Metabolic dysfunction – associated steatotic liver disease (MASLD) has a high global prevalence, requiring effective therapeutic options. This study investigated the effects of liraglutide and kombucha, alone and in combination, in a murine model of high-fat diet (HFD)-induced MASLD. Metabolic parameters, body composition, liver histology, lipid profile, and markers of lipophagy were evaluated. The results demonstrate that liraglutide reduced body weight, fat mass, and lean mass, as well as food and caloric intake, fasting blood glucose, hepatic triglycerides (TG), steatosis, and fibrosis, improved the lipid profile and glucose tolerance, and increased lysosomal acid lipase (LAL) expression in the liver. Kombucha reduced lean mass, liver steatosis, hepatic TG, food and caloric intake, fasting blood glucose, low-density lipoprotein cholesterol (LDL-C), and liver fibrosis, in addition to improving glucose tolerance. However, the combination of treatments did not show synergistic effects superior to those of liraglutide alone. Although liraglutide independently impacted LAL expression, none of the other lipophagy markers were modulated in the liver, suggesting that the beneficial mechanisms of action are independent of the lipophagy pathway. It is concluded that both liraglutide and kombucha are valid strategies for mitigating MASLD, but the combination does not offer superior advantages over liraglutide monotherapy. ### Competing Interest Statement The authors have declared no competing interest. * MASLD : Metabolic dysfunction–associated steatotic liver disease LDL-C : Low-density lipoprotein cholesterol HFD : High-fat diet MASH : Metabolic dysfunction–associated steatohepatitis LAL : Lysosomal acid lipase GLP-1 : Glucagon-like peptide-1 FDA : Food and Drug Administration T2DM : Type 2 diabetes mellitus AUC : Area under the curve log10 : Base-10 logarithm oGTT : Oral glucose tolerance test TG : Triglycerides TC : Total cholesterol HDL-C : High-density lipoprotein cholesterol VLDL-C : Very low-density lipoprotein cholesterol ORO : Oil Red O H&E : Hematoxylin and Eosin PSR : Picrosirius Red ALT : Alanine aminotransferase AST : Aspartate aminotransferase LC3-II : Microtubule-Associated Protein 1A/1B-Light Chain 3 p62 : Sequestosome-1 Atg7 : Autophagy Related 7 National Council for Scientific and Technological Development (CNPq), 140217/2022-3 São Paulo Research Foundation (FAPESP), 2016/25129-4, 2017/18972-0, 2021/10469-2

Purpose Grain-based control diets and purified diets are widely used in metabolic studies involving rodents, although their compositional differences may influence physiological outcomes and experimental interpretations. This study aimed to compare the metabolic profile of C57BL/6 mice fed a grain-based diet or a purified diet, both administered under normocaloric conditions. Methods Male C57BL/6 mice (7 weeks old) were fed a grain-based diet or a purified diet for 12 weeks. Body mass and composition, fasting blood glucose, oral glucose tolerance, and plasma lipid profile (triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol) were evaluated. Statistical analyses were conducted using an unpaired Student’s t-test (P ≤ 0.05). Results No significant differences were observed between groups in the evolution of body mass, body composition, fasting blood glucose, oral glucose tolerance, or plasma lipid parameters. Conclusion Under normocaloric conditions, grain-based or purified control diets produce equivalent metabolic profiles in C57BL/6 mice, supporting their interchangeable use as control diets in metabolic research studies. ### Competing Interest Statement The authors have declared no competing interest. National Council for Scientific and Technological Development (CNPq), 140217/2022-3 São Paulo Research Foundation (FAPESP), 2016/25129-4, 2017/18972-0, 2021/10469-2

The most common form of hypercortisolism is iatrogenic Cushing's syndrome. Lipodystrophy and metabolic disorders can result from the use of exogenous glucocorticoids (GC). Adipocytes play an important role in the production of circulating exosomal microRNAs, and knockdown of Dicer promotes lipodystrophy. The aim of this study is to investigate the effect of GCs on epididymal fat and to assess their influence on circulating microRNAs associated with fat turnover. The data indicate that despite the reduction in adipocyte volume due to increased lipolysis and apoptosis, there is no difference in tissue mass, suggesting that epididymal fat pad, related to animal size, is not affected by GC treatment. Although high concentrations of GC have no direct effect on epididymal microRNA-150-5p expression, GC can induce epididymal adipocyte uptake of microRNA-150-5p, which regulates transcription factor Ppar gamma during adipocyte maturation. In addition, GC treatment increased lipolysis and decreased glucose-derived lipid and glycerol incorporation. In conclusion, the similar control and GC epididymal fat mass results from increased dense fibrogenic tissue and decreased adipocyte volume induced by the lipolytic effect of GC. These findings demonstrate the complexity of epididymal fat. They also highlight how this disease alters fat distribution. This study is the first in a series published by our laboratory showing the detailed mechanism of adipocyte turnover in this disease.

Chronic and excessive glucocorticoid (GC) exposure can cause Cushing's syndrome, resulting in fat accumulation in selected body areas. Particularly in the brown adipose tissue (BAT), GC acts negatively, resulting in whitening of the tissue. We hypothesized that dysregulation of microRNAs by GC could be an additional mechanism to explain its negative actions in BAT. Male Wistar rats were divided into two groups: (1) Control sham and (2) GC group that was administered dexamethasone 6.25 mg/200 μL via osmotic pump implantation over 28 days. After this period, the animals were euthanized and BAT tissue was properly stored. Human fat cells treated with dexamethasone were used to translate the experimental results found in animals to human biology. GC-treated rat BAT presented with large lipid droplets, severely impaired thermogenic activation, and reduced glucose uptake measured by 18F-FDG PET/CT. GC exposure induced a reduction in the mitochondrial OXPHOS system and oxygen consumption. MicroRNA profiling of BAT revealed five top-regulated microRNAs and among them miR-21-5p was the most significantly upregulated in GC-treated rats compared to the control group. Although upregulation of miR-21-5p in the tissue, differentiated primary brown adipocytes from GC-treated rats had decreased miR-21-5p levels compared to the control group. To translate these results to the clinic, human brown adipocytes were treated with dexamethasone and miR-21-5p inhibitor. In human brown cells, inhibition of miR-21-5p increased brown adipocyte differentiation and prevented GC-induced glucose uptake, resulting in a lower glycolysis rate. In conclusion, high-dose GC therapy significantly impacts brown adipose tissue function, with a notable association between glucose uptake and miR-21-5p.

Background and objectivesVisceral adipocytes, typically larger and more pro-inflammatory than subcutaneous adipocytes, are less sensitive to insulin action and more susceptible to apoptosis. Melatonin is an anti-inflammatory, anti-apoptotic, and temporal cue to several tissues, including adipose tissue. The modern lifestyle often involves irregular sleep-wake cycles, exposure to artificial light at night, and shift work, all of which suppress nocturnal melatonin secretion and could disrupt adipose tissue homeostasis. This study aimed to examine the effect of pinealectomy on the temporal expression of core clock components and apoptosis-related transcripts and proteins in rat retroperitoneal (RP) adipose tissue.

BackgroundIntrauterine food restriction (IFR) during pregnancy is associated with low birth weight (LBW) and obesity in adulthood. It is known that white adipose tissue (WAT) plays critical metabolic and endocrine functions; however, this tissue’s behavior before weight gain and obesity into adulthood is poorly studied. Thus, we evaluated the repercussions of IFR on the lipogenesis and lipolysis processes in the offspring and described the effects on WAT inflammatory cytokine production and secretion.MethodsWe induced IFR by providing gestating rats with 50% of the necessary chow daily amount during all gestational periods. After birth, we monitored the offspring for 12 weeks. The capacity of isolated fat cells from mesenteric white adipose tissue (meWAT) to perform lipogenesis (14C-labeled glucose incorporation into lipids) and lipolysis (with or without isoproterenol) was assessed. The expression levels of genes linked to these processes were measured by real-time PCR. In parallel, Multiplex assays were conducted to analyze pro-inflammatory markers, such as IL-1, IL-6, and TNF-α, in the meWAT.ResultsTwelve-week-old LBW rats presented elevated serum triacylglycerol (TAG) content and attenuated lipogenesis and lipolysis compared to control animals. Inflammatory cytokine levels were increased in the meWAT of LBW rats, evidenced by augmented secretion by adipocytes and upregulated gene and protein expression by the tissue. However, there were no significant alterations in the serum cytokines content from the LBW group. Additionally, liver weight, TAG content in the hepatocytes and serum glucocorticoid levels were increased in the LBW group.ConclusionThe results demonstrate that IFR throughout pregnancy yields LBW offspring characterized by inhibited lipogenesis and lipolysis and reduced meWAT lipid storage at 12 weeks. The increased serum TAG content may contribute to the augmented synthesis and secretion of pro-inflammatory markers detected in the LBW group.

Chronic hypercortisolism has been associated with the development of several metabolic alterations, mostly caused by the effects of chronic glucocorticoid (GC) exposure over gene expression. The metabolic changes can be partially explained by the GC actions on different adipose tissues (ATs), leading to central obesity. In this regard, we aimed to characterize an experimental model of iatrogenic hypercortisolism in rats with significant AT redistribution. Male Wistar rats were distributed into control (CT) and GC-treated, which received dexamethasone sodium phosphate (0.5 mg/kg/day) by an osmotic minipump, for 4 weeks. GC-treated rats reproduced several characteristics observed in human hypercortisolism/Cushing's syndrome, such as HPA axis inhibition, glucose intolerance, insulin resistance, dyslipidemia, hepatic lipid accumulation, and AT redistribution. There was an increase in the mesenteric (meWAT), perirenal (prWAT), and interscapular brown (BAT) ATs mass, but a reduction of the retroperitoneal (rpWAT) mass compared to CT rats. Overexpressed lipolytic and lipogenic gene profiles were observed in white adipose tissue (WAT) of GC rats as BAT dysfunction and whitening. The AT remodeling in response to GC excess showed more importance than the increase of AT mass per se, and it cannot be explained just by GC regulation of gene transcription.

In adipose tissue, the expression of hundreds of genes exhibits circadian oscillation, which may or may not be affected by circulating melatonin levels. Using control and pinealectomized rats, we investigated the daily expression profile of Actb, Hprt-1, B2m, and Rpl37a, genes that are commonly used as reference genes for reverse transcription quantitative polymerase chain reaction (RT-qPCR), in epididymal (EP), retroperitoneal (RP), and subcutaneous (SC) adipose tissues. In control rats, Actb expression presented a daily oscillation in all adipose tissues investigated, Hprt-1 showed 24-h fluctuations in only RP and SC depots, B2m was stable over 24 h for EP and RP but oscillated over 24 h in SC adipose tissue, and Rpl37a presented a daily oscillation in only RP fat. In the absence of melatonin, the rhythmicity of Actb in all adipose depots was abolished, the daily rhythmicity of Hprt-1 and B2m was disrupted in SC fat, the peak expression of Rpl37a and Hprt-1 was delayed, and the amplitude of Rpl37a was reduced in RP adipose tissue. Collectively, our results demonstrate that the expression of putative reference genes displays a daily rhythm influenced by melatonin levels in a manner specific to the adipose depot. Thus, the proper standardization and daily profile expression of reference genes should be performed carefully in temporal studies using RT-qPCR analysis.

Aims: Previous work has demonstrated that ketogenic diets promote white fat browning; however, the exact mechanisms underlying this phenomenom have yet to be elucidated. Recently, an in vitro study showed that supraphysiological concentrations of beta-hydroxybutyrate (beta HB) had a strong influence on the induction of adipocyte browning. On the other hand, concentrations in the physiological range, achieved through ketogenic diets and prolonged fasting produce values of 1-3 mM and 4-7 mM, respectively. Herein, we investigated the impact of physiological concentrations of beta HB on metabolism, and the expression of uncoupling protein 1 (UCP1) and other browning markers in adipose tissues. Main methods: The effects of beta HB on adipocyte browning were investigated in vitro, using primary cultures of isolated visceral and subcutaneous fat cells and cultured 3T3-L1 adipocytes, and in vivo. Key findings: It was determined that beta HB failed to induce changes in the oxidative capacity, citrate synthase activity or browning gene expression patterns in isolated adipocytes, and did not exert a permissive effect on beta-adrenergic agonist-induced browning. In addition, 3T3-L1 adipocytes differentiated following beta HB treatment exhibited downregulated Ucpl expression levels, a result that was recapitulated in the subcutaneous adipose tissue of Wistar rats after beta HB salt treatment. Rats administered beta HB salts also presented reduced brown adipose tissue UCP1 protein expression. Significance: The mechanisms underlying ketogenic diet-induced browning of adipocytes are not known. The results from the present study indicate that physiological concentrations of beta HB are not responsible for this phenomenon, despite the observed beta HB-mediated downregulation of UCP1 expression.

Aims: We investigated the effects of physical detraining on lipogenesis/lipolysis and cellularity (apoptosis/adipogenesis) in rat subcutaneous (inguinal; SC) and visceral (retroperitoneal; RP) white adipose depots. Main methods: Three groups of male Wistar rats (6-wk old) were studied: (1) (T) trained for 12 weeks; (2) (D) trained for 8 weeks and detrained for 4 weeks; and (3) (S) age-matched sedentary. Training consisted of treadmill running sessions (1 h/day, 5 days/week, 50-60% maximal race capacity). Key findings: Physical detraining increased glucose oxidation, lipogenesis, and adipocyte size in the SC and RP depots. The number of apoptotic SC adipocytes was reduced by 53% in the T (p < 0.0001) and by 43% in the D (p < 0.001) as compared with S. RP adipocyte apoptosis in the T and D was 9.48% and 10.9% greater compared to the S, respectively (p < 0.05). In the SC stromal vascular fraction (SVF) of D rats, adiponectin, sterol regulatory element binding protein (SREBP)-1c, Peroxisome proliferator-activated receptor gamma (PPAR.), and Perilipin A mRNA expressions were more pronounced than S group, suggesting a more intense adipogenesis. This putative adipogenic effect was not observed in the RP depot. The physical detraining promoted rapid increase in the SC and RP depots however not through the same mechanisms. Significance: Physical detraining induced fat cell hypertrophy (increase of lipogenesis) in both SC and RP whereas hyperplasia (increase of adipogenesis and reduction of apoptosis) was found in SC only. These results indicate the mechanism associated with obesogenic effects of detraining varies with the fat depot.

AIMS:Melatonin treatment has been reported to be capable of ameliorating metabolic diabetes-related abnormalities but also to cause hypogonadism in rats. We investigated whether the combined treatment with melatonin and insulin can improve insulin resistance and other metabolic disorders in rats with streptozotocin-induced diabetes during neonatal period and the repercussion of this treatment on the hypothalamic-pituitary-gonadal axis.MAIN METHODS:At the fourth week of age, diabetic animals started an 8-wk treatment with only melatonin (0.2 mg/kg body weight) added to drinking water at night or associated with insulin (NHP, 1.5 U/100 g/day) or only insulin. Animals were then euthanized, and the subcutaneous (SC), epididymal (EP), and retroperitoneal (RP) fat pads were excised, weighed and processed for adipocyte isolation for morphometric analysis as well as for measuring glucose uptake, oxidation, and incorporation of glucose into lipids. Hypothalamus was collected for gene expression and blood samples were collected for biochemical assays.KEY FINDINGS:The treatment with melatonin plus insulin (MI) was capable of maintaining glycemic control. In epididymal (EP) and subcutaneous (SC) adipocytes, the melatonin plus insulin (MI) treatment group recovered the insulin responsiveness. In the hypothalamus, melatonin treatment alone promoted a significant reduction in kisspeptin-1, neurokinin B and androgen receptor mRNA levels, in relation to control group.SIGNIFICANCE:Combined treatment with melatonin and insulin promoted a better glycemic control, improving insulin sensitivity in white adipose tissue (WAT). Indeed, melatonin treatment reduced hypothalamic genes related to reproductive function.

Previous studies have shown that pinealectomy induces insulin resistance in rats. The present study aimed to verify whether pinealectomy modulates the expression of apoptosis‐related genes in rat subcutaneous adipose tissue (TA‐Sc). For this purpose, samples from the bank of frozen tissue of animals (Ethics Committee/Institute of Biomedical Sciences (ICB) Protocol No. 896/2017), belonging to the Laboratory of Adipose Tissue Physiology, University of Sao Paulo (USP), were used. The material came from Wistar rats (male and adults), whose were kept at the Experimentation Hall of the Department of Physiology and Biophysics of the ICB/USP and handled according to a certificate approved by the Ethics Committee on the Use of Animals (CEUA)/(03/10/2011, protocol no. 129) and standards established by the National Council for Control of Animal (CONCEA). The rats were housed in polypropylene boxes under controlled environmental conditions (25 ± 2 ºC) and light (12 h light/12 h dark), with water and standard ration for Nuvilab® rodents (Nuvital S/A, Colombo, PR) ad libitum. The animals, when completed 10 weeks old, were anesthetized and submitted to pinealectomy (P) by the method of Hoffman and Reiter (1965) or to the fictitious operation (C) and, following their recovery, they were kept in individual boxes. After four weeks of the surgery (14 weeks old) the animals P and C were killed by decapitation and inguinal TA‐Sc dissected. For the evaluation of gene expression related to apoptosis, samples of the Sc fat pad were submitted to the Total RNA Extraction stages; Synthesis of cDNA by Reverse Transcription and Polymerase Chain Reaction from cDNA (Real Time PCR). PCR reactions were performed by the StepOnePlus® Real Time PCR System (Applied Biosystems). The evaluated genes were: Caspases (3, 8, 9), Bax, Fas and BCL‐2. The data were analyzed according to the requirements of homoscedasticity and normality by means of the Shapiro‐Wilk test and later the Student's t‐test, unpaired and parametric. The 95% confidence interval and p value <0.05 were considered significant. The statistical program used was Graph Pad Prism version 6.0. The results showed that pinealectomy did not alter the expression of the anti and pro‐apoptotic genes evaluated (p> 0.05), with the exception of Caspase 9, whose gene expression was significantly reduced in group P in relation to C (Figure 1). In conclusion, pinealectomy is capable of selectively interfering with the gene expression of the apoptotic pathway, specifically in the caspase activator 9.Support or Funding InformationConselho Nacional de Desenvolvimento Científico e Tecnológico‐CNPqThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Chronic iatrogenic hypercortisolism, which is associated with the inhibition of the adrenal‐pituitary‐ hypothalamic axis, shows characteristic signs that are seen in different forms of Cushing's syndrome. In humans, fat redistribution with increased visceral obesity is one of the main metabolic changes in this syndrome that is related to the development of the metabolic syndrome (insulin resistance, dyslipidemia, and hypertension). However, the mechanisms of fat redistribution between different depots have not been fully elucidated yet, which can be clarified with the establishment of an experimental animal model for Cushing's syndrome.The aim of this study was to characterize the fat redistribution in an experimental model of hypercortisolism in rats (approved by the Ethics Committee in Animal Research [CEUA‐ICB/USP 89/2016]). Male Wistar SPF rats (12 weeks old) were used in experiments. The glucocorticoid (GC) [dexamethasone sodium phosphate 0.5 mg/kg/day] was continuously administered during 4 weeks, by an osmotic pump surgically implanted in the interscapular region. Control (CT) rats were submitted to the same procedure but with NaCl 0.9% administration. Adrenal glands (histologically examined, HE staining) and inguinal subcutaneous, mesenteric and perirenal fat were collected after euthanasia, weighed and the fat was enzymatically digested for adipocyte isolation and morphologic analysis (Motic‐Image Plus 3.0). GC treatment promoted reduction (60%, p<0.0001) of adrenal mass, and the gland atrophy can be verified by qualitative histological analysis. The treatment also promoted intense loss of body mass (150% lower, p<0.0001) and a reduction of 9% (p<0.0001) of the Lee index. However, the rats treated with GC showed an increase of 29% of visceral fat mass represented by mesenteric (p<0.01) and perirenal (p<0.05) depots. Although these depots showed an increased mass, no difference was observed in adipocyte number and volume in the mesenteric fat, whereas in the perirenal, the cell number was higher (p <0.001) and adipocyte volume was lower (p<0.01). Additionally, no difference was observed in inguinal subcutaneous fat mass in GC treated rats. In fact, there was no change in the cellularity of this fat depot, but the adipocyte volume of the GC treated rats was lower in comparison to the CT group. In conclusion, we showed that chronic GC treatment promotes adipose remodeling inducing increased visceral fat mass, reproducing an important characteristic of Cushing's syndrome in humans. This remodeling is certainly associated with several processes that affect lipolysis/lipogenesis, apoptosis/adipogenesis and maybe browning/whitening balances which mechanisms underlying them are now under intense investigation in our laboratory.Support or Funding InformationFAPESP (2016/25129‐4) and CNPq (170545/2017‐2)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Background Melatonin is a neuroendocrine hormone that regulates many functions involving energy metabolism and behavior in mammals throughout the light/dark cycle. It is considered an output signal of the central circadian clock, located in the suprachiasmatic nucleus of the hypothalamus. Melatonin synthesis can be influenced by other hormones, such as insulin and glucocorticoids in pathological conditions or during stress. Furthermore, glucocorticoids appear to modulate circadian clock genes in peripheral tissues and are associated with the onset of metabolic diseases. In the pineal gland, the modulation of melatonin synthesis by clock genes has already been demonstrated. However, few studies have shown the effects of glucocorticoids on clock genes expression in the pineal gland. Results We verified that rats treated with dexamethasone (2 mg/kg body weight, intraperitoneal) for 10 consecutive days, showed hyperglycemia and pronounced hyperinsulinemia during the dark phase. Insulin sensitivity, glucose tolerance, melatonin synthesis, and enzymatic activity of arylalkylamine N-acetyltransferase, the key enzyme of melatonin synthesis, were reduced. Furthermore, we observed an increase in the expression of Bmal1, Per1, Per2, Cry1, and Cry2 in pineal glands of rats treated with dexamethasone. Conclusion These results show that chronic treatment with dexamethasone can modulate both melatonin synthesis and circadian clock expression during the dark phase.

Ketosis can be induced in humans and in animals by fasting or dietary interventions, such as ketogenic diets. However, the increasing interest on the ketogenic state has motivated the development of alternative approaches to rapidly increase ketonemia using less drastic interventions. Here, it was tested whether oral intake of a β-hydroxybutyrate (βHB) mineral salt mixture could increase ketonemia in Wistar rats without any other dietary changes, thereby being a useful model to study ketones effects alone on metabolism.

Aim: Most studies developed to investigate the effects of glucocorticoids chronic treatment on white adipose tissue uses high doses of these hormones. This study analyzes some effects of a chronic, continuous and steady infusion of low-dose hydrocortisone and the relationship with lipid accumulation in white adipose depots in rats. Main methods: Nineteen male Wistar rats were divided into control (CON) and cortisol (CORT) groups. Along six weeks CORT group received continuous infusion of 0.6 mg/kg/day of hydrocortisone, while CON group received saline. After euthanasia, subcutaneous and visceral (retroperitoneal and mesenteric) fat pads were excised, weighted and analyzed for: lipogenic enzymes activity; molecular changes of 11-hydroxysteroid dehydrogenase type 1 (11 beta HSD1) enzyme; enzymes involved in lipid uptake, incorporation, and metabolism and in fatty acids esterification. Besides, morphometric cell analysis was performed. Key findings: CORT group showed increased triglycerides, changes in lipoprotein profile and 26,8% increment in central subcutaneous (SC) mass, while visceral fat pads masses remained unchanged. Adipocytes from SC, only, presented increased fatty acid synthase, ATP-citrate lyase and glucose-6-phosphate dehydrogenase activity, in addition to reduced AMP-activated protein kinase and 11 beta HSD1 enzymes content. Significance: Chronic low-dose hydrocortisone treatment consequences seem to be different from those commonly seen in long term hypercortisolism. While high doses promote lipid accumulation in visceral depots, a low dose showed an increase in central SC depot only. This appears to involve an increment in lipid storage and in de novo lipogenesis enzymes activity.

Cancer cachexia is a multifactorial syndrome characterized by body weight loss, atrophy of adipose tissue (AT) and systemic inflammation. However, there is limited information regarding the mechanisms of immunometabolic response in AT from cancer cachexia. Male Wistar rats were inoculated with 2 × 107 of Walker 256 tumor cells [tumor bearing (TB) rats]. The mesenteric AT (MeAT) was collected on d 0, 4, 7 (early stage), and 14 (cachexia stage) after tumor cell injection. Surgical biopsies for MeAT were obtained from patients who had gastrointestinal cancer with cachexia. Lipolysis showed an early decrease in glycerol release in TB d 4 (TB4) rats in relation to the control, followed by a 6-fold increase in TB14 rats, whereas de novo lipogenesis was markedly lower in the incorporation of glucose into fatty acids in TB14 rats during the development of cachexia. CD11b and CD68 were positive in TB7 and TB14 rats, respectively. In addition, we found cachexia stage results similar to those of animals in MeAT from patients: an increased presence of CD68+, iNOS2+, TNFα+, and HSL+ cells. In summary, translational analysis of MeAT from patients and an animal model of cancer cachexia enabled us to identify early disruption in Adl turnover and subsequent inflammatory response during the development of cancer cachexia.-Henriques, F. S., Sertié, R. A. L., Franco, F. O., Knobl, P., Neves, R. X., Andreotti, S., Lima, F. B., Guilherme, A., Seelaender, M., Batista, M. L., Jr. Early suppression of adipocyte lipid turnover induces immunometabolic modulation in cancer cachexia syndrome.

Due to the presence of the renin-angiotensin system (RAS) in tissues and its specific influence on white adipose tissue, fat cells are possible targets of pharmacological RAS blockers commonly used as anti-hypertensive drugs. In the present study, we investigated the effects of different RAS blockers on fat cell metabolism, more specifically on lipolysis, lipogenesis and oxidation of energy substrates. Isolated primary adipocytes were incubated with different RAS blockers (aliskiren, captopril and losartan) in vitro for 24 h and lipolysis, lipogenesis and glucose oxidation capacities were determined in dose-response assays to a β-adrenergic agonist and to insulin. Although no change was found in lipolytic capacity, the RAS blockers modulated lipogenesis and glucose oxidation in a different way. While captopril decreased insulin-stimulated lipogenesis (−19% of maximal response and −60% of insulin responsiveness) due to reduced glucose derived glycerol synthesis (−19% of maximal response and 64% of insulin responsiveness), aliskiren increased insulin-stimulated glucose oxidation (+49% of maximal response and +292% of insulin responsiveness) in fat cells. Our experiments demonstrate that RAS blockers can differentially induce metabolic alterations in adipocyte metabolism, characterized by a reduction in lipogenic responsiveness or an increase in glucose oxidation. The impact of RAS blockers on adipocyte metabolism may have beneficial implications on metabolic disorders during their therapeutic use in hypertensive patients.

Melatonin, the main hormone produced by the pineal gland, is secreted in a circadian manner (24‐hr period), and its oscillation influences several circadian biological rhythms, such as the regulation of clock genes expression (chronobiotic effect) and the modulation of several endocrine functions in peripheral tissues. Assuming that the circadian synchronization of clock genes can play a role in the regulation of energy metabolism and it is influenced by melatonin, our study was designed to assess possible alterations as a consequence of melatonin absence on the circadian expression of clock genes in the epididymal adipose tissue of male Wistar rats and the possible metabolic repercussions to this tissue. Our data show that pinealectomy indeed has impacts on molecular events: it abolishes the daily pattern of the expression of Clock, Per2, and Cry1 clock genes and Pparγ expression, significantly increases the amplitude of daily expression of Rev‐erbα, and affects the pattern of and impairs adipokine production, leading to a decrease in leptin levels. However, regarding some metabolic aspects of adipocyte functions, such as its ability to synthesize triacylglycerols from glucose along 24 hr, was not compromised by pinealectomy, although the daily profile of the lipogenic enzymes expression (ATP‐citrate lyase, malic enzyme, fatty acid synthase, and glucose‐6‐phosphate dehydrogenase) was abolished in pinealectomized animals.