New Mediators in the Crosstalk between Different Adipose Tissues.

Adipose tissue is a multifunctional organ that regulates many physiological processes such as energy homeostasis, nutrition, the regulation of insulin sensitivity, body temperature, and immune response. In this review, we highlight the relevance of the different mediators that control adipose tissue activity through a systematic review of the main players present in white and brown adipose tissues. Among them, inflammatory mediators secreted by the adipose tissue, such as classical adipokines and more recent ones, elements of the immune system infiltrated into the adipose tissue (certain cell types and interleukins), as well as the role of intestinal microbiota and derived metabolites, have been reviewed. Furthermore, anti-obesity mediators that promote the activation of beige adipose tissue, e.g., myokines, thyroid hormones, amino acids, and both long and micro RNAs, are exhaustively examined. Finally, we also analyze therapeutic strategies based on those mediators that have been described to date. In conclusion, novel regulators of obesity, such as microRNAs or microbiota, are being characterized and are promising tools to treat obesity in the future.

The prognostic impact of non-driver gene mutations and variant allele frequency in primary myelofibrosis.

Prognostic impact of non-MPN driver gene mutations in primary myelofibrosis. MIPSS70: Mutation-Enhanced International Prognostic Score System.

Gut Microbiota Dysbiosis in COVID-19: Modulation and Approaches for Prevention and Therapy.

Inflammation and oxidative stress are critical underlying mechanisms associated with COVID-19 that contribute to the complications and clinical deterioration of patients. Additionally, COVID-19 has the potential to alter the composition of patients' gut microbiota, characterized by a decreased abundance of bacteria with probiotic effects. Interestingly, certain strains of these bacteria produce metabolites that can target the S protein of other coronaviruses, thereby preventing their transmission and harmful effects. At the same time, the presence of gut dysbiosis can exacerbate inflammation and oxidative stress, creating a vicious cycle that perpetuates the disease. Furthermore, it is widely recognized that the gut microbiota can metabolize various foods and drugs, producing by-products that may have either beneficial or detrimental effects. In this regard, a decrease in short-chain fatty acid (SCFA), such as acetate, propionate, and butyrate, can influence the overall inflammatory and oxidative state, affecting the prevention, treatment, or worsening of COVID-19. This review aims to explore the current evidence regarding gut dysbiosis in patients with COVID-19, its association with inflammation and oxidative stress, the molecular mechanisms involved, and the potential of gut microbiota modulation in preventing and treating SARS-CoV-2 infection. Given that gut microbiota has demonstrated high adaptability, exploring ways and strategies to maintain good intestinal health, as well as an appropriate diversity and composition of the gut microbiome, becomes crucial in the battle against COVID-19.

Polyphenols and Triterpenes Combination in an In Vitro Model of Cardiac Damage: Protective Effects.

Olive products contain high levels of monounsaturated fatty acids as well as other minor components such as triterpenic alcohols and other pentacyclic triterpenes, which together form the main triterpenes of virgin olive oil. Olive fruits and leaves contain significant amounts of hydrophilic and lipophilic bioactives including flavones, phenolic acids and phenolic alcohols, amongst others. Several studies have shown the benefits of these substances on the cardiovascular system. Regardless, little is known about the specific combination of bioactive compounds in cardiovascular health. Thus, we aimed to test the combination of a triterpenes (TT70) and a polyphenols (HT60) olive oil bioactive extract in H9c2 cells under stress conditions: LPS and H2O2 stimulation. To evaluate the effectiveness of the combination, we measured cell viability, superoxide production and protein expression of caspase 3, eNOS, peNOS, TNF-α and Il-6. Overall, cells stimulated with LPS or H2O2 and co-incubated with the combination of triterpenes and polyphenols had increased cell survival, lower levels of superoxide anion, lower protein expression of eNOS and higher expression of peNOS, increased protein expression of SOD-1 and lower protein expression of TNF-α and Il-6. The specific combination of HT60+TT70 is of great interest for further study as a possible treatment for cardiovascular damage.

Toxicity of Asciminib in Real Clinical Practice: Analysis of Side Effects and Cross-Toxicity with Tyrosine Kinase Inhibitors.

(1) Background: Despite the prognostic improvements achieved with tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), a minority of patients still fail TKIs. The recent introduction of asciminib may be a promising option in intolerant patients, as it is a first-in-class inhibitor with a more selective mechanism of action different from the ATP-competitive inhibition that occurs with TKIs. Therefore, our goal was to analyze toxicities shown with asciminib as well as to study cross-toxicity with previous TKIs. (2) Methods: An observational, multicenter, retrospective study was performed with data from 77 patients with CML with therapeutic failure to second-generation TKIs who received asciminib through a managed-access program (MAP) (3) Results: With a median follow-up of 13.7 months, 22 patients (28.5%) discontinued treatment: 32% (7/22) due to intolerance and 45% (10/22) due to resistance. Fifty-five percent of the patients reported adverse effects (AEs) with asciminib and eighteen percent grade 3-4. Most frequent AEs were: fatigue (18%), thrombocytopenia (17%), anemia (12%), and arthralgias (12%). None of the patients experienced cardiovascular events or occlusive arterial disease. Further, 26%, 25%, and 9% of patients required dose adjustment, temporary suspension, or definitive discontinuation of treatment, respectively. Toxicities under asciminib seemed lower than with prior TKIs for anemia, cardiovascular events, pleural/pericardial effusion, diarrhea, and edema. Cross-toxicity risk was statistically significant for thrombocytopenia, anemia, neutropenia, fatigue, vomiting, and pancreatitis. (4) Conclusion: Asciminib is a molecule with a good safety profile and with a low rate of AEs. However, despite its new mechanism of action, asciminib presents a risk of cross-toxicity with classical TKIs for some AEs.

Melatonin as an Anti-Aging Therapy for Age-Related Cardiovascular and Neurodegenerative Diseases.

The concept of "aging" is defined as the set of gradual and progressive changes in an organism that leads to an increased risk of weakness, disease, and death. This process may occur at the cellular and organ level, as well as in the entire organism of any living being. During aging, there is a decrease in biological functions and in the ability to adapt to metabolic stress. General effects of aging include mitochondrial, cellular, and organic dysfunction, immune impairment or inflammaging, oxidative stress, cognitive and cardiovascular alterations, among others. Therefore, one of the main harmful consequences of aging is the development and progression of multiple diseases related to these processes, especially at the cardiovascular and central nervous system levels. Both cardiovascular and neurodegenerative pathologies are highly disabling and, in many cases, lethal. In this context, melatonin, an endogenous compound naturally synthesized not only by the pineal gland but also by many cell types, may have a key role in the modulation of multiple mechanisms associated with aging. Additionally, this indoleamine is also a therapeutic agent, which may be administered exogenously with a high degree of safety. For this reason, melatonin could become an attractive and low-cost alternative for slowing the processes of aging and its associated diseases, including cardiovascular and neurodegenerative disorders.

Autologous stem-cell transplantation as consolidation of first-line chemotherapy in patients with peripheral T-cell lymphoma: a multicenter GELTAMO/FIL study.

Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of rare lymphoid malignancies that mostly have poor prognoses with currently available treatments. Upfront consolidation with autologous stem cell transplantation (ASCT) is frequently carried out, but its efficacy has never been investigated in randomized trials. We designed a multicenter, international, retrospective study with the main objective of comparing progression-free survival and overall survival of patients with PTCL who underwent ASCT in complete remission (CR) after first-line chemotherapy with a control group who did not undergo ASCT. From the initial population of 286 registered patients, 174 patients with PTCL other than anaplastic large cell lymphoma, ALK-positive, deemed fit for ASCT at the time of diagnosis, and who were in CR or uncertain CR after induction therapy (CR1) were included in our analysis. one hundred and three patients underwent ASCT, whereas 71 did not, in most cases (n=53) because the physician decided against it. With a median follow-up of 65.5 months, progression-free survival was significantly better in the transplanted patients than in the non-transplanted group: 63% versus 48% at 5 years (P=0.042). Overall survival was significantly longer for ASCT patients in the subgroup with advanced stage at diagnosis (5-year overall survival: 70% vs. 50%, P=0.028). In the multivariate analysis, first-line ASCT was associated with significantly prolonged progression-free survival (HR=0.57, 95% CI: 0.35-0.93) and overall survival (HR=0.57, 95% CI: 0.33-0.99). In conclusion, our study supports the use of ASCT as a consolidation strategy for patients with PTCL in CR1. These results should be confirmed in a prospective randomized study.

Relevance of mitochondrial dysfunction in heart disease associated with insulin resistance conditions.

Insulin resistance plays a key role in the development and progression of obesity, diabetes, and their complications. Moreover, insulin resistance is considered the principal link between metabolic diseases and cardiovascular diseases. Heart disease associated with insulin resistance is one of the most important consequences of both obesity and diabetes, and it is characterized by impaired cardiac energetics, diastolic dysfunction, and finally heart failure. Mitochondrion plays a key role in cell energy homeostasis and is the main source of reactive oxygen species. Obesity and diabetes are associated with alterations in mitochondrial function and dynamics. Mitochondrial dysfunction is characterized by changes in mitochondrial respiratory chain with reduced ATP production and elevated reactive oxygen species production. These mitochondrial alterations together with inflammation contribute to the development and progression of heart disease under insulin resistance conditions. Finally, numerous miRNAs participate in the regulation of energy substrate metabolism, reactive oxygen species production, and apoptotic pathways within the mitochondria. This notion supports the relevance of interactions between miRNAs and mitochondrial dysfunction in the pathophysiology of metabolic heart disease.

Proanthocyanidins Maintain Cardiac Ionic Homeostasis in Aldosterone-Induced Hypertension and Heart Failure.

Excess aldosterone promotes pathological remodeling of the heart and imbalance in cardiac ion homeostasis of sodium, potassium and calcium. Novel treatment with proanthocyanidins in aldosterone-treated rats has resulted in downregulation of cardiac SGK1, the main genomic aldosterone-induced intracellular mediator of ion handling. It therefore follows that proanthocyanidins could be modulating cardiac ion homeostasis in aldosterone-treated rats. Male Wistar rats received aldosterone (1 mg kg-1 day-1) +1% NaCl for three weeks. Half of the animals in each group were simultaneously treated with the proanthocyanidins-rich extract (80% w/w) (PRO80, 5 mg kg-1 day-1). PRO80 prevented cardiac hypertrophy and decreased calcium content. Expression of ion channels (ROMK, NHE1, NKA and NCX1) and calcium transient mediators (CAV1.2, pCaMKII and oxCaMKII) were reduced by PRO80 treatment in aldosterone-treated rats. To conclude, our data indicate that PRO80 may offer an alternative treatment to conventional MR-blockade in the prevention of aldosterone-induced cardiac pathology.

Severe Hepatic Insulin Resistance Induces Vascular Dysfunction: Improvement by Liver-Specific Insulin Receptor Isoform A Gene Therapy in a Murine Diabetic Model.

BACKGROUND: Cardiovascular dysfunction is linked to insulin-resistant states. In this paper, we analyzed whether the severe hepatic insulin resistance of an inducible liver-specific insulin receptor knockout (iLIRKO) might generate vascular insulin resistance and dysfunction, and whether insulin receptor (IR) isoforms gene therapy might revert it. METHODS: We studied in vivo insulin signaling in aorta artery and heart from iLIRKO. Vascular reactivity and the mRNA levels of genes involved in vascular dysfunction were analyzed in thoracic aorta rings by qRT-PCR. Finally, iLIRKO mice were treated with hepatic-specific gene therapy to analyze vascular dysfunction improvement. RESULTS: Our results suggest that severe hepatic insulin resistance was expanded to cardiovascular tissues. This vascular insulin resistance observed in aorta artery from iLIRKO mice correlated with a reduction in both PI3K/AKT/eNOS and p42/44 MAPK pathways, and it might be implicated in their vascular alterations characterized by endothelial dysfunction, hypercontractility and eNOS/iNOS levels' imbalance. Finally, regarding long-term hepatic expression of IR isoforms, IRA was more efficient than IRB in the improvement of vascular dysfunction observed in iLIRKO mice. CONCLUSION: Severe hepatic insulin resistance is sufficient to produce cardiovascular insulin resistance and dysfunction. Long-term hepatic expression of IRA restored the vascular damage observed in iLIRKO mice.

Potential Effects of Melatonin and Micronutrients on Mitochondrial Dysfunction during a Cytokine Storm Typical of Oxidative/Inflammatory Diseases.

Exaggerated oxidative stress and hyper-inflammation are essential features of oxidative/inflammatory diseases. Simultaneously, both processes may be the cause or consequence of mitochondrial dysfunction, thus establishing a vicious cycle among these three factors. However, several natural substances, including melatonin and micronutrients, may prevent or attenuate mitochondrial damage and may preserve an optimal state of health by managing the general oxidative and inflammatory status. This review aims to describe the crucial role of mitochondria in the development and progression of multiple diseases as well as the close relationship among mitochondrial dysfunction, oxidative stress, and cytokine storm. Likewise, it attempts to summarize the main findings related to the powerful effects of melatonin and some micronutrients (vitamins and minerals), which may be useful (alone or in combination) as therapeutic agents in the treatment of several examples of oxidative/inflammatory pathologies, including sepsis, as well as cardiovascular, renal, neurodegenerative, and metabolic disorders.

Patient General Condition at Diagnosis: A Systematic Evaluation for Adults Diagnosed with Hematologic Malignancies.

Several societies have published recommendations for evaluating older adults with cancer in standard conditions. It is vital to assure a proper systematic patient condition evaluation, not only in the oldest (geriatric assessment) but in all adult patients. We have investigated the feasibility of a systematic evaluation of the general condition of all patients diagnosed with hematologic malignancies, and the degree of acceptance by the clinical team, in a prospective cohort of 182 consecutive adults, by using the ECOG performance status scale (ECOG, age 18 and over, 18+), Lee Index for Older Adults (LEE, 50+), Geriatric Assessment in Hematology (GAH, 65+), and the Comprehensive Geriatric Assessment (CGA, 75+). Clinical team acceptance was analyzed with a visual analogue scale, and the objective feasibility was calculated as the proportion of patients that could be finally evaluated with each tool. Acceptance was high, but the objective feasibility was progressively lower as the complexity of the different tools increased (ECOG 100%, LEE 99.4%, GAH 93.2%, and CGA 67.9%). LEE and GAH categories showed a weak concordance (Cohen's Kappa 0.24) that was slight between LEE and CGA (Kappa 0.18). Unexpectedly, we found no significant association between the GAH and CGA categories (p = 0.16). We confirm that a systematic evaluation of all adult patients diagnosed with hematologic malignancies is feasible in daily practice by using an age-adapted approach. Direct comparisons among the different predictive tools in regard to patients' tolerance to treatments of different intensities must be a priority research subject in the coming years.

Comprehensive Custom NGS Panel Validation for the Improvement of the Stratification of B-Acute Lymphoblastic Leukemia Patients.

BACKGROUND: B-acute lymphoblastic leukemia (B-ALL) is a hematological neoplasm of the stem lymphoid cell of the B lineage, characterized by the presence of genetic alterations closely related to the course of the disease. The number of alterations identified in these patients grows as studies of the disease progress, but in clinical practice, the conventional techniques frequently used are only capable of detecting the most common alterations. However, techniques, such as next-generation sequencing (NGS), are being implemented to detect a wide spectrum of new alterations that also include point mutations. METHODS: In this study, we designed and validated a comprehensive custom NGS panel to detect the main genetic alterations present in the disease in a single step. For this purpose, 75 B-ALL diagnosis samples from patients previously characterized by standard-of-care diagnostic techniques were sequenced. RESULTS: The use of the custom NGS panel allowed the correct detection of the main genetic alterations present in B-ALL patients, including the presence of an aneuploid clone in 14 of the samples and some of the recurrent fusion genes in 35 of the samples. The panel was also able to successfully detect a number of secondary alterations, such as single nucleotide variants (SNVs) and copy number variations (CNVs) in 66 and 46 of the samples analyzed, respectively, allowing for further refinement of the stratification of patients. The custom NGS panel could also detect alterations with a high level of sensitivity and reproducibility when the findings obtained by NGS were compared with those obtained from other conventional techniques. CONCLUSIONS: The use of this custom NGS panel allows us to quickly and efficiently detect the main genetic alterations present in B-ALL patients in a single assay (SNVs and insertions/deletions (INDELs), recurrent fusion genes, CNVs, aneuploidies, and single nucleotide polymorphisms (SNPs) associated with pharmacogenetics). The application of this panel would thus allow us to speed up and simplify the molecular diagnosis of patients, helping patient stratification and management.

Implications of Oxidative Stress and Potential Role of Mitochondrial Dysfunction in COVID-19: Therapeutic Effects of Vitamin D.

Due to its high degree of contagiousness and like almost no other virus, SARS-CoV-2 has put the health of the world population on alert. COVID-19 can provoke an acute inflammatory process and uncontrolled oxidative stress, which predisposes one to respiratory syndrome, and in the worst case, death. Recent evidence suggests the mechanistic role of mitochondria and vitamin D in the development of COVID-19. Indeed, mitochondrial dynamics contribute to the maintenance of cellular homeostasis, and its uncoupling involves pathological situations. SARS-CoV-2 infection is associated with altered mitochondrial dynamics with consequent oxidative stress, pro-inflammatory state, cytokine production, and cell death. Furthermore, vitamin D deficiency seems to be associated with increased COVID-19 risk. In contrast, vitamin D can normalize mitochondrial dynamics, which would improve oxidative stress, pro-inflammatory state, and cytokine production. Furthermore, vitamin D reduces renin-angiotensin-aldosterone system activation and, consequently, decreases ROS generation and improves the prognosis of SARS-CoV-2 infection. Thus, the purpose of this review is to deepen the knowledge about the role of mitochondria and vitamin D directly involved in the regulation of oxidative stress and the inflammatory state in SARS-CoV-2 infection. As future prospects, evidence suggests enhancing the vitamin D levels of the world population, especially of those individuals with additional risk factors that predispose to the lethal consequences of SARS-CoV-2 infection.

Integrated Genomic Analysis of Chromosomal Alterations and Mutations in B-Cell Acute Lymphoblastic Leukemia Reveals Distinct Genetic Profiles at Relapse.

The clonal basis of relapse in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is complex and not fully understood. Next-generation sequencing (NGS), array comparative genomic hybridization (aCGH), and multiplex ligation-dependent probe amplification (MLPA) were carried out in matched diagnosis-relapse samples from 13 BCP-ALL patients to identify patterns of genetic evolution that could account for the phenotypic changes associated with disease relapse. The integrative genomic analysis of aCGH, MLPA and NGS revealed that 100% of the BCP-ALL patients showed at least one genetic alteration at diagnosis and relapse. In addition, there was a significant increase in the frequency of chromosomal lesions at the time of relapse (p = 0.019). MLPA and aCGH techniques showed that IKZF1 was the most frequently deleted gene. TP53 was the most frequently mutated gene at relapse. Two TP53 mutations were detected only at relapse, whereas the three others showed an increase in their mutational burden at relapse. Clonal evolution patterns were heterogeneous, involving the acquisition, loss and maintenance of lesions at relapse. Therefore, this study provides additional evidence that BCP-ALL is a genetically dynamic disease with distinct genetic profiles at diagnosis and relapse. Integrative NGS, aCGH and MLPA analysis enables better molecular characterization of the genetic profile in BCP-ALL patients during the evolution from diagnosis to relapse.

Effect of Pectin on the Expression of Proteins Associated with Mitochondrial Biogenesis and Cell Senescence in HT29-Human Colorectal Adenocarcinoma Cells.

Mitochondria dynamic is regulated by different proteins, maintaining a balance between fission and fusion. An imbalance towards mitochondrial fission has been associated with tumor cell proliferation. The aim of this study was to analyze whether pectin modifies the viability of human colon cancer cells and the expression of proteins involved in mitochondrial fusion and fission. The human colon carcinoma cell line HT29 cells was growth in 10% fetal bovine serum in the absence and presence of pectin. Pectin reduced HT29 cell viability in a concentration-dependent manner, reaching a plateau at 150~300 µmol/L pectin. The presence of 200 µmol/L pectin reduced the expression of dynamin-related protein-1 and increased expression of the mitochondrial fusion-associated proteins mitofusin-1 and 2. Expression of cyclin B1, a protein involved in G2/M transition, was found decreased in pectin-incubated HT29 cells. Moreover, expression of p53 protein, the amount of p53 in the nucleous and ß-galactosidase activity, which are all biomarkers for cellular senescence, were significantly higher in pectin-incubated HT29 cells than in HT29 cells incubated without pectin. Expression of the protein B-cell lymphoma 2 (Bcl-2) homologous antagonist/killer was increased in response to incubation with pectin. However, incubation with pectin did not affect expression of Bcl-2-associated X protein or Bcl-2, or the caspase-3 activity. Overall, we concluded that pectin reduces the viability of human HT29 colon cancer cells, which is accompanied with a shift in the expression of proteins associated with mitochondrial dynamics towards mitochondrial fusion. Moreover, incubation with pectin favors cellular senescence over apoptosis in HT29 cells.

Supplementation with an insoluble fiber obtained from carob pod (Ceratonia siliqua L.) rich in polyphenols prevents dyslipidemia in rabbits through SIRT1/PGC-1α pathway.

PURPOSE: To investigate the mechanism implicated in the effect of an insoluble fiber (obtained from carob pod) rich in polyphenols (IFCP) in lipid metabolism in the liver. METHODS: Male New Zealand rabbits were fed with the following diets for 8 weeks: control diet (CT group), dyslipidemic diet supplemented with 0.5% cholesterol + 14% coconut oil (DL group) and dyslipidemic diet containing 0.5% cholesterol + 14% coconut oil plus 3% IFCP (DL + IFCP group). RESULTS: Dyslipidemic diet with IFCP was able to reduce development of mixed dyslipidemia, liver relative weight and collagen I protein expression compared to DL rabbits. Analyses of the main enzymes implicated in cholesterol and triglycerides metabolism revealed that IFCP increased hepatic concentration of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase) and cytochrome P450, family 7, subfamily a, polypeptide 1C (CYP7A1) (82.34, 114.42%, respectively) as well as protein expression of LDL receptor (42.48%) in DL rabbits. Importantly, IFCP also increased hepatic lipase (HL) levels (91.43%) and decreased glycerol phosphate acyltransferase (GPAT) and sterol regulatory element-binding protein 1C (SREBP1c) liver expression levels (20.38 and 41.20%, respectively). Finally, sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1α) hepatic expression increased in DL + IFCP group compared with DL (159.81 and 48.00%, respectively). CONCLUSIONS: These findings show that IFCP is able to abrogate the deleterious effects of hepatic dyslipidemia by modulating SIRT1 and PGC-1α pathways.

Low Phytanic Acid-Concentrated DHA Prevents Cognitive Deficit and Regulates Alzheimer Disease Mediators in an ApoE-/- Mice Experimental Model.

Alzheimer's disease (AD) is the main cause of dementia and cognitive impairment. It has been associated with a significant diminution of omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) levels in the brain. Clinical trials with DHA as a treatment in neurological diseases have shown inconsistent results. Previously, we reported that the presence of phytanic acid (PhA) in standard DHA compositions could be blunting DHA's beneficial effects. Therefore, we aimed to analyze the effects of a low PhA-concentrated DHA and a standard PhA-concentrated DHA in Apolipoprotein E knockout (ApoE-/-) mice. Behavioral tests and protein expression of pro-inflammatory, pro-oxidant, antioxidant factors, and AD-related mediators were evaluated. Low PhA-concentrated DHA decreased Aß, ß-amyloid precursor protein (APP), p-tau, Ca2+/calmodulin-dependent protein kinase II (CAMKII), caspase 3, and catalase, and increased brain derived neurotrophic factor (BDNF) when compared to standard PhA-concentrated DHA. Low PhA-concentrated DHA decreased interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α) protein expression in ApoE-/- mice when compared to standard PhA-concentrated DHA. No significant differences were found in p22phox, inducible nitric oxide synthase (iNOS), glutathione peroxidase (GPx), superoxide dismutase 1 (SOD-1), and tau protein expression. The positive actions of a low PhA-concentrated DHA were functionally reflected by improving the cognitive deficit in the AD experimental model. Therefore, reduction of PhA content in DHA compositions could highlight a novel pathway for the neurodegeneration processes related to AD.

Chronic Exercise Improves Mitochondrial Function and Insulin Sensitivity in Brown Adipose Tissue.

The aim of the present work was to study the consequences of chronic exercise training on factors involved in the regulation of mitochondrial remodeling and biogenesis, as well as the ability to produce energy and improve insulin sensitivity and glucose uptake in rat brown adipose tissue (BAT). Male Wistar rats were divided into two groups: (1) control group (C; n = 10) and (2) exercise-trained rats (ET; n = 10) for 8 weeks on a motor treadmill (five times per week for 50 min). Exercise training reduced body weight, plasma insulin, and oxidized LDL concentrations. Protein expression of ATP-independent metalloprotease (OMA1), short optic atrophy 1 (S-OPA1), and dynamin-related protein 1 (DRP1) in BAT increased in trained rats, and long optic atrophy 1 (L-OPA1) and mitofusin 1 (MFN1) expression decreased. BAT expression of nuclear respiratory factor type 1 (NRF1) and mitochondrial transcription factor A (TFAM), the main factors involved in mitochondrial biogenesis, was higher in trained rats compared to controls. Exercise training increased protein expression of sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) and AMP-activated protein kinase (pAMPK/AMPK ratio) in BAT. In addition, training increased carnitine palmitoyltransferase II (CPT II), mitochondrial F1 ATP synthase α-chain, mitochondrial malate dehydrogenase 2 (mMDH) and uncoupling protein (UCP) 1,2,3 expression in BAT. Moreover, exercise increased insulin receptor (IR) ratio (IRA/IRB ratio), IRA-insulin-like growth factor 1 receptor (IGF-1R) hybrids and p42/44 activation, and decreased IGF-1R expression and IR substrate 1 (p-IRS-1) (S307) indicating higher insulin sensitivity and favoring glucose uptake in BAT in response to chronic exercise training. In summary, the present study indicates that chronic exercise is able to improve the energetic profile of BAT in terms of increased mitochondrial function and insulin sensitivity.