Adipose Tissue Metabolism Research Articles

The Role of Brown Adipose Tissue and Energy Metabolism in Mammalian Thermoregulation during the Perinatal Period.

Hypothermia is one of the most common causes of mortality in neonates, and it could be developed after birth because the uterus temperature is more elevated than the extrauterine temperature. Neonates use diverse mechanisms to thermoregulate, such as shivering and non-shivering thermogenesis. These strategies can be more efficient in some species, but not in others, i.e., altricials, which have the greatest difficulty with achieving thermoneutrality. In addition, there are anatomical and neurological differences in mammals, which may present different distributions and amounts of brown fat. This article aims to discuss the neuromodulation mechanisms of thermoregulation and the importance of brown fat in the thermogenesis of newborn mammals, emphasizing the analysis of the biochemical, physiological, and genetic factors that determine the distribution, amount, and efficiency of this energy resource in newborns of different species. It has been concluded that is vital to understand and minimize hypothermia causes in newborns, which is one of the main causes of mortality in neonates. This would be beneficial for both animals and producers.

Oral administration of kynurenic acid delays the onset of type 2 diabetes in Goto-Kakizaki rats

Kynurenic acid (KYNA) is an endogenous catabolite of tryptophan that has been found to demonstrate neuroprotective properties in psychiatric disorders. Recently, accumulating data have suggested that KYNA may also play a significant role in various metabolic diseases by stimulating energy metabolism in adipose tissue and muscle. However, whether KYNA can serves as an anti-diabetes agent has yet to be studied. In this study, we investigated the potential anti-diabetic effects of administering KYNA orally through drinking water in pre-diabetic Goto-Kakizaki rats and examined how this treatment may influence energy metabolism regulation within the liver. We found that hyperglycemic Goto-Kakizaki rats showed lower plasmatic KYNA levels compared to normal rats. Oral administration of KYNA significantly delayed the onset of diabetes in Goto-Kakizaki rats compared to untreated animals. Moreover, we found that KYNA treatment significantly increased respiration exchange ratio and promoted the energy expenditure by stimulating the expression of uncoupling protein (UCP). We confirmed that KYNA stimulated the UCP expression in HepG2 cells and mouse hepatocytes at mRNA and protein levels. Our study reveals that KYNA could potentially act as an anti-diabetic agent and KYNA-induced UCP upregulation is closely associated with the regulation of energy metabolism. These results provide further evidence for the therapeutic potential of KYNA in diabetes.

Dose- and Time-Dependent Effects of Radiofrequency Electromagnetic Field on Adipose Tissue: Implications of Thermoregulation and Mitochondrial Signaling

Recent studies have shed light on the effects of low-intensity radiofrequency (RF) fields on thermoregulation and adipose tissue metabolism. The present study aims to further explore these effects by analyzing the expression of thermoregulatory genes and investigating the involvement of mitochondria in adipose tissue metabolism. Male mice (n = 36 C57BL/6J) were assigned to either exposed or control groups. The exposed groups were subjected to RF fields at 900 MHz, with specific absorption rates (SAR) of 0.1 W/kg or 0.4 W/kg, either for three or seven consecutive days. The findings indicate that RF exposure leads to changes in adipose tissue markers, with some effects being dose-dependent and time-dependent. In brown adipose tissue (BAT), after 3 days of RF exposure, thermogenesis is reduced, mitochondrial activity in BAT decreases, and an increase in gene expression, responsible for balancing the regulatory and damaging effects of reactive oxygen species (ROS), was observed. This effect was partially compensated after 7 days of exposure. In white adipose tissue (WAT), RF exposure results in reduced fatty acid oxidation, impaired energy production, and hindered adipocyte differentiation. Notably, no effects of RF on mitochondrial biogenesis in WAT were observed. These findings contribute to understanding the effects of RF exposure on adipose tissue metabolism and thermoregulation, highlighting dose-dependent and time-dependent responses.

Green Tea Induces the Browning of Adipose Tissue—Systematic Review

Several foods and nutrients are being studied extensively because they have a positive effect on thermogenesis and the browning of white adipose tissue. Therefore, this study aims to evaluate, through a systematic review, the effect of green tea for inducing browning of adipose tissue. The systematic review was built following the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyze. We searched the following electronic databases: PubMed (Medline), Science Direct, Scopus, and Web of Science. We included ten experimental articles that used green tea to treat induced obesity in rodents. Green tea reduced the weight of white and brown adipose tissue, positively regulated gene expression and microRNA that regulate the metabolism of adipose tissue, and morphological changes were identified as beige tissue. According to the results found, the factors involved in this induction to browning are PPARγ, PGC-1α, UCP1, CPT, and PRDM16. Therefore, green tea promotes the browning of adipose tissue in rodents. It is important to emphasize the need for studies in obese humans to identify whether the same metabolic response occurs.

301-OR: Estrogen Signaling in the Ventromedial Hypothalamus Modulates Adipose Tissue Metabolic Adaptation

Brain estrogen receptor α (ERα) signaling plays a vital role in the regulation of energy homeostasis and adipose tissue metabolism. It has been demonstrated that ERα is abundantly expressed in the ventrolateral region of the ventromedial hypothalamus (vlVMH), a sex-dimorphic structure that directly modulates brown adipose tissue (BAT) thermogenesis. We previously showed that an ERαvlVMH-originated neural circuit responds to changes in ambient temperature and nutritional states, suggesting a potential role of this neural circuit in metabolic adaptation. Here, we found that chronic activation of ERαvlVMH neurons in male mice reduces body weight, decreases adiposity, and prevents diet-induced obesity (DIO), which is associated with increases in BAT thermogenesis and core temperature. Conversely, chronic inhibition of ERαvlVMH neurons increases body weight, promotes adiposity, and decreases baseline BAT temperature. Notably, ERαvlVMH neural inhibition also impairs cold-induced food consumption and BAT thermogenesis, resulting in lethal phenotypes during chronic cold exposure. Post hoc histology analysis further revealed that ERαvlVMH neural inhibition induces adipose tissue whitening. Finally, we explored the anatomical distribution of ERαvlVMH downstream neural circuitries. Anterograde tracing revealed ERαvlVMH-originated projections to the medial preoptic area (MPA), paraventricular nucleus (PVN), substantia nigra (SNR) and dorsal raphe nucleus (DRN). Interestingly, transsynaptic retrograde tracing further demonstrated that these brain regions send projections to inguinal white adipose tissue (iWAT), suggesting potential ERαvlVMH-originated circuits involved in adipose tissue adaptation. Together, these findings support a model that estrogens act through ERαvlVMH neurons to modulate fat-specific outputs and subsequently regulate adipose tissue adaptation to cold challenges. Disclosure V.C.Torres irizarry: None. P.Xu: None. H.Ye: None. P.Luo: None. L.Carrillo-sáenz: None. X.Yang: None. M.D.Munoz: None. N.Antony: None. Y.Jiang: None. Y.He: None. Funding National Institutes of Health (R01DK123098, T32AA026577); U.S. Department of Defense (W81XWH-19-PRMRP-DA); National Institute of Diabetes and Digestive and Kidney Diseases (DK020595); American Heart Association (915789)

Age-related changes in adipose tissue metabolomics and inflammation, cardiolipin metabolism, and ferroptosis markers in female aged rat model

Aging adipose tissue exhibits elevated inflammation and oxidative stress that are major sources of age-related metabolic dysfunction. However, the exact metabolic changes associated with inflammation and oxidative stress are unclear. To address this topic, we assessed variation in metabolic phenotypes of adipose tissue from 18 months adult sedentary (ASED), 26 months old sedentary (OSED), and 8 months young sedentary (YSED). The results of metabolomic analysis showed that ASED and OSED group had higher palmitic acid, elaidic acid, 1-heptadecanol, and α-tocopherol levels than YSED, but lower sarcosine levels. Furthermore, stearic acid was specifically elevated in ASED compared with YSED. Cholesterol was upregulated specifically in the OSED group compared with YSED, whereas linoleic acid was downregulated. In addition, ASED and OSED had more inflammatory cytokines, lower antioxidant capacity, and higher expression of ferroptosis-related genes than YSED. Moreover, mitochondrial dysfunction associated with abnormal cardiolipin synthesis was more pronounced in the OSED group. In conclusion, both ASED and OSED can affect the FA metabolism and increase oxidative stress in adipose tissue, leading to inflammation. In particular, linoleic acid content specifically decreases in OSED, which associated with abnormal cardiolipin synthesis and mitochondrial dysfunction in adipose tissue.

Circadian mechanisms in adipose tissue bioenergetics and plasticity.

The circadian clock plays an essential role in coordinating feeding and metabolic rhythms with the light/dark cycle. Disruption of clocks is associated with increased adiposity and metabolic disorders, whereas aligning feeding time with cell-autonomous rhythms in metabolism improves health. Here, we provide a comprehensive overview of recent literature in adipose tissue biology as well as our understanding of molecular mechanisms underlying the circadian regulation of transcription, metabolism, and inflammation in adipose tissue. We highlight recent efforts to uncover the mechanistic links between clocks and adipocyte metabolism, as well as its application to dietary and behavioral interventions to improve health and mitigate obesity.

The role of long non-coding RNAs in the development of adipose cells.

In recent times, the rising prevalence of obesity and its associated comorbidities have had a severe impact on human health and social progress. Therefore, scientists are delving deeper into the pathogenesis of obesity, exploring the role of non-coding RNAs. Long non-coding RNAs (lncRNAs), once regarded as mere "noise" during genome transcription, have now been confirmed through numerous studies to regulate gene expression and contribute to the occurrence and progression of several human diseases. LncRNAs can interact with protein, DNA, and RNA, respectively, and participate in regulating gene expression by modulating the levels of visible modification, transcription, post-transcription, and biological environment. Increasingly, researchers have established the involvement of lncRNAs in regulating adipogenesis, development, and energy metabolism of adipose tissue (white and brown fat). In this article, we present a literature review of the role of lncRNAs in the development of adipose cells.

Gene co-expression network and differential expression analyses of subcutaneous white adipose tissue reveal novel insights into the pathological mechanisms underlying ketosis in dairy cows

Ketosis is a common nutritional metabolic disease during the perinatal period in dairy cows. Although various risk factors have been identified, the molecular mechanism underlying ketosis remains elusive. In this study, subcutaneous white adipose tissue (sWAT) was biopsied for transcriptome sequencing on 10 Holstein cows with type II ketosis [blood β-hydroxybutyric acid (BHB) >1.4 mmol/L; Ket group] and another 10 cows without type II ketosis (BHB ≤1.4 mmol/L; Nket group) at d 10 after calving. Serum concentrations of nonesterified fatty acids (NEFA) and BHB, as indicators of excessive fat mobilization and circulating ketone bodies, respectively, were significantly higher in the Ket group than in the Nket group. Aspartate transaminase (AST) and total bilirubin (TBIL), as indicators of liver damage, were higher in the Ket group than in the Nket group. Weighted gene co-expression network analysis (WGCNA) of the sWAT transcriptome revealed modules significantly correlated with serum BHB, NEFA, AST, TBIL, and total cholesterol. The genes in these modules were enriched in the regulation of the lipid biosynthesis process. Neurotrophic tyrosine kinase receptor type 2 (NTRK2) was identified as the key hub gene by intramodular connectivity, gene significance, and module membership. Quantitative reverse transcription PCR analyses for these samples, as well as a set of independent samples, validated the downregulation of NTRK2 expression in the sWAT of dairy cows with type II ketosis. NTRK2 encodes tyrosine protein kinase receptor B (TrkB), which is a high-affinity receptor for brain-derived neurotrophic factor, suggesting that abnormal lipid mobilization in cows with type II ketosis might be associated with impaired central nervous system regulation of adipose tissue metabolism, providing a novel insight into the pathogenesis underlying type II ketosis in dairy cows.

The anti-obesity effects of resveratrol on the 3T3-L1 adipocytes.

Obesity is a severe health problem worldwide due to its association with various adverse health consequences. The present study aims to evaluate the anti-obesity effects of resveratrol, as a natural polyphenol, on the 3T3-L1 adipocytes. PubMed, Scopus, ScienceDirect, Web of Sciences, and Google Scholar databases were searched up to March 2022 using relevant keywords. All original articles, written in English, evaluating the anti-obesity effects of resveratrol on the 3T3-L1 adipocytes were eligible for this review. Initially, 4361 records were found in the electronic search databases. After removing duplicates and irrelevant studies according to the title and abstract, the full text of the 51 articles was critically screened and 38 in vitro studies were included in this review. Except for one case, all of these studies reported that different doses (ranged 1-200 μM) of resveratrol treatment have anti-obesity effects on 3T3L1 adipocytes through various mechanisms such as induction of apoptosis, a decrease of fat accumulation and adipogenesis, promotion of white adipocytes browning, inhibition of preadipocyte proliferation and consequent differentiation, and up-regulation of miRNA that involved in the antiadipogenic and triacylglycerol metabolism in white adipose tissue. The findings indicate that resveratrol has anti-obesity effects. Therefore, resveratrol treatment could be used to prevent and treat obesity and its related disorders. Well-designed randomized clinical trials with different doses of resveratrol are recommended to be performed on obese subjects.

Targeting the Inflammatory Hallmarks of Obesity-Associated Osteoarthritis: Towards Nutraceutical-Oriented Preventive and Complementary Therapeutic Strategies Based on n-3 Polyunsaturated Fatty Acids.

Obesity (Ob), which has dramatically increased in the last decade, is one of the main risk factors that contribute to the incidence and progression of osteoarthritis (OA). Targeting the characteristics of obesity-associated osteoarthritis (ObOA) may offer new chances for precision medicine strategies in this patient cohort. First, this review outlines how the medical perspective of ObOA has shifted from a focus on biomechanics to the significant contribution of inflammation, mainly mediated by changes in the adipose tissue metabolism through the release of adipokines and the modification of fatty acid (FA) compositions in joint tissues. Preclinical and clinical studies on n-3 polyunsaturated FAs (PUFAs) are critically reviewed to outline the strengths and weaknesses of n-3 PUFAs' role in alleviating inflammatory, catabolic and painful processes. Emphasis is placed on potential preventive and therapeutic nutritional strategies based on n-3 PUFAs, with a focus on ObOA patients who could specifically benefit from reformulating the dietary composition of FAs towards a protective phenotype. Finally, tissue engineering approaches that involve the delivery of n-3 PUFAs directly into the joint are explored to address the perspectives and current limitations, such as safety and stability issues, for implementing preventive and therapeutic strategies based on dietary compounds in ObOA patients.

Pharmacological antagonism of receptor for advanced glycation end products signaling promotes thermogenesis, healthful body mass and composition, and metabolism in mice.

Optimal body mass and composition as well as metabolic fitness require tightly regulated and interconnected mechanisms across tissues. Disturbances in these regulatory networks tip the balance between metabolic health versus overweight and obesity and their complications. The authors previously demonstrated roles for the receptor for advanced glycation end products (RAGE) in obesity, as global- or adipocyte-specific deletion of Ager (the gene encoding RAGE) protected mice from high-fat diet-induced obesity and metabolic dysfunction. To explore translational strategies evoked by these observations, a small molecule antagonist of RAGE signaling, RAGE229, was administered to lean mice and mice with obesity undergoing diet-induced weight loss. Body mass and composition and whole body and adipose tissue metabolism were examined. This study demonstrates that antagonism of RAGE signaling reduced body mass and adiposity and improved glucose, insulin, and lipid metabolism in lean male and female mice and in male mice with obesity undergoing weight loss. In adipose tissue and in human and mouse adipocytes, RAGE229 enhanced phosphorylation of protein kinase A substrates, which augmented lipolysis, mitochondrial function, and thermogenic programs. Pharmacological antagonism of RAGE signaling is a potent strategy to optimize healthful body mass and composition and metabolic fitness.

Impact of short and long exposure to cafeteria diet on food intake and white adipose tissue lipolysis mediated by glucagon-like peptide 1 receptor.

The modern food environment facilitates excessive calorie intake, a major driver of obesity. Glucagon-like peptide 1 (GLP1) is a neuroendocrine peptide that has been the basis for developing new pharmacotherapies against obesity. The GLP1 receptor (GLP1R) is expressed in central and peripheral tissues, and activation of GLP1R reduces food intake, increases the expression of thermogenic proteins in brown adipose tissue (BAT), and enhances lipolysis in white adipose tissue (WAT). Obesity decreases the efficiency of GLP1R agonists in reducing food intake and body weight. Still, whether palatable food intake before or during the early development of obesity reduces the effects of GLP1R agonists on food intake and adipose tissue metabolism remains undetermined. Further, whether GLP1R expressed in WAT contributes to these effects is unclear. Food intake, expression of thermogenic BAT proteins, and WAT lipolysis were measured after central or peripheral administration of Exendin-4 (EX4), a GLP1R agonist, to mice under intermittent-short exposure to CAF diet (3 h/d for 8 days) or a longer-continuous exposure to CAF diet (24 h/d for 15 days). Ex-vivo lipolysis was measured after EX4 exposure to WAT samples from mice fed CAF or control diet for 12 weeks. . During intermittent-short exposure to CAF diet (3 h/d for 8 days), third ventricle injection (ICV) and intra-peritoneal administration of EX4 reduced palatable food intake. Yet, during a longer-continuous exposure to CAF diet (24 h/d for 15 days), only ICV EX4 administration reduced food intake and body weight. However, this exposure to CAF diet blocked the increase in uncoupling protein 1 (UCP1) caused by ICV EX4 administration in mice fed control diet. Finally, GLP1R expression in WAT was minimal, and EX4 failed to increase lipolysis ex-vivo in WAT tissue samples from mice fed CAF or control diet for 12 weeks. . Exposure to a CAF diet during the early stages of obesity reduces the effects of peripheral and central GLP1R agonists, and WAT does not express a functional GLP1 receptor. These data support that exposure to the obesogenic food environment, without the development or manifestation of obesity, can alter the response to GLP1R agonists. .

An Isocaloric High-Fat Diet Regulates Partially Genetically Determined Fatty Acid and Carbohydrate Uptake and Metabolism in Subcutaneous Adipose Tissue of Lean Adult Twins.

The dysfunction of energy metabolism in white adipose tissue (WAT) induces adiposity. Obesogenic diets that are high in saturated fat disturb nutrient metabolism in adipocytes. This study investigated the effect of an isocaloric high-fat diet without the confounding effects of weight gain on the gene expression of fatty acid and carbohydrate transport and metabolism and its genetic inheritance in subcutaneous (s.c.) WAT of healthy human twins. Forty-six healthy pairs of twins (34 monozygotic, 12 dizygotic) received an isocaloric carbohydrate-rich diet (55% carbohydrates, 30% fat, 15% protein; LF) for 6 weeks followed by an isocaloric diet rich in saturated fat (40% carbohydrates, 45% fat, 15% protein; HF) for another 6 weeks. Gene expression analysis of s.c. WAT revealed that fatty acid transport was reduced after one week of the HF diet, which persisted throughout the study and was not inherited, whereas intracellular metabolism was decreased after six weeks and inherited. An increased inherited gene expression of fructose transport was observed after one and six weeks, potentially leading to increased de novo lipogenesis. An isocaloric dietary increase of fat induced a tightly orchestrated, partially inherited network of genes responsible for fatty acid and carbohydrate transport and metabolism in human s.c. WAT.

Food Polyphenols and Type II Diabetes Mellitus: Pharmacology and Mechanisms.

Type II diabetes mellitus and its related complications are growing public health problems. Many natural products present in our diet, including polyphenols, can be used in treating and managing type II diabetes mellitus and different diseases, owing to their numerous biological properties. Anthocyanins, flavonols, stilbenes, curcuminoids, hesperidin, hesperetin, naringenin, and phenolic acids are common polyphenols found in blueberries, chokeberries, sea-buckthorn, mulberries, turmeric, citrus fruits, and cereals. These compounds exhibit antidiabetic effects through different pathways. Accordingly, this review presents an overview of the most recent developments in using food polyphenols for managing and treating type II diabetes mellitus, along with various mechanisms. In addition, the present work summarizes the literature about the anti-diabetic effect of food polyphenols and evaluates their potential as complementary or alternative medicines to treat type II diabetes mellitus. Results obtained from this survey show that anthocyanins, flavonols, stilbenes, curcuminoids, and phenolic acids can manage diabetes mellitus by protecting pancreatic β-cells against glucose toxicity, promoting β-cell proliferation, reducing β-cell apoptosis, and inhibiting α-glucosidases or α-amylase. In addition, these phenolic compounds exhibit antioxidant anti-inflammatory activities, modulate carbohydrate and lipid metabolism, optimize oxidative stress, reduce insulin resistance, and stimulate the pancreas to secrete insulin. They also activate insulin signaling and inhibit digestive enzymes, regulate intestinal microbiota, improve adipose tissue metabolism, inhibit glucose absorption, and inhibit the formation of advanced glycation end products. However, insufficient data are available on the effective mechanisms necessary to manage diabetes.

32 Depot-Specific Transcriptome and Adipocyte Metabolism in Intramuscular and Subcutaneous Adipose Tissue in Beef Cattle

Abstract Intramuscular adipose tissue (IMAT; marbling) deposition is the primary determination of beef quality grade in the U.S. While finishing diets increase marbling, they also increase subcutaneous adipose tissue (SAT) accumulation, leading to excessive fattening and economic losses due to ‘waste fat’. Our objective was to investigate the IMAT and SAT-specific transcriptional profile and adipocyte function in vitro. A better understanding of the mechanisms underlying IMAT and SAT-specific characteristics will help to identify molecular and cellular molecules for developing targeted strategies to enhance marbling while limiting overall fatness in beef animals. A section of the Longissimus dorsi muscle from 9-11th ribs was collected to dissect IMAT and adjacent SAT (backfat) from six beef animals harvested at the Texas Tech University Meat Lab. The SAT and IMAT RNA was extracted and sequenced in an Illumina NovaSeq 6000 targeting a minimum of 30 million reads per sample. Transcriptome analysis showed more than 1,800 differently expressed genes (DEGs) in IMAT and SAT. There was a downregulation of genes associated with adipogenesis, lipolysis regulation, insulin sensitivity, and fatty acid metabolism (e.g., LEP, INSIG1, and PLIN4) in IMAT vs. SAT, while pathways of insulin resistance and ß-adrenergic signaling were activated. To elucidate whether the differences between IMAT and SAT transcriptional profiles were translated into changes in the adipocyte function, preadipocytes were isolated, cultured, and differentiated into adipocytes in vitro for 14 followed by functional analyses of adipogenic capacity, insulin sensitivity, and lipolytic responses. Statistical analysis was performed in GraphPad 9. Even though preadipocytes were more abundant in IMAT than in SAT (flow cytometry quantification of CD45-CD31- cell), IMAT preadipocyte proliferation rates were decreased compared with SAT. Additionally, SAT adipocytes were larger than IMAT. These findings suggest an enhancement in SAT adipogenesis/lipogenesis compared with IMAT. Metabolically, SAT adipocytes released greater glycerol concentrations compared with IMAT upon ß-adrenergic stimulation of lipolysis with isoproterenol and tended to have greater insulin-stimulated glucose uptake compared with IMAT. Altogether, these findings indicate that IMAT is unable to accumulate lipids as efficiently as SAT, and these differences may be underlined by a decreased preadipocyte hyperplasia, insulin resistance, and potential dysregulation of ß-adrenergic receptors, all of these similarly suggested by the transcriptome analysis. Our study revealed molecular and cellular differences between IMAT and SAT that may partly explain why it is common to observe increased SAT fatness and limited marbling beef cattle.

Effects of physical exercise on glycemic metabolism, aerobic capacity and structure of brown adipose tissue in diabetic animals

The ability of brown adipose tissue (BAT) and aerobic physical exercise (AET) to improve energy metabolism is widely known. Since AET has been used as an insulin- sensitizing therapy for diabetes, here we tested whether the effects of AET on the glycemic metabolism and aerobic capacity of diabetic animals are accompanied by structural changes in BAT. Adult male C57BL6/J mice were assigned into groups: non-diabetic sedentary (NDS, n=6), non-diabetic trained (NDT, n=6), diabetic sedentary (DS, n=4) and diabetic trained (DT, n=7). Diabetes was induced by high-fat and -fructose diet and intraperitoneal injection of streptozotocin (120 mg/g). AET consisted of 8-wk running session of 60 min at 60% of maximal speed, 5 days/wk. Experimental procedures were approved by Ethics Committees from Faculty of Medicine and from School of Arts, Science and Humanities of University of São Paulo (#1473/2020 and #001/2020, respectively). Initial body weight (BW) did not differ among groups, however the DS and DT groups had lower final BW compared with NDS. The BW gain of DS group was lower compared with NDS group. Food consumption (Kcal/animal/day) was higher in DT group compared with NDS and NDT. The DS and DT groups had higher fasting blood glucose, and DS group had greater area under the curve on the glucose tolerance test than the NDS and NDT groups. Indirect calorimetry measurement at rest revealed no difference in the variables oxygen uptake (VO2), carbon dioxide expiration (VCO2), respiratory exchange ratio (RER), energy expenditure (EE), carbohydrate and fat oxidation among groups. During maximal exercise test, NDT and DT increased the time to exhaustion, maximal speed, intensity corresponding to the VO2máx (iVO2) compared with NDS and DS. An increase in VO2máx and VCO2máx was observed in NDT group compared with DS and DT group. No differences were observed in the weight of white adipose tissue depots (retroperitoneal, periepididymal and subcutaneous), interscapular brown adipose tissue (iBAT), skeletal muscle (gastrocnemius and soleus), and other organs (heart, lung, and kidney). Morphometric analysis of the iBAT revealed that the area, diameter, volume, mass, frequency of lipid droplet distribution by size (small, medium, large, and very large) and amount of lipid droplets did not differ among groups, however, collagen deposition in the iBAT increased in the DS and DT groups compared with NDS group. In conclusion, the AET-induced improvement in glucose tolerance and aerobic capacity in diabetic animals is not accompanied by changes in morphometry and collagen deposition in the iBAT. This study was supported by grants from the São Paulo Research Foundation (FAPESP) #2020/15748-4 and #2020/12005-0. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Ablation of Siglec-E enhances adipose tissue inflammation through CXCR3 activation and induces monocytic myeloid-derived suppressor cells

Abstract Obesity is a worldwide epidemic associated with dysregulated metabolism and chronic low-grade inflammation in adipose tissue (AT). AT infiltrates with several immune cells, which secrete proinflammatory cytokines that mediate the severity of AT inflammation during obesity. During our ongoing studies, we observed the downregulation of various genes, particularly sialic acid-binding Ig-like lectin E (Siglec-E) by RNA-seq analysis in AT immune cells isolated from high-fat diet (HFD) fed mice as compared to normal diet (ND) mice. Siglec-E is mainly expressed in the cells of myeloid lineages, including macrophages, dendritic cells (DCs), and neutrophils. We confirmed the RNA-seq data of downregulation of Siglec-E in AT derived from HFD-fed mice by RT-PCR analysis. To determine the role of Siglec-E in mediating AT inflammation, we fed ND and HFD to wild-type (WT) and Siglec-E knockout mice (Siglec-E −/−), respectively. HFD consumption increased the body weight and blood glucose levels in Siglec-E −/−mice as compared to WT mice. Further, we observed increased infiltration of macrophages and decreased frequency of DCs in HFD-fed Siglec-E −/−mice AT compared to WT HFD-fed mice. We also noticed an increase in the frequency of CD8 +CXCR3 +cells and monocytic myeloid-derived suppressor cells (M-MDSCs) in AT of HFD-fed Siglec-E −/−mice as compared to WT HFD-fed mice. We also noticed the increased expression of AKT, and TNF receptor-associated factor 3 (TRAF3) in HFD-fed Siglec-E −/−mice. These results suggest that Siglec-E deletion plays a role in AT inflammation and obesity through the activation of CXCR3 and M-MDSCs. This study supports the notion that modulating Siglec-E pathways protect from AT inflammation and metabolic disorders. This research is supported by NIH grant R01 AI140405

IRF3 in adipose tissue inflammation and metabolism

Abstract Dysfunction of adipocytes and adipose tissue is a primary defect in obesity and obesity-associated metabolic diseases. Interferon regulatory factor 3 (IRF3) has been implicated in adipogenesis. However, the role of IRF3 in obesity and obesity associated disorders still remains unclear. Here we show that IRF3 expression in human adipose tissue was positively associated with insulin sensitivity and negatively associated with type 2 diabetes. In mouse preadipocytes, IRF3 not only acts as a brake negatively regulating the adipogenic transcriptional network centered on the PPARg pathway, but also is important for the functionality of adipocytes. In macrophages, IRF3 inhibits inflammatory cytokine expression through IFNb/IL-10 axis, thereby restraining adipose tissue inflammation in obesity. Mice deficient in IRF3 developed obesity and type 2 diabetes spontaneously associated with increased adipose tissue inflammation. This study demonstrates that IRF3 regulates the biology of multiple cell types including adipocytes and macrophages to prevent the development of obesity and obesity-related complications, hence, could be a target for therapeutic interventions for prevention and treatment of obesity-associated metabolic disorders. National Medical Research Council of Singapore

Role of histone deacetylase 3 (HDAC3) in adipose tissue metabolism and immunophenotype: Selected Abstract - SITeCS Congress 2022

Introduction: Obesity is associated with comorbidities such as cardiovascular disease and type 2 diabetes. HDAC3 regulates adipose tissue physiology (WAT), and its genetic inactivation causes metabolic reprogramming of white adipocytes toward browning. The aim of this work is to evaluate the effect of HDAC3 silencing at different stages of differentiation and investigate the influence of adipocyte metabolism on the immunophenotype of WAT. Materials and Methods: Following HDAC3 silencing in mesenchymal stem cells and mature adipocytes, adipocyte function, RNA, DNA and protein levels, and proliferation at the end of differentiation were analyzed. Visceral WAT immunophenotype (vWAT) of Hdac3 KO mice in WAT (Hdac3fatKO) and controls (FL) was performed by FACS. Results: Silencing HDAC3 in precursors amplifies the expression of genes and proteins that regulate differentiation, oxidative metabolism, browning and mitochondrial activity. Following silencing, we found increased 1)phosphorylation of AKT (1.64 fold change, P<0.0001), indicative of increased insulin signaling, and 2)proliferation, characteristic of the early phase of differentiation. Mitochondrial content was unchanged, but increased mitochondrial activity was observed in terms of maximal respiration (1.42 fold change, P=0.0151) and uncoupling of the electron transport chain (+11.6%, P<0.0001). No difference was observed following HDAC3 silencing in mature adipocytes. We hypothesized that the enhancement of oxidative metabolism may cause cellular damage or senescence and, consequently, the immunophenotype of vWAT might be affected by HDAC3 ablation. Analysis reveals an increase of macrophages (2.48 fold change, P=0.0311) in the vWAT of Hdac3fatKO mice polarizing toward the M2 population. Coculture of adipocytes with macrophages from bone marrow indicates that HDAC3 silencing in adipocytes stimulates macrophage activation. Conclusions: HDAC3 is a key factor in the WAT phenotype, and its inactivation triggers mechanisms that support browning. Early epigenetic events mediated by HDAC3 silencing are crucial in directing adipocyte precursors toward the oxidative phenotype. Finally, results obtained from ex vivo and in vitro studies suggest that specific factors produced by KO adipocytes may be involved in determining the observed immunophenotype. [FONDAZIONE CARIPLO 2015-0641]