such as tissue loss and inflammatory response.

Short-term treatment with metformin reduces hepatic lipid accumulation but induces liver inflammation in obese mice.

The study aimed to evaluate the metabolic and inflammatory effects of short-term treatments (10 days) with metformin (MET) on the NAFLD caused by a high-fat diet (HFD) in C57BL/6 mice. After the treatment, histological liver slices were obtained, hepatocytes and macrophages were extracted and cultured with phosphate buffered saline, LPS (2.5 µg/mL) and MET (1 µM) for 24 h. Cytokine levels were determined by ELISA. NAFLD caused by the HFD was partially reduced by MET. The lipid accumulation induced by the HFD was not associated with liver inflammation; however, MET seemed to promote pro-inflammatory effects in liver, since it increased hepatic concentration of IL-1ß, TNF-α, IL-6, MCP-1 and IFN-γ. Similarly, MET increased the concentration of IL-1ß, IL-6 in hepatocyte cultures. However, in macrophages culture, MET lowered levels of IL-1ß, IL-6 and TNF-α stimulated by LPS. Overall, MET reduced liver NAFLD but promoted hepatocyte increase in pro-inflammatory cytokines, thus, leading to liver inflammation.

Effect of an acute moderate-exercise session on metabolic and inflammatory profile of PPAR-α knockout mice.

Peroxisome proliferator-activated receptors (PPARs) play a major role in metabolism and inflammatory control. Exercise can modulate PPAR expression in skeletal muscle, adipose tissue, and macrophages. Little is known about the effects of PPAR-α in metabolic profile and cytokine secretion after acute exercise in macrophages. In this context, the aim of this study was to understand the influence of PPAR-α on exercise-mediated immune metabolic parameters in peritoneal macrophages. Mice C57BL/6 (WT) and PPAR-α knockout (KO) were examined in non-exercising control (n = 4) or 24 hours after acute moderate exercise (n = 8). Metabolic parameters (glucose, non-esterified fatty acids, total cholesterol [TC], and triacylglycerol [TG]) were assessed in serum. Cytokine concentrations (IL-1ß, IL-6, IL-10, TNF-α, and MCP-1) were measured from peritoneal macrophages cultured or not with LPS (2.5 µg/mL) and Rosiglitazone (1 µM). Exercised KO mice exhibited low glucose concentration and higher TC and TG in serum. At baseline, no difference in cytokine production between the genotypes was observed. However, IL-1ß was significantly higher in KO mice after LPS stimulus. IL-6 and IL-1ß had increased concentrations in KO compared with WT, even after exercise. MCP-1 was not restored in exercised KO LPS group. Rosiglitazone was not able to reduce proinflammatory cytokine production in KO mice at baseline level or associated with exercise. Acute exercise did not alter mRNA expression in WT mice. CONCLUSION: PPAR-α seems to be needed for metabolic glucose homeostasis and anti-inflammatory effect of acute exercise. Its absence may induce over-expression of pro-inflammatory cytokines in LPS stimulus. Moreover, moderate exercise or PPAR-γ agonist did not reverse this response.

Palmitoleic acid reduces the inflammation in LPS-stimulated macrophages by inhibition of NFκB, independently of PPARs.

Palmitoleic acid (PM, 16:1n-7) has anti-inflammatory properties that could be linked to higher expression of PPARα, an inhibitor of NFκB. Macrophages play a major role in the pathogenesis of chronic inflammation, however, the effects of PM on macrophages are underexplored. Thus, we aimed to investigate the effects of PM in activated macrophages as well the role of PPARα. Primary macrophages were isolated from C57BL/6 wild type (WT) and PPARα knockout (KO) mice, cultured under standard conditions and exposed to lipopolysaccharides LPS (2.5 µg/ml) and PM 600 µmol/L conjugated with albumin for 24 hours. The stimulation with LPS increased the production of interleukin (IL)-6 and IL-1ß while PM decreased the production of IL-6 in WT macrophages. In KO macrophages, LPS increased the production of tumour necrosis factor (TNF)-α and IL-6 and PM decreased the production of TNFα. The expression of inflammatory markers such NFκB and IL1ß were increased by LPS and decreased by PM in both WT and KO macrophages. PM reduced the expression of MyD88 and caspase-1 in KO macrophages, and the expression of TLR4 and HIF-1α in both WT and KO macrophages, although LPS had no effect. CD86, an inflammatory macrophage marker, was reduced by PM independently of genotype. PM increased PPARγ and reduced PPARß gene expression in macrophages of both genotypes, and increased ACOX-1 expression in KO macrophages. In conclusion, PM promotes anti-inflammatory effects in macrophages exposed to LPS through inhibition of inflammasome pathway, which was independent of PPARα, PPARϒ and AMPK, thus the molecular mechanisms of anti-inflammatory response caused by PM is still unclear.

Palmitoleic Acid Improves Metabolic Functions in Fatty Liver by PPARα-Dependent AMPK Activation.

BACKGROUND: Palmitoleic acid, since described as lipokine, increases glucose uptake by modulation of 5'AMP-activated protein kinase (AMPK), as well as increasing lipolysis by activation of peroxisome proliferator-activated receptor-α (PPARα), in adipose tissue. However, in liver, the effects of palmitoleic acid on glucose metabolism and the role of PPARα remain unknown. OBJECTIVE: To investigate whether palmitoleic acid improved the hepatic insulin sensitivity of obese mice. METHODS: C57BL6 and PPARα knockout (KO) mice were fed for 12 weeks with a standard diet (SD) or high-fat diet (HF), and in the last 2 weeks were treated with oleic or palmitoleic acid. RESULTS: Palmitoleic acid promoted a faster uptake of glucose in the body, associated with higher insulin concentration; however, even when stimulated with insulin, palmitoleic acid did not modulate the insulin pathway (AKT, IRS). Palmitoleic acid increased the phosphorylation of AMPK, upregulated glucokinase and downregulated SREBP-1. Regarding AMPK downstream, palmitoleic acid increased the production of FGF-21 and stimulated the expression of PPARα. Palmitoleic acid treatment did not increase AMPK phosphorylation, modulate glucokinase or increase FGF-21 in liver of PPARα KO mice. CONCLUSIONS: In mice fed with a high-fat diet, palmitoleic acid supplementation stimulated the uptake of glucose in liver through activation of AMPK and FGF-21, dependent on PPARα. J. Cell. Physiol. 232: 2168-2177, 2017. © 2016 Wiley Periodicals, Inc.

Association Between Aerobic Exercise and Rosiglitazone Avoided the NAFLD and Liver Inflammation Exacerbated in PPAR-α Knockout Mice.

Nonalcoholic fatty liver disease (NAFLD) is one of the main liver diseases today, and may progress to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Some studies have shown the beneficial effects of aerobic exercise on reversing NAFLD. To verify whether chronic aerobic exercise improves the insulin resistance, liver inflammation, and steatohepatitis caused by a high fat diet (HF) and whether PPARα is involved in these actions. C57BL6 wild type (WT) and PPAR-α knockout (KO) mice were fed with a standard diet (SD) or HF during 12 weeks; the HF mice were trained on a treadmill during the last 8 weeks. Serum glucose and insulin tolerances, serum levels of aspartate aminotransferase, hepatic content of triacylglycerol, cytokines, gene expression, and protein expression were evaluated in all animals. Chronic exposure to HF diet increased triacylglycerol accumulation in the liver, leading to NAFLD, increased aminotransferase in the serum, increased peripheral insulin resistance, and higher adiposity index. Exercise reduced all these parameters in both animal genotypes. The liver lipid accumulation was not associated with inflammation; trained KO mice, however, presented a huge inflammatory response that was probably caused by a decrease in PPAR-γ expression. We conclude that exercise improved the damage caused by a HF independently of PPARα, apparently by a peripheral fatty acid oxidation in the skeletal muscle. We also found that the absence of PPARα together with exercise leads to a decrease in PPAR-γ and a huge inflammatory response. J. Cell. Physiol. 232: 1008-1019, 2017. © 2016 Wiley Periodicals, Inc.

Aerobic Exercise Modulates the Free Fatty Acids and Inflammatory Response During Obesity and Cancer Cachexia.

White adipose tissue (WAT) is no longer considered a tissue whose main function is the storage of TAG. Since the discovery of leptin in 1994, several studies have elucidated the important role of WAT as an endocrine organ, the source of the adipokines. The low-grade inflammation observed in obese and cancer cachexia patients is explained, at least partially, by the exacerbated release of proinflammatory adipokines. Despite of the recent progress in the characterization of the various adipokines and lipokines produced by WAT, little is known about the mechanisms regulating the secretion of these molecules in different physiological and pathological circumstances. Chronic exercise is a nonpharmacological therapy employed in several chronic diseases and shows an anti-inflammatory effect through the regulation of the cytokine network. In this review, we address the potential mechanisms by which the aerobic physical exercise modulate the production and release of inflammatory adipokines, as well as the inflammation-lipolysis axis in WAT, with special focus in the therapeutic role of exercise in obesity-associated insulin resistance and cancer cachexia.

Impact of Doxorubicin Treatment on the Physiological Functions of White Adipose Tissue.

White adipose tissue (WAT) plays a fundamental role in maintaining energy balance and important endocrine functions. The loss of WAT modifies adipokine secretion and disrupts homeostasis, potentially leading to severe metabolic effects and a reduced quality of life. Doxorubicin is a chemotherapeutic agent used clinically because of its good effectiveness against various types of cancer. However, doxorubicin has deleterious effects in many healthy tissues, including WAT, liver, and skeletal and cardiac muscles. Our objective was to investigate the effects of doxorubicin on white adipocytes through in vivo and in vitro experiments. Doxorubicin reduced the uptake of glucose by retroperitoneal adipocytes and 3T3-L1 cells via the inhibition of AMP-activated protein kinase Thr172 phosphorylation and glucose transporter 4 content. Doxorubicin also reduced the serum level of adiponectin and, to a greater extent, the expression of genes encoding lipogenic (Fas and Acc) and adipogenic factors (Pparg, C/ebpa, and Srebp1c) in retroperitoneal adipose tissue. In addition, doxorubicin inhibited both lipogenesis and lipolysis and reduced the hormone-sensitive lipase and adipose tissue triacylglycerol lipase protein levels. Therefore, our results demonstrate the impact of doxorubicin on WAT. These results are important to understand some side effects observed in patients receiving chemotherapy and should encourage new adjuvant treatments that aim to inhibit these side effects.