Sidney B. Peres

Melatonin and the circadian entrainment of metabolic and hormonal activities in primary isolated adipocytes.

Abstract:  The aim of this work was to investigate the effect of the in vitro circadian‐like exposure to melatonin [in the presence or absence of insulin (Ins)] on the metabolism and clock gene expression in adipocytes. To simulate the cyclic characteristics of the daily melatonin profile, isolated rat adipocytes were exposed in a circadian‐like pattern to melatonin added to the incubating medium for 12 hr (mimicking the night), followed by an equal period without melatonin (mimicking the day) combined or not with Ins. This intermittent incubation was interrupted when four and a half 24‐hr cycles were fulfilled. At the end, either during the induced night (melatonin present) or the induced day (melatonin absent), the rates of lipolysis and D‐[U‐14C]‐glucose incorporation into lipids were estimated, in addition to the determination of lipogenic [glucose‐6‐phosphate dehydrogenase and fatty acid synthase (FAS)] and lipolytic (hormone sensitive lipase) enzymes and clock gene (Bmal‐1b, Clock, Per‐1 and Cry‐1) mRNA expression. The leptin release was also measured. During the induced night, the following effects were observed: an increase in the mRNA expression of Clock, Per‐1 and FAS; a rise in lipogenic response and leptin secretion; and a decrease in the lipolytic activity. The intermittent exposure of adipocytes to melatonin temporally and rhythmically synchronized their metabolic and hormonal function in a circadian fashion, mimicking what is observed in vivo in animals during the daily light–dark cycle. Therefore, this work helps to clarify the physiological relevance of the circadian pattern of melatonin secretion and its interactions with Ins, contributing to a better understanding of the adipocyte biology.

Reduced lipolysis and increased lipogenesis in adipose tissue from pinealectomized rats adapted to training

Abstract:  The current study investigated the effects of chronic training and pinealectomy on the lipogenic and lipolytic activity of adipose tissue. Pinealectomized and sham‐operated adult male Wistar rats were distributed in to four subgroups: pinealectomized untrained, pinealectomized trained, control untrained and control trained. At the end of the training period (8 wk) the rats were killed. Blood samples were collected for glucose, insulin and leptin determinations. Peri‐epididymal adipocytes were isolated for measurement of in vitro rates of lipolysis and incorporation of substrates (d‐[U‐14C]‐glucose, l‐[U‐14C]‐lactate, [2‐14C]‐acetate and [1‐14C]‐palmitate) into lipids, and samples of epididymal adipose tissue were homogenized for evaluation of glucose‐6‐phosphate dehydrogenase maximal activity. Pinealectomy resulted in a significantly increased lipolytic capacity in response to isoproterenol and a decrease in circulating leptin levels without affecting the rates of incorporation of different substrates into lipids. However, only in the intact control group did training promote a higher basal and isoproterenol‐stimulated lipolysis, increase the incorporation of palmitate (esterification), decrease the incorporation of acetate (lipogenesis) into lipids and diminish circulating leptin levels. These effects of exercise training were not seen in pinealectomized rats. However, pinealectomized trained animals showed a marked reduction in lipolysis and an increased rate of acetate incorporation. In conclusion, we demonstrated for the first time that the pineal gland plays an important role in the regulation of lipid metabolism in such a way that its absence caused a severe alteration in the balance between lipogenesis and lipolysis, which becomes evident with the adaptation to exercise training.

Pinealectomy impairs adipose tissue adaptability to exercise in rats

Abstract:  This study investigated the effects of pinealectomy and exercise training on rat adipose tissue metabolism. Pinealectomized (PINX) and sham‐operated (CONTROL) adult male Wistar rats were subdivided into four subgroups, including PINX untrained, PINX trained, CONTROL untrained and CONTROL trained. At the end of the training period (8 wk), the rats were killed and peri‐epididymal adipocytes were isolated for in vitro insulin‐stimulated glucose uptake, conversion of d‐[U‐14C]‐glucose, l‐[U‐14C]‐lactate, [2‐14C]‐acetate and [1‐14C]‐palmitate into 14CO2, and insulin binding. Pinealectomy resulted in a significantly decreased insulin‐stimulated glucose uptake in adipocytes without affecting insulin‐binding capacity. However, in intact control animals only, training promoted a higher baseline glucose uptake in adipocytes. Training influenced the adipocyte ability to oxidize the different substrates: the rates of glucose and palmitate oxidation increased while the rates of lactate and acetate diminished. Nevertheless, these effects of exercise training were not seen in pinealectomized rats. Additionally, an increase in palmitate oxidation was observed in sedentary pinealectomized animals. In conclusion, these data show that the pineal gland alters the patterns of substrate utilization by the adipocyte, in such a way that its absence disrupts the ability to adapt to the metabolic demands evoked by exercise training in rats.

Pinealectomy reduces hepatic and muscular glycogen content and attenuates aerobic power adaptability in trained rats

Abstract:  The current study emphasizes the crucial role of the pineal gland on the effects of chronic training in different tissues focusing on carbohydrate metabolism. We investigated the maximal oxygen uptake (aerobic power), muscle and liver glycogen content, and also the enzymes involved in the carbohydrate metabolism of rat adipose tissue. Pinealectomized and sham‐operated adult male Wistar rats were distributed into four groups: pinealectomized (PINX) untrained, pinealectomized trained, control untrained and control trained. The maximal oxygen uptake capability was assayed before and after the training protocol by indirect open circuit calorimetry. The rats were killed after 8 wk of training. Blood samples were collected for glucose and insulin determinations. The glycogen content was assayed in the liver and muscle. Maximal activities of epididymal adipose tissue enzymes (hexokinase, pyruvate kinase, lactate dehydrogenase, citrate synthase and malic enzyme) as well as adipocyte size were determined. The exercise training in control animals promoted an increase in the aerobic power and in liver glycogen content but caused a reduction in the malic enzyme activity in adipose tissue. However, PINX trained animals, in contrast to trained controls, showed a decrease in the aerobic power and in liver and muscle glycogen content, as well as an increase in the activity of the adipocyte enzymes involved in carbohydrate metabolism. In conclusion, these data show that the pineal gland integrity is necessary for the homeostatic control of energy metabolism among adipose, muscle and hepatic tissues. The pinealectomized animals showed alterations in adaptive responses of the maximal oxygen uptake to training. Therefore, the pineal gland must be considered an influential participant in the complex adaptation to exercise and is involved in the improvement of endurance capacity.

Pioglitazone Treatment Increases Survival and Prevents Body Weight Loss in Tumor–Bearing Animals: Possible Anti-Cachectic Effect

Cachexia is a multifactorial syndrome characterized by profound involuntary weight loss, fat depletion, skeletal muscle wasting, and asthenia; all symptoms are not entirely attributable to inadequate nutritional intake. Adipose tissue and skeletal muscle loss during cancer cachexia development has been described systematically. The former was proposed to precede and be more rapid than the latter, which presents a means for the early detection of cachexia in cancer patients. Recently, pioglitazone (PGZ) was proposed to exhibit anti-cancer properties, including a reduction in insulin resistance and adipose tissue loss; nevertheless, few studies have evaluated its effect on survival. For greater insight into a potential anti-cachectic effect due to PGZ, 8-week-old male Wistar rats were subcutaneously inoculated with 1 mL (2×107) of Walker 256 tumor cells. The animals were randomly assigned to two experimental groups: TC (tumor + saline-control) and TP5 (tumor + PGZ/5 mg). Body weight, food ingestion and tumor growth were measured at baseline and after removal of tumor on days 7, 14 and 26. Samples from different visceral adipose tissue (AT) depots were collected on days 7 and 14 and stored at -80o C (5 to 7 animals per day/group). The PGZ treatment showed an increase in the survival average of 27.3% (P< 0.01) when compared to TC. It was also associated with enhanced body mass preservation (40.7 and 56.3%, p< 0.01) on day 14 and 26 compared with the TC group. The treatment also reduced the final tumor mass (53.4%, p<0.05) and anorexia compared with the TC group during late-stage cachexia. The retroperitoneal AT (RPAT) mass was preserved on day 7 compared with the TC group during the same experimental period. Such effect also demonstrates inverse relationship with tumor growth, on day 14. Gene expression of PPAR-γ, adiponectin, LPL and C/EBP-α from cachectic rats was upregulated after PGZ. Glucose uptake from adipocyte cells (RPAT) was entirely re-established due to PGZ treatment. Taken together, the results demonstrate beneficial effects of PGZ treatment at both the early and final stages of cachexia.

Effects of 16 Weeks of Concurrent Training on Resting Heart Rate Variability and Cardiorespiratory Fitness in People Living With HIV/AIDS Using Antiretroviral Therapy: A Randomized Clinical Trial.

Abstract Pedro, RE, Guariglia, DA, Okuno, NM, Deminice, R, Peres, SB, and Moraes, SMF. Effects of 16 weeks of concurrent training on resting heart rate variability and cardiorespiratory fitness in people living with HIV/AIDS using antiretroviral therapy: a randomized clinical trial. J Strength Cond Res 30(12): 3494–3502, 2016—The study evaluated the effects of concurrent training on resting heart rate variability (HRVrest) and cardiorespiratory fitness in people living with HIV/AIDS undergoing antiretroviral therapy (ART). Fifty-eight participants were randomized into 2 groups (control and training group); however, only 33 were analyzed. The variables studied were HRVrest indices, submaximal values of oxygen uptake (V[Combining Dot Above]O2sub) and heart rate (HR5min), peak speed (Vpeak), and peak oxygen uptake (V[Combining Dot Above]O2peak). The training group performed concurrent training (15–20 minutes of aerobic exercise plus 40 minutes of resistance exercise), 3 times per week, for 16 weeks. Posttraining V[Combining Dot Above]O2peak and Vpeak increased, and HR5min decreased. Resting heart rate variability indices did not present statistical differences posttraining; however, the magnitude-based inferences demonstrated a “possibly positive effect” for high frequency (HF) and low frequency (LF) plus high frequency (LF + HF) and a “likely positive effect” for R-Rmean posttraining. In conclusion, concurrent training was effective at improving cardiorespiratory fitness and endurance performance. Moreover, it led to probably a positive effect on HF and a likely positive effect on R-Rmean in people living with HIV/AIDS undergoing ART.

Exercise improves cytokine profile in HIV-infected people: A randomized clinical trial

Purpose Verify the effects of concurrent training on cytokines in people living with HIV under antiretroviral therapy (ART) treatment. Methods This was a blinded, parallel‐group, clinical trial, where 49 participants, divided in two groups, either control group or concurrent training group, took part in the intervention. The control group performed recreational activities and concurrent training group participated of 16‐week, 3 times per week of heart rate guided‐aerobic plus resistance training for major muscular groups. Cytokines (interleukins 4, 5, 6, 8, 10, tumor necrosis factor‐&agr;, interferon‐&ggr;, and granulocyte‐macrophage colony‐stimulating factor) were measured before and after 16‐week experimental period using flow cytometry. Results From 49 participants who took part in the intervention, 28 completed the program and had data analyzed. There was a significant interaction for IL‐8, which increased for control group: 7.1 ± 5.1 vs. 8.1 ± 6.0 and a decrease for concurrent training: 8.0 ± 4.4 vs. 5.4 ± 2.3. In addition, magnitude‐based inference showed a likely beneficial effect for the training group when compared to the control group for IL‐8, IL‐5, and IL‐10. The difference perceptual: mean and [CI 90%] between delta of difference within groups was −43.1 [−64.0 to −10.0] and ‐6.6 [−14.7 to 2.3], respectively. Conclusion Short‐term exercise is able to decrease the levels of IL‐5, IL‐8, and IL‐10 in HIV‐infected people undergoing ART. HighlightsConcurrent training was beneficial on circulating cytokines HIV‐infected people.Concurrent training decreases the pro‐inflammatory effects induced by ART.Some circulating cytokines were not changed after training in HIV‐infected people. Graphical abstract Figure. No Caption available.

Toll-Like Receptor-4 Disruption Suppresses Adipose Tissue Remodeling and Increases Survival During Cancer Cachexia Syndrome

Cancer-induced cachexia, characterized by systemic inflammation, body weight loss, adipose tissue (AT) remodeling and muscle wasting, is a malignant metabolic syndrome with undefined etiology. Here, we show that Toll-like receptor 4 (TLR4) mediates AT remodeling, in particular, AT browning and inflammatory response in mice bearing Lewis lung carcinoma (LLC). LLC tumor-bearing (TB) TLR4−/− mice were spared from AT remodeling due to a reduced macrophage infiltration and adipocyte atrophy. TLR4−/− mice were also resistant to cold-induced browning of subcutaneous AT (scAT). Importantly, pharmacological inhibition of TLR4 reproduced the main protective effect against AT remodeling found in TLR4−/− TB mice. Moreover, the treatment was effective in prolonging the survival and attenuating tumor mass growth when compared to non-treated-TB animals. Further, tumor-induced elevation of circulating pro-inflammatory cytokines was similarly abolished in both genetic ablation and pharmacological inhibition of TLR4. These data suggest that TLR4 is a critical mediator and a promising therapeutic target for cancer-induced AT remodeling. HIGHLIGHTS Genetic ablation and pharmacological inhibition of TLR4 attenuate adipose tissue remodeling during cancer-associated cachexia; TLR4 suppression play an essential role in the browning phenotype induced by cachexia; Administration of TLR4 drug inhibitor increase survival and reduces tumor mass growth in tumor bearing mice; TLR4 pathway is a promising target for cancer-cachexia therapeutic intervention.

Aerobic exercise training performed by parents reduces mice offspring adiposity

ABSTRACT The present study aimed to determine the effects of physical training performed by parents on mice offspring adiposity. Male and female parents underwent an aerobic training protocol for 7 weeks. The trained and sedentary parents were allowed to mate and the resultant offspring divided in: S (Offspring from Sedentary Parents), T (Offspring from Trained Parents), ST (Offspring from Sedentary Father and Trained Mother) and TS (Offspring from Trained Father and Sedentary Mother). After weaning, offspring was euthanized, blood collected and samples of mesenteric and inguinal fat pads used to isolate adipocytes for morphologic and histological analyses. Lee index, mesenteric fat pad, sum of visceral fat and total fat weight of female T was reduced in comparison to the other groups (p < 0.05). Periepididymal and sum of visceral fat in male T group was also reduced when compared to the other groups (p < 0.05). The diameter of mesenteric and inguinal adipocytes of T group was smaller compared to all groups comparisons for both sexes (p < 0.05). In summary, exercise training performed by parents reduced visceral offspring adiposity, the diameter of subcutaneous adipocytes and improved metabolic parameters associated to metabolic syndrome.

LLC tumor cells-derivated factors reduces adipogenesis in co-culture system

Cancer cachexia (CC) is a multifactorial syndrome with an unknown etiology. The primary symptom is the progressive reduction of the body weight. Recently, down-regulation of adipogenic and lipogenic genes were demonstrated to be early affected during cachexia progression in adipose tissue (AT), resulting in AT remodeling. Thus, this study aimed to evaluate in a co-culture system the influence of the Lewis Lung Carcinoma (LLC) tumor cells (c/c-LLC) in an established pre-adipocyte cell line 3T3-L1 adipogenic capacity. c/c-LLC in the presence of 3T3-L1 caused a reduction in lipids accumulation, suggesting that secretory tumor cells products may affect adipogenesis. Interestingly, a very early (day 2) down-regulation of proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein alpha (C/EBPα), followed by late genes (day 4 and 8), adiponectin, perilipin, and fatty acid-binding protein 4 (FABP4). Caspase-3 expression was increased on the last day of cell differentiation; it occurred in the expression of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α). Overall, our results suggest that LLC secretory products impair adipocyte differentiation in a co-culture system and increased apoptosis. In summary, our study has shown the inhibition of the adipogenic process in the 3T3-L1 co-culture system with LLC cells.