Glucagon-like peptide-1 analog, liraglutide, regulates Sertoli cell energy metabolism.

Liraglutide, an analog of the incretin hormone glucagon-like peptide 1 (GLP-1), is widely used for obesity and type 2 diabetes treatment. However, there is scarce information about its effects on testicular function. Within the testis, Sertoli cells (SCs) provide nutritional support for germ cells; they metabolize glucose to lactate, which is delivered to germ cells to be used as a preferred energy substrate. Besides, SCs use fatty acids (FAs) as an energy source and store them as triacylglycerols (TAGs) within lipid droplets (LDs), which serve as an important energy reserve. In the present study, 20-day-old rat SC cultures were used to assess whether liraglutide affects their metabolic functions related to nutritional support and lipid storage. The results show that liraglutide does not modify glucose consumption or lactate production. However, it increases TAG levels and LD content. These effects are accompanied by an increase in the mRNA levels of the fatty acid transporter FAT/CD36, glycerol-3-phosphate-acyltransferase 3, and perilipins 1 and 4. The participation of the cAMP/PKA signaling pathway was explored. We observed that H89 (a PKA inhibitor) decreases the LD upregulation elicited by liraglutide, and that dibutyryl cAMP increases LD content and the expression of related genes. In summary, liraglutide promotes lipid storage in SCs through the regulation of key regulatory genes involved in FA transport, TAG synthesis, and LD formation. Considering the importance of lipid storage in SC energetic homeostasis maintenance, we postulate that liraglutide might improve the overall energetic status of the seminiferous tubule.

Identification of Antioxidant Methyl Derivatives of Ortho-Carbonyl Hydroquinones That Reduce Caco-2 Cell Energetic Metabolism and Alpha-Glucosidase Activity.

α-glucosidase, a pharmacological target for type 2 diabetes mellitus (T2DM), is present in the intestinal brush border membrane and catalyzes the hydrolysis of sugar linkages during carbohydrate digestion. Since α-glucosidase inhibitors (AGIs) modulate intestinal metabolism, they may influence oxidative stress and glycolysis inhibition, potentially addressing intestinal dysfunction associated with T2DM. Herein, we report on a study of an ortho-carbonyl substituted hydroquinone series, whose members differ only in the number and position of methyl groups on a common scaffold, on radical-scavenging activities (ORAC assay) and correlate them with some parameters obtained by density functional theory (DFT) analysis. These compounds' effect on enzymatic activity, their molecular modeling on α-glucosidase, and their impact on the mitochondrial respiration and glycolysis of the intestinal Caco-2 cell line were evaluated. Three groups of compounds, according their effects on the Caco-2 cells metabolism, were characterized: group A (compounds 2, 3, 5, 8, 9, and 10) reduces the glycolysis, group B (compounds 1 and 6) reduces the basal mitochondrial oxygen consumption rate (OCR) and increases the extracellular acidification rate (ECAR), suggesting that it induces a metabolic remodeling toward glycolysis, and group C (compounds 4 and 7) increases the glycolysis lacking effect on OCR. Compounds 5 and 10 were more potent as α-glucosidase inhibitors (AGIs) than acarbose, a well-known AGI with clinical use. Moreover, compound 5 was an OCR/ECAR inhibitor, and compound 10 was a dual agent, increasing the proton leak-driven OCR and inhibiting the maximal electron transport flux. Additionally, menadione-induced ROS production was prevented by compound 5 in Caco-2 cells. These results reveal that slight structural variations in a hydroquinone scaffold led to diverse antioxidant capability, α-glucosidase inhibition, and the regulation of mitochondrial bioenergetics in Caco-2 cells, which may be useful in the design of new drugs for T2DM and metabolic syndrome.

The impact of settleable atmospheric particulate on the energy metabolism, biochemical processes, and behavior of a sentinel mangrove crab.

We use the sentinel mangrove crab, Minuca rapax, as a model to investigate the effects of metallic settleable particulate matter (SePM) on wetland. Multiple levels of energetic responses, including (i) metabolic rate and energy budget, (ii) oxidative stress, and (iii) behavioral response by righting time, were assessed as well as the metal and metalloid content in crabs exposed to 0, 0.1 and 1 g.L-1 of SePM, under emerged and submerged conditions over five days, simulating the rigors of the intertidal habitat. Al, Fe, Mn, Cr, and Y exhibited a concentration-dependent increase. Metal concentrations were higher in submerged crabs due to the continuous ingestion of SePM and direct exposure through gills. Exposure concentration up to 1 g.L-1 decreased metabolic rate and enzymatic activities, reduced assimilation efficiency and energy for maintenance, and induces a slower response to righting time, probably by metal effects on nervous system and energy deficits. In conclusion, SePM exposure affects the redox status and physiology of M. rapax depending on he submersion regime and SePM concentration. The disruption to the energy budget and the lethargic behavior in M. rapax exposed to SePM implies potential ecological alterations in the mangrove ecosystem with unknown consequences for the local population.

Kinin B1 receptor deficiency promotes enhanced adipose tissue thermogenic response to ß3-adrenergic stimulation.

OBJECTIVE AND DESIGN: Kinin B1 receptor (B1R) has a key role in adipocytes to protect against obesity and glycemic metabolism, thus becoming a potential target for regulation of energy metabolism and adipose tissue thermogenesis. MATERIAL OR SUBJECTS: Kinin B1 knockout mice (B1KO) were subjected to acute induction with CL 316,243 and chronic cold exposure. METHODS: Metabolic and histological analyses, gene and protein expression and RNA-seq were performed on interscapular brown adipose tissue (iBAT) and inguinal white adipose tissue (iWAT) of mice. RESULTS: B1KO mice, under acute effect of CL 316,243, exhibited increased energy expenditure and upregulated thermogenic genes in iWAT. They were also protected from chronic cold, showing enhanced non-shivering thermogenesis with increased iBAT mass (~ 90%) and recruitment of beige adipocytes in iWAT (~ 50%). Positive modulation of thermogenic and electron transport chain genes, reaching a 14.5-fold increase for Ucp1 in iWAT. RNA-seq revealed activation of the insulin signaling pathways for iBAT and oxidative phosphorylation, tricarboxylic acid cycle, and browning pathways for iWAT. CONCLUSION: B1R deficiency induced metabolic and gene expression alterations in adipose tissue, activating thermogenic pathways and increasing energy metabolism. B1R antagonists emerge as promising therapeutic targets for regulating obesity and associated metabolic disorders, such as inflammation and diabetes.

Nicotinamide riboside Induced Energy Stress and Metabolic Reprogramming in BEAS-2B Cells.

Nicotinamide riboside (NR), a NAD+ precursor, has received attention due to several health benefits it has induced in experimental models. Studies in cultured cells, animals, and humans consistently show increased NAD+ availability after NR supplementation, which is considered the only mode of NR action that leads to health benefits. In the present study, we show that a persistently low NR concentration (1 µM) in the growth medium of BEAS-2B human cells, grown in a monolayer, induces energy stress, which precedes a cellular NAD+ increase after 192 h. NR concentrations greater than 1 µM under the specified conditions were cytotoxic in the 2D cell culture model, while all concentrations tested in the 3D cell culture model (BEAS-2B cell spheroids exposed to 1, 5, 10, and 50 µM NR) induced apoptosis. Shotgun proteomics revealed that NR modulated the abundance of proteins, agreeing with the observed effects on cellular energy metabolism and cell growth or survival. Energy stress may activate pathways that lead to health benefits such as cancer prevention. Accordingly, the premalignant 1198 cell line was more sensitive to NR cytotoxicity than the phenotypically normal parent BEAS-2B cell line. The role of a mild energy stress induced by low concentrations of NR in its beneficial effects deserves further investigation. On the other hand, strategies to increase the bioavailability of NR require attention to toxic effects that may arise.

STAT5 Is Necessary for the Metabolic Switch Induced by IL-2 in Cervical Cancer Cell Line SiHa.

The tumor cells reprogram their metabolism to cover their high bioenergetic demands for maintaining uncontrolled growth. This response can be mediated by cytokines such as IL-2, which binds to its receptor and activates the JAK/STAT pathway. Some reports show a correlation between the JAK/STAT pathway and cellular metabolism, since the constitutive activation of STAT proteins promotes glycolysis through the transcriptional activation of genes related to energetic metabolism. However, the role of STAT proteins in the metabolic switch induced by cytokines in cervical cancer remains poorly understood. In this study, we analyzed the effect of IL-2 on the metabolic switch and the role of STAT5 in this response. Our results show that IL-2 induces cervical cancer cell proliferation and the tyrosine phosphorylation of STAT5. Also, it induces an increase in lactate secretion and the ratio of NAD+/NADH, which suggest a metabolic reprogramming of their metabolism. When STAT5 was silenced, the lactate secretion and the NAD+/NADH ratio decreased. Also, the expression of HIF1α and GLUT1 decreased. These results indicate that STAT5 regulates IL-2-induced cell proliferation and the metabolic shift to aerobic glycolysis by regulating genes related to energy metabolism. Our results suggest that STAT proteins modulate the metabolic switch in cervical cancer cells to attend to their high demand of energy required for cell growth and proliferation.

Melatonin changes energy metabolism and reduces oncogenic signaling in ovarian cancer cells.

Ovarian cancer (OC) adjusts energy metabolism in favor of its progression and dissemination. Because melatonin (Mel) has antitumor actions, we investigated its impact on energy metabolism and kinase signaling in OC cells (SKOV-3 and CAISMOV-24). Cells were divided into control and Mel-treated groups, in the presence or absence of the antagonist luzindole. There was a decrease in the levels of HIF-1α, G6PDH, GAPDH, PDH, and CS after Mel treatment even in the presence of luzindole in both OC cells. Mel treatment also reduced the activity of OC-related enzymes including PFK-1, G6PDH, LDH, CS, and GS whereas PDH activity was increased. Lactate and glutamine levels dropped after Mel treatment. Mel further promoted a reduction in the concentrations of CREB, JNK, NF-kB, p-38, ERK1/2, AKT, P70S6K, and STAT in both cell lines. Mel reverses Warburg-type metabolism and possibly reduces glutaminolysis, thereby attenuating various oncogenic molecules associated with OC progression and invasion.

Effects of methylphenidate on mitochondrial dynamics and bioenergetics in the prefrontal cortex of juvenile rats are sex-dependent.

Methylphenidate (MPH) is a central nervous system stimulant drug and a first order prescription in the treatment of Attention Deficit Hyperactivity Disorder (ADHD). Although MPH biochemistry in neurodevelopment is not completely understood, studies showed it alters energy metabolism in rat brains. ADHD prevalence during neurodevelopment is related to males and the investigation has been mainly done in these subjects, therefore, little is known about MPH action in females and, consequently, about sexual dimorphism. In the present study we evaluated markers of mitochondrial dynamics (DRP1 and MFN2, fission and fusion, respectively), biogenesis (mtTFA) and bioenergetics (respiratory chain complexes) in prefrontal cortex of male and female juvenile rats submitted to exposure to MPH to better understand MPH effect during postnatal neurodevelopment. ATP and oxidative stress levels were also evaluated. Wistar rats received intraperitoneal injection of MPH (2.0 mg/kg) or control (saline), once a day, from 15th to 45th day of age. Results showed that MPH increased DRP1 and decreased MFN2, as well as increased mtTFA in prefrontal cortex of male rats. In female, MPH decreased NRF1 and increased Parkin, which are mitochondrial regulatory proteins. Respiratory chain complexes (complex I, SDH, complexes III and IV), ATP production and oxidative stress parameters were altered and shown to be sex-dependent. Taken together, results suggest that chronic MPH exposure at an early age in healthy animals changes mitochondrial dynamics, biogenesis and bioenergetics differently depending on the sex of the subjects.

Chronic Cadmium Exposure can Alter Energy Allocation to Physiological Functions in the Shrimp Penaeus vannamei.

Environmental stressors in aquatic organisms can be assessed using a bioenergetic approach based on the evaluation of changes in their physiological parameters. We evaluated the chronic effects of cadmium (Cd2+) on the energy balance as well as the survival, growth, metabolism, nitrogen excretion, hepatosomatic index, oxidized energy substrate, and osmoregulation of the shrimp Penaeus vannamei with the hypothesis that the high energy demand related to the homeostatic regulation of Cd2+could disrupt the energy balance and as a consequence, their physiological functions. The shrimp exposed to Cd2+ had higher mortality (30%), directed more energy into growth (33% of energy intake), ingested 10% more energy, and defecated less than control animals. Cd2+ exposure caused a tendency to decrease metabolism and ammonia excretion but did not alter the hepatosomatic index, type of energy substrate oxidized, and the hyperosmorregulatory pattern of the species. The Cd+2 exposure may have induced a trade-off response because there was a growth rate increase accompanied by increased mortality.

Multiprotease improves amino acid release in vitro, energy, and nutrient utilization in broilers fed diets varying in crude protein levels.

Low crude protein (CP) diets can reduce nitrogen (N) excretion and costs by increasing N utilization efficiency. Exogenous proteases may further improve protein digestibility in low CP diets. This study first evaluated in vitro the efficacy of a multiprotease on amino acid (AA) release from feedstuffs and broiler feed. Later, a broiler study evaluated the effect of feeding corn-soybean meal diets containing 3 CP levels (17, 19, and 21% CP) with supplementation on top of 0 or 2,400 U/kg multiprotease on chicken growth performance, total tract CP, and ileal AA digestibilities, and energy utilization. Ross 708 male chickens were placed in 42 cages and assigned to 6 treatments resulting from a 3 × 2 factorial arrangement. Three isocaloric basal diets were formulated to reduce CP, but all diets maintained digestible Lys:CP in 5.47% and the same ideal protein profile. Data were analyzed in a completely randomized design. On average, the multiprotease increased (P < 0.05) in vitro free AA release by 27.81% in most feedstuffs evaluated compared to the control. For broiler feed, 1,200 U/g multiprotease addition improved (P < 0.001) in vitro free AA release by 18.90%. This multiprotease showed interaction effects (P < 0.05) on chicken FCR, energy, and CP digestibility. As expected, BW at 24 d, BW gain, and FCR (8-24 d) worsened (P < 0.001) as dietary CP reduced from 21 to 17%, and multiprotease addition did not improve (P > 0.05) these parameters. BW gain decreased by 12.9% when N intake was reduced from 49.32 to 38.49 g/bird. Multiprotease supplementation improved (P < 0.01) AMEn by 71 kcal/kg, CP digestibility from 59.45 to 63.51%, ileal AA digestibility, and DM digestibility from 67.08 to 73.49%, but only in the 21% CP diet. No differences in ileal AA digestibility due to CP level (P > 0.05) were detected, except for Cys digestibility (P < 0.01). In conclusion, low CP diets reduced growth performance and improved N utilization but negatively affected energy utilization efficiency. Exogenous multiprotease supplementation improved AME, AMEn, protein, ileal AA, and DM digestibility in the 21% CP diet without significantly affecting growth performance.

Efectos cardiovasculares de los inhibidores del cotransportador 2 de sodio-glucosa (ISGLT2): los mecanismos del beneficio en pacientes con insuficiencia cardíaca / Cardiovascular effects of sodium-glucose co-transporter 2 inhibitors (ISGLT2)

La insuficiencia cardíaca (IC) es un problema de salud mundial. En la actualidad existe una clara asociación entre la IC y la diabetes mellitus tipo 2 (DM2), con una prevalencia cada vez mayor de pacientes que presentan concomitantemente ambas patologías. Los inhibidores del cotransportador 2 de sodio-glucosa (ISGLT2) han demostrado disminuir los eventos cardiovasculares, incluida la muerte de origen cardiovascular, por lo que se han instalado como uno de los pilares en su tratamiento. En el presente artículo se describen los principales mecanismos de acción de los ISGLT2 y sus efectos: mejora de condiciones de carga ventricular, metabolismo cardíaco, bioenergética, remodelado ventricular y sus efectos cardioprotectores directos y posiblemente antiarrítmicos.

Heart failure (HF) is a global health problem. Currently there is a clear association between HF and type 2 diabetes mellitus (DM2), with an increasing prevalence of patients presenting with both pathologies concomitantly. Sodium-glucose cotransporter 2 inhibitors (ISGLT2) have shown to significantly reduce cardiovascular events, including cardiovascular death. These results have placed ISGLT2 as one of the main pillars in the treatment of HF. This article will focus on the mechanisms of action, and their effects: improved ventricular loading conditions, cardiac metabolism, bioenergetics, ventricular remodeling, direct cardioprotective and possibly antiarrhythmic effects.

Environmentally realistic concentrations of cocaine in seawater disturbed neuroendrocrine parameters and energy status in the marine mussel Perna perna.

Cocaine (COC) is a powerful illicit drug frequently detected in the aquatic environment. COC acts by inhibiting the reuptake of dopamine (DOPA) and 5-hydroxytryptamine (5-HT - serotonin) and causes endocrine disturbances in mammals. This study investigated similar effects from cocaine exposure in the marine mussel Perna perna, as well as neurotoxicity and energy imbalances. Mussels were exposed to COC (0.2 µg.L-1 and 2 µg.L-1) for periods of 48, 96, and 168 h. Acetylcholinesterase (AChE) was measured in adductor muscle tissue to determine neurotoxicity, and neurotransmitter levels (DOPA and 5-HT), monoamine oxidase (MAO) and cyclooxygenase (COX) activity, and energy status (mitrochondrial electron transport, MET, and total lipids, TLP) were evaluated in the mussels' gonads. COC decreased AChE activity in the mussels exposed to 0.2 µg.L-1 and 2 µg.L -1 after 168 h, and all concentrations of COC increased neurotransmitter levels. Increases in MET (0.2 µg.L -1, for all exposure periods) and TLP (0.2 µg.L 1 after 48 h, and 2 µg.L -1 after 96 h and 168 h) were also observed. No significant change was detected in MAO activity. COC also decreased COX activity in the mussels exposed to 0.2 µg.L -1 (48 h and 96 h) and 2 µg.L -1 (96 h). These results suggest that COC may compromise neurotransmitter levels and COX activity. Furthermore, the changes in MET and LPT suggest that COC affects the energy balance of the mussels, and could negatively affect physiological processes such as metabolism, hormone production, and embryonic development.

Maternal high fructose diet exacerbates white adipose tissue thermogenic process in offspring upon exposure to cold temperature.

AIM: An adverse endogenous environment during early life predisposes to metabolic disorder development. We previously reported adverse metabolic and adipose tissue effects in adult male rats born to dams fed with a fructose-rich diet (FRD). The aim of this work was to determine the effect of a FRD consumed by the pregnant mother on the white adipose tissue (WAT) browning capacity of male offspring at adulthood. MAIN METHODS: Adult SD male offspring from control (C) and FRD-fed mothers were exposed during one week to a cold stimulus. WAT browning capacity was studied through in vivo and in vitro approaches. KEY FINDINGS: After cold exposure, WAT browning was higher in fructose-programmed animals as evidenced by an increase in ucp-1 gene expression, protein levels, and higher UCP-1 positive foci. Moreover, pgc1-α gene expression was increased. In vitro studies showed a lower adipogenic capacity in cells of prenatally fructose-exposed animals differentiated with a white differentiation cocktail, while a higher ucp-1 expression was noted when their cells were treated with a pro-beige differentiation cocktail. SIGNIFICANCE: For the first time we demonstrate that pre-natal fructose exposure predisposes programmed male rats to a higher WAT browning-induced response, under stimulated conditions, despite an apparent lower basal thermogenic capacity. These results should be considered in future studies to generate new therapeutic approaches to deal with adverse programming malnutrition effects.

Increased oxidative stress contributes to enhance brain amyloidogenesis and blunts energy metabolism in sucrose-fed rat: effect of AMPK activation.

Metabolic disturbances are linked to neurodegenerative diseases such as Alzheimer disease (AD). However, the cellular mechanisms underlying this connection are unclear. We evaluated the role of oxidative stress (OS), during early metabolic syndrome (MetS), on amyloidogenic processes in a MetS rat model induced by sucrose. MetS caused OS damage as indicated by serum and hypothalamus lipid peroxidation and elevated serum catalase activity. Tissue catalase and superoxide dismutase activity were unchanged by MetS, but gene expression of nuclear factor erythroid-derived 2-like 2 (NFE2L2), which up-regulates expression of antioxidant enzymes, was higher. Expression of amyloid-ß cleaving enzyme 1 (BACE-1) and amyloid precursor protein (APP), key proteins in the amyloidogenesis pathway, were slightly increased by sucrose-intake in the hippocampus and hypothalamus. Activation and expression of protein kinase B (PKB) and AMP-dependent protein kinase (AMPK), pivotal proteins in metabolism and energy signaling, were similarly affected in the hippocampus and hypothalamus of MetS rats. Brain creatine kinase activity decreased in brain tissues from rats with MetS, mainly due to irreversible oxidation. Chronic metformin administration partially reversed oxidative damage in sucrose-fed animals, together with increased AMPK activation; probably by modulating BACE-1 and NFE2L2. AMPK activation may be considered as a preventive therapy for early MetS and associated neurodegenerative diseases.

Effects of Growth Hormone Receptor Ablation in Corticotropin-Releasing Hormone Cells.

Corticotropin-releasing hormone (CRH) cells are the dominant neuronal population responsive to the growth hormone (GH) in the paraventricular nucleus of the hypothalamus (PVH). However, the physiological importance of GH receptor (GHR) signaling in CRH neurons is currently unknown. Thus, the main objective of the present study was to investigate the consequences of GHR ablation in CRH-expressing cells of male and female mice. GHR ablation in CRH cells did not cause significant changes in body weight, body composition, food intake, substrate oxidation, locomotor activity, glucose tolerance, insulin sensitivity, counterregulatory response to 2-deoxy-D-glucose and ghrelin-induced food intake. However, reduced energy expenditure was observed in female mice carrying GHR ablation in CRH cells. The absence of GHR in CRH cells did not affect anxiety, circadian glucocorticoid levels or restraint-stress-induced corticosterone secretion and activation of PVH neurons in both male and female mice. In summary, GHR ablation, specifically in CRH-expressing neurons, does not lead to major alterations in metabolism, hypothalamic-pituitary-adrenal axis, acute stress response or anxiety in mice. Considering the previous studies showing that central GHR signaling regulates homeostasis in situations of metabolic stress, future studies are still necessary to identify the potential physiological importance of GH action on CRH neurons.

Effects of long-term consumption of sucralose associated with high-fat diet in male mice.

Sucralose is a widely consumed non-nutritive sweetener (NNS). Studies have shown that some NNS can favor weight gain by altering the intestinal microbiota, satiety hormone production, or aspects related to glucose homeostasis. In this study, we investigated the effects of ad libitum sucralose consumption in mice fed with normal or high-fat diet (HFD) for an extended period (16 weeks). Weight gain, final body composition, energy expenditure, intestinal and pancreatic hormone production, and endotoxemia during a voracity test, as well as liver and skeletal muscles were evaluated after 16 weeks. We observed that sucralose supplementation reduced weight gain in HFD-fed mice but did not change weight gain in mice fed with normal diet. The evaluation of HFD mice showed that sucralose supplementation resulted in improvements in glycemic homeostasis, hepatic steatosis, and increased energy expenditure. Our results suggest that sucralose consumption promotes different outcomes in relation to weight gain when combined with different diets, which may explain the controversial data in previous studies, and can be considered in future clinical research aimed at clarifying the impact of NNS consumption on human health.

Energy homeostasis deregulation is attenuated by TUDCA treatment in streptozotocin-induced Alzheimer's disease mice model.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. While cognitive deficits remain the major manifestation of AD, metabolic and non-cognitive abnormalities, such as alterations in food intake, body weight and energy balance are also present, both in AD patients and animal models. In this sense, the tauroursodeoxycholic acid (TUDCA) has shown beneficial effects both in reducing the central and cognitive markers of AD, as well as in attenuating the metabolic disorders associated with it. We previously demonstrated that TUDCA improves glucose homeostasis and decreases the main AD neuromarkers in the streptozotocin-induced AD mouse model (Stz). Besides that, TUDCA-treated Stz mice showed lower body weight and adiposity. Here, we investigated the actions of TUDCA involved in the regulation of body weight and adiposity in Stz mice, since the effects of TUDCA in hypothalamic appetite control and energy homeostasis have not yet been explored in an AD mice model. The TUDCA-treated mice (Stz + TUDCA) displayed lower food intake, higher energy expenditure (EE) and respiratory quotient. In addition, we observed in the hypothalamus of the Stz + TUDCA mice reduced fluorescence and gene expression of inflammatory markers, as well as normalization of the orexigenic neuropeptides AgRP and NPY expression. Moreover, leptin-induced p-JAK2 and p-STAT3 signaling in the hypothalamus of Stz + TUDCA mice was improved, accompanied by reduced acute food intake after leptin stimulation. Taken together, we demonstrate that TUDCA treatment restores energy metabolism in Stz mice, a phenomenon that is associated with reduced food intake, increased EE and improved hypothalamic leptin signaling. These findings suggest treatment with TUDCA as a promising therapeutic intervention for the control of energy homeostasis in AD individuals.

Acute melatonin administration improves exercise tolerance and the metabolic recovery after exhaustive effort.

The present study investigated the effects of acute melatonin administration on the biomarkers of energy substrates, GLUT4, and FAT/CD36 of skeletal muscle and its performance in rats subjected to exhaustive swimming exercise at an intensity corresponding to the maximal aerobic capacity (tlim). The incremental test was performed to individually determine the exercise intensity prescription and 48 h after, the animals received melatonin (10 mg·kg-1) or vehicles 30 min prior to tlim. Afterwards, the animals were euthanized 1 or 3 h after the exhaustion for blood and muscles storage. The experiment 1 found that melatonin increased the content of glycogen and GLUT4 in skeletal muscles of the animals that were euthanized 1 (p < 0.05; 22.33% and 41.87%) and 3 h (p < 0.05; 37.62% and 57.87%) after the last procedures. In experiment 2, melatonin enhanced the tlim (p = 0.01; 49.42%), the glycogen content (p < 0.05; 40.03%), GLUT4 and FAT/CD36 in exercised skeletal muscles (F = 26.83 and F = 25.28, p < 0.01). In summary, melatonin increased energy substrate availability prior to exercise, improved the exercise tolerance, and accelerated the recovery of muscle energy substrates after the tlim, possibly through GLUT4 and FAT/CD36.

Suppression of Mitochondria-Related Bioenergetics Collapse and Redox Impairment by Tanshinone I, a Diterpenoid Found in Salvia miltiorrhiza Bunge (Danshen), in the Human Dopaminergic SH-SY5Y Cell Line Exposed to Chlorpyrifos.

Tanshinone I (T-I, C18H12O3) is a diterpene found in Salvia miltiorrhiza Bunge (Danshen) and promotes cytoprotection in several experimental models. Chlorpyrifos (CPF) is an agrochemical that causes bioenergetics failure, redox impairment, inflammation, and cell death in animal tissues. Here, we investigated whether T-I would be able to prevent the consequences resulting from the exposure of the human dopaminergic SH-SY5Y cells to CPF. We found that a pretreatment with T-I at 2.5 µM for 2 h suppressed lipid peroxidation and protein carbonylation and nitration on the membranes of mitochondria extracted from the CPF-treated cells. Also, T-I reduced the production of radical superoxide (O2-•) by the mitochondria of the CPF-challenged cells. The production of nitric oxide (NO•) and hydrogen peroxide (H2O2) was also decreased by T-I in the cells exposed to CPF. The CPF-induced decrease in the activity of the complexes I-III, II-III, and V was abolished by a pretreatment with T-I. Loss of mitochondrial membrane potential (ΔΨm) and reduction in the production of adenosine triphosphate (ATP) were also prevented by T-I in the CPF-treated cells. T-I also induced anti-inflammatory effects in the CPF-treated cells by decreasing the levels of interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) and the activity of the nuclear factor-κB (NF-κB). Inhibition of heme oxygenase-1 (HO-1) or silencing of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) blocked the T-I-promoted mitochondrial protection and anti-inflammatory action. Overall, T-I depended on the Nrf2/HO-1 axis to prevent the deleterious effects caused by CPF in this experimental model.

Experimental evidence of tyrosine neurotoxicity: focus on mitochondrial dysfunction.

Tissue exposure to high levels of tyrosine, which is characteristic of an inborn error of metabolism named Tyrosinemia, is related to severe symptoms, including neurological alterations. The clinical manifestations and pathogenesis of tyrosine neurotoxicity can be recapitulated in experimental models in vivo and in vitro. A widely used experimental model to study brain tyrosine damage is the chronic and acute administration of this amino acid in infant rats. Other research groups and we have extensively studied the pathogenic events in the brain structures of rats exposed to high tyrosine levels. Rats administered acutely and chronically with tyrosine presented decreased and inhibition of the essential metabolism enzymes, e.g., Krebs cycle enzymes and mitochondrial respiratory complexes in the brain structures. These alterations induced by tyrosine toxicity were associated with brain oxidative stress, astrocytes, and, ultimately, cognitive impairments. Notably, in vivo data were corroborated by in vitro studies using cerebral regions homogenates incubated with tyrosine excess. Considering metabolism's importance to brain functioning, we hypothesized that mitochondrial and metabolic dysfunctions are closely related to neurological alterations induced by tyrosine neurotoxicity. Herein, we reviewed the main mechanisms associated with tyrosine neurotoxicity in experimental models, emphasizing the role of mitochondrial dysfunction.