Sex differences in white adipose tissue expansion: emerging molecular mechanisms.

The escalating prevalence of individuals becoming overweight and obese is a rapidly rising global health problem, placing an enormous burden on health and economic systems worldwide. Whilst obesity has well described lifestyle drivers, there is also a significant and poorly understood component that is regulated by genetics. Furthermore, there is clear evidence for sexual dimorphism in obesity, where overall risk, degree, subtype and potential complications arising from obesity all differ between males and females. The molecular mechanisms that dictate these sex differences remain mostly uncharacterised. Many studies have demonstrated that this dimorphism is unable to be solely explained by changes in hormones and their nuclear receptors alone, and instead manifests from coordinated and highly regulated gene networks, both during development and throughout life. As we acquire more knowledge in this area from approaches such as large-scale genomic association studies, the more we appreciate the true complexity and heterogeneity of obesity. Nevertheless, over the past two decades, researchers have made enormous progress in this field, and some consistent and robust mechanisms continue to be established. In this review, we will discuss some of the proposed mechanisms underlying sexual dimorphism in obesity, and discuss some of the key regulators that influence this phenomenon.

Group IIA secreted phospholipase A2 (PLA2G2A) augments adipose tissue thermogenesis.

Group IIA secreted phospholipase A2 (PLA2G2A) hydrolyzes glycerophospholipids at the sn-2 position resulting in the release of fatty acids and lysophospholipids. C57BL/6 mice do not express Pla2g2a due to a frameshift mutation (wild-type [WT] mice). We previously reported that transgenic expression of human PLA2G2A in C57BL/6 mice (IIA+ mice) protects against weight gain and insulin resistance, in part by increasing total energy expenditure. Additionally, we found that brown and white adipocytes from IIA+ mice have increased expression of mitochondrial uncoupling markers, such as uncoupling protein 1 (UCP1), peroxisome proliferator-activated receptor-gamma coactivator, and PR domain containing 16, suggesting that the energy expenditure phenotype might be due to an increased thermogenic capacity in adipose tissue. Here, we further characterize the impact of PLA2G2A on thermogenic mechanisms in adipose tissue. Metabolic analysis of WT and IIA+ mice revealed that even when housed within their thermoneutral zone, IIA+ mice have elevated energy expenditure compared to WT littermates. Increased energy expenditure in IIA+ mice is associated with increased citrate synthase activity in brown adipose tissue (BAT) and increased mitochondrial respiration in both brown and white adipocytes. We also observed that direct addition of recombinant PLA2G2A enzyme to in vitro cultured adipocytes results in the marked induction of UCP1 protein expression. Finally, we report that PLA2G2A induces the expression of numerous transcripts related to energy substrate transport and metabolism in BAT, suggestive of an increase in substrate flux to fuel BAT activity. These data demonstrate that PLA2G2A enhances adipose tissue thermogenesis, in part, through elevated substrate delivery and increased mitochondrial content in BAT.

Anti-Obesity and Hypocholesterolemic Actions of Protamine-Derived Peptide RPR (Arg-Pro-Arg) and Protamine in High-Fat Diet-Induced C57BL/6J Mice.

Dietary protamine can ameliorate hyperlipidemia; however, the protamine-derived active peptide and its hypolipidemic mechanism of action are unclear. Here, we report the discovery of a novel anti-obesity and hypocholesterolemic peptide, RPR (Arg-Pro-Arg), derived from protamine in mice fed a high-fat diet for 50 days. Serum cholesterol levels were significantly lower in the protamine and RPR groups than in the control group. White adipose tissue weight was significantly decreased in the protamine and RPR groups. The fecal excretion of cholesterol and bile acid was significantly higher in the protamine and RPR groups than in the control group. We also observed a significant decrease in the expression of hepatic SCD1, SREBP1, and adipocyte FAS mRNA, and significantly increased expression of hepatic PPARα and adipocyte PPARγ1 mRNA in the protamine group. These findings demonstrate that the anti-obesity effects of protamine are linked to the upregulation of adipocyte PPARγ1 and hepatic PPARα and the downregulation of hepatic SCD1 via SREBP1 and adipocyte FAS. RPR derived from protamine has a crucial role in the anti-obesity action of protamine by evaluating the effective dose of adipose tissue weight loss.

Partial Deficiency of Zfp217 Resists High-Fat Diet-Induced Obesity by Increasing Energy Metabolism in Mice.

Obesity-induced adipose tissue dysfunction and disorders of glycolipid metabolism have become a worldwide research priority. Zfp217 plays a crucial role in adipogenesis of 3T3-L1 preadipocytes, but about its functions in animal models are not yet clear. To explore the role of Zfp217 in high-fat diet (HFD)-induced obese mice, global Zfp217 heterozygous knockout (Zfp217+/-) mice were constructed. Zfp217+/- mice and Zfp217+/+ mice fed a normal chow diet (NC) did not differ significantly in weight gain, percent body fat mass, glucose tolerance, or insulin sensitivity. When challenged with HFD, Zfp217+/- mice had less weight gain than Zfp217+/+ mice. Histological observations revealed that Zfp217+/- mice fed a high-fat diet had much smaller white adipocytes in inguinal white adipose tissue (iWAT). Zfp217+/- mice had improved metabolic profiles, including improved glucose tolerance, enhanced insulin sensitivity, and increased energy expenditure compared to the Zfp217+/+ mice under HFD. We found that adipogenesis-related genes were increased and metabolic thermogenesis-related genes were decreased in the iWAT of HFD-fed Zfp217+/+ mice compared to Zfp217+/- mice. In addition, adipogenesis was markedly reduced in mouse embryonic fibroblasts (MEFs) from Zfp217-deleted mice. Together, these data indicate that Zfp217 is a regulator of energy metabolism and it is likely to provide novel insight into treatment for obesity.

Mechanical overload-induced muscle-derived extracellular vesicles promote adipose tissue lipolysis.

How regular physical activity is able to improve health remains poorly understood. The release of factors from skeletal muscle following exercise has been proposed as a possible mechanism mediating such systemic benefits. We describe a mechanism wherein skeletal muscle, in response to a hypertrophic stimulus induced by mechanical overload (MOV), released extracellular vesicles (EVs) containing muscle-specific miR-1 that were preferentially taken up by epidydimal white adipose tissue (eWAT). In eWAT, miR-1 promoted adrenergic signaling and lipolysis by targeting Tfap2α, a known repressor of Adrß3 expression. Inhibiting EV release prevented the MOV-induced increase in eWAT miR-1 abundance and expression of lipolytic genes. Resistance exercise decreased skeletal muscle miR-1 expression with a concomitant increase in plasma EV miR-1 abundance, suggesting a similar mechanism may be operative in humans. Altogether, these findings demonstrate that skeletal muscle promotes metabolic adaptations in adipose tissue in response to MOV via EV-mediated delivery of miR-1.

Skeletal Muscle-Adipose Tissue-Tumor Axis: Molecular Mechanisms Linking Exercise Training in Prostate Cancer.

Increased visceral adiposity may influence the development of prostate cancer (PCa) aggressive tumors and cancer mortality. White adipose tissue (WAT), usually referred to as periprostatic adipose tissue (PPAT), surrounds the prostatic gland and has emerged as a potential mediator of the tumor microenvironment. Exercise training (ET) induces several adaptations in both skeletal muscle and WAT. Some of these effects are mediated by ET-induced synthesis and secretion of several proteins, known as myo- and adipokines. Together, myokines and adipokines may act in an endocrine-like manner to favor communication between skeletal muscle and WAT, as they may work together to improve whole-body metabolic health. This crosstalk may constitute a potential mechanism by which ET exerts its beneficial role in the prevention and treatment of PCa-related disorders; however, this has not yet been explored. Therefore, we reviewed the current evidence on the effects of skeletal muscle-WAT-tumor crosstalk in PCa, and the potential mediators of this process to provide a better understanding of underlying ET-related mechanisms in cancer.

Chronic Intake of Energy Drinks and Their Sugar Free Substitution Similarly Promotes Metabolic Syndrome.

Energy drinks containing significant quantities of caffeine, taurine and sugar are increasingly consumed, particularly by adolescents and young adults. The putative effects of chronic ingestion of either standard energy drink, MotherTM (ED), or its sugar-free formulation (sfED) on metabolic syndrome were determined in wild-type C57BL/6J mice, in comparison to a soft drink, Coca-Cola (SD), a Western-styled diet enriched in saturated fatty acids (SFA), and a combination of SFA + ED. Following 13 weeks of intervention, mice treated with ED were hyperglycaemic and hypertriglyceridaemic, indicating higher triglyceride glucose index, which was similar to the mice maintained on SD. Surprisingly, the mice maintained on sfED also showed signs of insulin resistance with hyperglycaemia, hypertriglyceridaemia, and greater triglyceride glucose index, comparable to the ED group mice. In addition, the ED mice had greater adiposity primarily due to the increase in white adipose tissue, although the body weight was comparable to the control mice receiving only water. The mice maintained on SFA diet exhibited significantly greater weight gain, body fat, cholesterol and insulin, whilst blood glucose and triglyceride concentrations remained comparable to the control mice. Collectively, these data suggest that the consumption of both standard and sugar-free forms of energy drinks induces metabolic syndrome, particularly insulin resistance.

Gab2 deficiency suppresses high-fat diet-induced obesity by reducing adipose tissue inflammation and increasing brown adipose function in mice.

Obesity is caused by a long-term imbalance between energy intake and consumption and is regulated by multiple signals. This study investigated the effect of signaling scaffolding protein Gab2 on obesity and its relevant regulation mechanism. Gab2 knockout (KO) and wild-type (WT) mice were fed with a standard diet (SD) or high-fat diet (HFD) for 12 weeks. The results showed that the a high-fat diet-induced Gab2 expression in adipose tissues, but deletion of Gab2 attenuated weight gain and improved glucose tolerance in mice fed with a high-fat diet. White adipose tissue and systemic inflammations were reduced in HFD-fed Gab2 deficiency mice. Gab2 deficiency increased the expression of Ucp1 and other thermogenic genes in brown adipose tissue. Furthermore, the regulation of Gab2 on the mature differentiation and function of adipocytes was investigated in vitro using primary or immortalized brown preadipocytes. The expression of brown fat-selective genes was found to be elevated in differentiated adipocytes without Gab2. The mechanism of Gab2 regulating Ucp1 expression in brown adipocytes involved with its downstream PI3K (p85)-Akt-FoxO1 signaling pathway. Our research suggests that deletion of Gab2 suppresses diet-induced obesity by multiple pathways and Gab2 may be a novel therapeutic target for the treatment of obesity and associated complications.

Rifampicin impairs adipogenesis by suppressing NRF2-ARE activity in mice fed a high-fat diet.

Prolonged treatment with rifampicin (RFP), a first-line antibacterial agent used in the treatment of drug-sensitive tuberculosis, may cause various side effects, including metabolic disorders. The nuclear factor (erythroid-derived 2)-like 2 (NFE2L2, also known as NRF2) plays an essential regulatory role in cellular adaptive responses to stresses via the antioxidant response element (ARE). Our previous studies discovered that NRF2 regulates the expression of CCAAT-enhancer-binding protein ß (Cebpb) and peroxisome proliferator-activated receptor gamma (Pparg) in the process of adipogenesis. Here, we found that prolonged RFP treatment in adult male mice fed a high-fat diet developed insulin resistance, but reduced fat accumulation and decreased expression of multiple adipogenic genes in white adipose tissues. In 3 T3-L1 preadipocytes, RFP reduced the induction of Cebpb, Pparg and Cebpa at mRNA and protein levels in the early and/or later stage of hormonal cocktail-induced adipogenesis. Mechanistic investigations demonstrated that RFP inhibits NRF2-ARE luciferase reporter activity and expression of NRF2 downstream genes under normal culture condition and in the early stage of adipogenesis in 3 T3-L1 preadipocytes, suggesting that RFP can disturb adipogenic differentiation via NRF2-ARE interference. Taken together, we demonstrate a potential mechanism that RFP impairs adipose function by which RFP likely inhibits NRF2-ARE pathway and thereby interrupts its downstream adipogenic transcription network.

Enalapril and treadmill running reduce adiposity, but only the latter causes adipose tissue browning in mice.

This study investigated whether regulation of the renin-angiotensin system (RAS) by enalapril and/or aerobic exercise training (AET) causes browning of the subcutaneous white adipose tissue (sWAT). C57BL/6 mice were fed either a standard chow or a high-fat (HF) diet for 16 weeks. At Week 8, HF-fed animals were divided into sedentary (HF), enalapril (HF-E), AET (HF-T), and enalapril plus AET (HF-ET) groups. Subsequently, sWAT was extracted for morphometry, determination of RAS expression, and biomarkers of WAT browning. The HF group displayed adipocyte hypertrophy and induction of the classical RAS axis. Conversely, all interventions reduced adiposity and induced the counterregulatory RAS axis. However, only AET raised plasma irisin, increased peroxisome proliferator-activated receptor-γ coactivator-1α, and uncoupling protein-1 levels, and the expression of PR-domain containing 16 in sWAT. Therefore, we concluded that AET-induced sWAT browning was independent of the counterregulatory axis shifting of RAS in HF diet-induced obesity.

Effects of Hyperthyroidism on Adipose Tissue Activity and Distribution in Adults.

Background: Positron emission tomography (PET) has provided evidence that adult humans retain metabolically active brown adipose tissue (BAT) depots. Thyroid hormones (TH) stimulate BAT thermogenesis by central and peripheral mechanisms. However, the effect of hyperthyroidism on BAT activity and BAT volume in humans is yet not fully understood. The aim of this study was to investigate the effect of TH on (i) the metabolic activity of brown and white adipose tissue (WAT) depots, (ii) on abdominal visceral and subcutaneous adipose tissue area, and (iii) on serum levels of metabolically active cytokines. Methods: Nineteen patients with overt hyperthyroidism were investigated through repeated 2-[18F]fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (2-[18F]FDG PET/CT) in the hyperthyroid and in the euthyroid state. The 2-[18F]FDG uptake was calculated as standard uptake ratio with blood pool as reference. Fat areas were quantified by means of CT segmentation. Serum levels of fetuin A and B, fibroblast growth factor 21, adipocyte fatty acid-binding protein (AFABP), retinol-binding protein 4, pro-enkephalin, pro-neurotensin, and neuregulin 4 were determined in the hyperthyroid and in the euthyroid state for each subject. Results: 2-[18F]FDG uptake was increased in the hyperthyroid state in BAT in comparison with the euthyroid phase (p = 0.001). There was no correlation between serum free triiodothyronine (fT3) and free thyroxine (fT4) levels and 2-[18F]FDG uptake in BAT or WAT. In the hyperthyroid state, fT3 levels were positively associated with skeletal muscle standardized uptake value ratios. Areas of visceral adipose tissue and skeletal muscle were significantly decreased in hyperthyroidism. AFABP levels correlated positively with fT3 (p = 0.031, ß = 0.28) and fT4 (p = 0.037, ß = 0.27) in the hyperthyroid state. Conclusions: Our results suggest that the contribution of increased TH levels to the glucose uptake of BAT and WAT is low compared with that of the skeletal muscle. Hyperthyroid subjects have reduced areas of visceral adipose tissue and increased AFABP levels.

The Lipid Handling Capacity of Subcutaneous Fat Is Programmed by mTORC2 during Development.

Overweight and obesity are associated with type 2 diabetes, non-alcoholic fatty liver disease, cardiovascular disease and cancer, but all fat is not equal, as storing excess lipid in subcutaneous white adipose tissue (SWAT) is more metabolically favorable than in visceral fat. Here, we uncover a critical role for mTORC2 in setting SWAT lipid handling capacity. We find that subcutaneous white preadipocytes differentiating without the essential mTORC2 subunit Rictor upregulate mature adipocyte markers but develop a striking lipid storage defect resulting in smaller adipocytes, reduced tissue size, lipid re-distribution to visceral and brown fat, and sex-distinct effects on systemic metabolic fitness. Mechanistically, mTORC2 promotes transcriptional upregulation of select lipid metabolism genes controlled by PPARγ and ChREBP, including genes that control lipid uptake, synthesis, and degradation pathways as well as Akt2, which encodes a major mTORC2 substrate and insulin effector. Further exploring this pathway may uncover new strategies to improve insulin sensitivity.

Spinophilin-deficient mice are protected from diet-induced obesity and insulin resistance.

Browning of white adipose tissue (WAT) has been shown to reduce obesity and obesity-related complications, suggesting that factors that promote WAT browning may have applications in the development of therapeutic strategies for treating obesity. Here, we show that ablation of spinophilin (SPL), a ubiquitously expressed, multidomain scaffolding protein, increases metabolism and improves energy balance. Male and female SPL knockout (KO) and wild-type (WT) littermate controls were fed a chow diet or a high-fat diet (HFD). Body weight, hepatic steatosis, glucose and insulin tolerance, physical activity, and expression of browning genes in adipose tissues were measured and compared. Male SPL knockout (KO) mice fed a chow diet were significantly leaner, had lower body weights, and exhibited better glucose tolerance and insulin sensitivity than wild-type (WT) littermate controls. When fed an HFD, SPL KO mice were protected from increased body fat, weight gain, hepatic steatosis, hyperinsulinemia, and insulin resistance. Physical activity of SPL KO mice was markedly increased compared with WT controls. Furthermore, expression of the brown adipocyte marker, uncoupling protein-1 (UCP-1), and the mitochondrial activity markers, cd137 and c-idea, were significantly increased in visceral WAT (vWAT) of SPL KO mice, suggesting that SPL knockout protected the mice from HFD-induced obesity and its metabolic complications, at least in part, by promoting the browning of white adipocytes in vWAT. Our data identify a critical role of SPL in regulating glucose homeostasis, obesity, and adipocyte browning. These results suggest SPL may serve as a drug target for obesity and diabetes.

Stromal cell-derived factor 1 (SDF1) attenuates platelet-derived growth factor-B (PDGF-B)-induced vascular remodeling for adipose tissue expansion in obesity.

Platelet-derived growth factor-B (PDGF-B) is a main factor to promote adipose tissue angiogenesis, which is responsible for the tissue expansion in obesity. In this process, PDGF-B induces the dissociation of pericytes from blood vessels; however, its regulatory mechanism remains unclear. In the present study, we found that stromal cell-derived factor 1 (SDF1) plays an essential role in this regulatory mechanism. SDF1 mRNA was increased in epididymal white adipose tissue (eWAT) of obese mice. Ex vivo pharmacological analyses using cultured adipose tissue demonstrated that physiological concentrations (1-100 pg/mL) of SDF1 inhibited the PDGF-B-induced pericyte dissociation from vessels via two cognate SDF1 receptors, CXCR4 and CXCR7. In contrast, higher concentrations (> 1 ng/mL) of SDF1 alone caused the dissociation of pericytes via CXCR4, and this effect disappeared in the cultured tissues from PDGF receptor ß (PDGFRß) knockout mice. To investigate the role of SDF1 in angiogenesis in vivo, the effects of anagliptin, an inhibitor of dipeptidyl peptidase 4 (DPP4) that degrades SDF1, were examined in mice fed a high-fat diet. Anagliptin increased the SDF1 levels in the serum and eWAT. These changes were associated with a reduction of pericyte dissociation and fat accumulation in eWAT. AMD3100, a CXCR4 antagonist, cancelled these anagliptin effects. In flow-cytometry analysis, anagliptin increased and decreased the PDGF-B expression in endothelial cells and macrophages, respectively, whereas anagliptin reduced the PDGFRß expression in pericytes of eWAT. These results suggest that SDF1 negatively regulates the adipose tissue angiogenesis in obesity by altering the reactivity of pericytes to PDGF-B.

Review on multifaceted involvement of perivascular adipose tissue in vascular pathology.

Perivascular adipose tissue (PVAT) is a fat tissue deposit that encircles the vasculature. PVAT is traditionally known to protect the vasculature from external stimuli that could cause biological stress. In addition to the protective role of PVAT, it secretes certain biologically active substances known as adipokines that induce paracrine effects on proximate blood vessels. These adipokines influence vascular tones. There are different types of PVAT and they are phenotypically and functionally distinct. These are the white and brown PVATs. Under certain conditions, white PVAT could undergo phenotypic switch to attain a brown PVAT-like phenotype. This type of PVAT is referred to as Beige PVAT. The morphology of adipose tissue is influenced by species, age, and sex. These factors play significant roles in adipose tissue mass, functionality, paracrine activity, and predisposition to vascular diseases. The difficulty that is currently experienced in extrapolating animal models to human physiology could be traceable to these factors. Up till now, the involvement of PVAT in the development of vascular pathology is still not well understood. Brown and white PVAT contribute differently to vascular pathology. Thus, the PVAT could be a therapeutic target in curbing certain vascular diseases. In this review, knowledge would be updated on the multifaceted involvement of PVAT in vascular pathology and also explore its vascular therapeutic potential.

Exposure to Low Doses of Dechlorane Plus Promotes Adipose Tissue Dysfunction and Glucose Intolerance in Male Mice.

The prevalence of type 2 diabetes (T2D) continues to increase worldwide. It is well established that genetic susceptibility, obesity, overnutrition and a sedentary life style are risk factors for the development of T2D. However, more recently, studies have also proposed links between exposure to endocrine-disrupting chemicals (EDCs) and altered glucose metabolism. Human exposure to environmental pollutants that are suspected to have endocrine disruptor activity is ubiquitous. One such chemical is Dechlorane Plus (DP), a flame retardant, that is now detected in humans and the environment. Here we show that exposure of mice to low, environmentally relevant doses of DP promoted glucose intolerance in mice fed a high-fat diet independent of weight gain. Furthermore, DP had pronounced effects on the adipose tissue, where it induced the development of hypertrophied white adipose tissue (WAT), and increased serum levels of resistin, leptin, and plasminogen activator inhibitor-1. In addition, DP exposure induced "whitening" of brown adipose tissue (BAT), and reduced BAT uncoupling protein 1 expression. Importantly, some of these effects occurred even when the mice were fed a regular, low-fat, diet. Finally, WAT adipogenic markers were reduced with DP treatment in the WAT. We also show that DP directly inhibited insulin signaling in murine adipocytes and human primary subcutaneous adipocytes in vitro. Taken together, our results show that the exposure to low and environmentally relevant levels of DP may contribute to the development of T2D.

Post-weaning exposure to high-sucrose diet induces early non-alcoholic fatty liver disease onset and progression in male mice: role of dysfunctional white adipose tissue.

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) particularly among chronic consumers of added sugar-rich diets. However, the impact of early consumption of such diets on NAFLD onset and progression is unclear. Thus, this study sought to characterise metabolic factors involved in NAFLD progression in young mice fed with a high-sucrose diet (HSD). Male Swiss mice were fed HSD or regular chow (CTR) from weaning for up to 60 or 90 days. Obesity development, glucose homeostasis and serum biochemical parameters were determined at each time-point. At day 90, mice were euthanised and white adipose tissue (WAT) collected for lipolytic function assessment and liver for histology, gene expression and cytokines quantification. At day 60, HSD mice presented increased body mass, hypertriglyceridemia, peripheral insulin resistance (IR) and simple steatosis. Upon 90 days on diet, WAT from HSD mice displayed impaired insulin sensitivity, which coincided with increased fasting levels of glucose and free fatty acids (FFA), as well as NAFLD progression to NASH. Transcriptional levels of lipogenic genes, particularly stearoyl-CoA desaturase-1, were consistently increased, leading to hepatic leukocyte infiltration and pro-inflammatory cytokines spillover. Therefore, our dataset supports IR triggering in the WAT as a major factor for dysfunctional release of FFA towards portal circulation and consequent upregulation of lipogenic genes and hepatic inflammatory onset, which decisively concurred for NAFLD-to-NASH progression in young HSD-fed mice. Notwithstanding, this study forewarns against the early introduction of dietary sugars in infant diet, particularly following breastfeeding cessation.

Pancreastatin inhibitor PSTi8 protects the obesity associated skeletal muscle insulin resistance in diet induced streptozotocin-treated diabetic mice.

Pancreastatin (PST), a chromogranin A (CHGA) derived peptide connects obesity with insulin resistance by inducing inflammation. Previously, we have evaluated potential activity of PST inhibitor (PSTi8) in liver and adipose tissue in type 2 diabetic mice model. In this study we further explore the therapeutic effect of PSTi8 on glucose metabolism in skeletal muscle cells/tissue and its effect on energy homeostasis in diet induced diabetic mice model. In in-vitro studies, we found that PSTi8 increases glucose uptake via enhanced GLUT4 translocation in L6 cells. This positive effect of PSTi8 led us to proceed with in-vivo studies in diabetic mice. C57BL/6 mice were fed HFD or HFrD diet for 12 weeks along with single STZ induction at 4th week followed by PSTi8 treatment. We found that HFD and HFrD model showed increased fat mass, caused glucose intolerance and insulin resistance, with accompanying proinflammatory effect on epididymal white adipose tissue (eWAT) together leading to skeletal muscle insulin resistance. Administration of PSTi8 protects from diet induced inflammatory response and enhances glucose tolerance and insulin sensitivity. PSTi8 improves circulating adipokine and lipid parameters, along with switch in macrophage polarisation from M1 to M2 in stromal vascular fraction of adipose tissue. In addition, treatment of PSTi8 also improves energy homeostasis, decreases circulatory non-esterified fatty acids level and inhibits ceramide deposition in muscle tissue. Overall this increased muscle insulin sensitivity is mediated via AKT/AS160/GLUT4 pathway activation. Our results reveal that PSTi8 inhibits the obesity mediated inflammation which enhances glucose disposal in skeletal muscle.

Misadjustment of diurnal expression of core temperature and locomotor activity in lactating rabbits associated with maternal over-nutrition before and during pregnancy.

Metabolic parameters ranging from circulating nutrient levels and substrate utilization to energy expenditure and thermogenesis are temporally modulated by the circadian timing system. During critical embryonic developmental periods, maternal over-nutrition could alter key elements in different tissues associated with the generation of circadian rhythmicity, compromising normal rhythmicity development. To address this issue, we determine whether maternal over-nutrition leads to alterations in the development of circadian rhythmicity at physiological and behavioral levels in the offspring. For this, female rabbits were fed a standard diet (SD) or high-fat and carbohydrate diet (HFCD) before mating and during gestation. Core body temperature and gross locomotor activity were continuously recorded in newborn rabbits, daily measurements of body weight and the amount of milk ingested was carried out. At the end of lactation, tissue samples, including brown adipose tissue (BAT) and white adipose tissue (WAT), were obtained for determining the expression of uncoupling protein-1 (UCP1) and cell death-inducing DNA fragmentation factor-like effector A (CIDEA) genes. HFCD pups exhibited conspicuous differences in the development of the daily rhythm of temperature and locomotor activity compared to the SD pups, including a significant increase in the daily mean core temperature, changes in the time when temperature or activity remains above the average, shifts in the acrophase, decrease in the duration and intensity of the anticipatory rise previous to nursing, and changes in frequency of the rhythms. HFCD pups exhibited a significant increase in BAT thermogenesis markers, and a decrease of these markers in WAT, indicating more heat generation by brown adipocytes and alterations in the browning process. These results indicate that maternal over-nutrition alters offspring homeostatic and chronostatic regulation at the physiological and behavioral levels. Further studies are needed to determine whether these alterations are associated with the changes in the organization of the circadian system of the progeny.

Eicosapentaenoic and Docosahexaenoic Acids Differentially Alter Gut Microbiome and Reverse High-Fat Diet-Induced Insulin Resistance.

SCOPE: To assess the individual effects of dietary eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on insulin resistance (IR), gut microbiome, and gut metabolites in high-fat-diet-induced obese (DIO) mice. METHODS AND RESULTS: DIO mice are fed an either high-fat diet (HFD), EPA (1% w/w) enriched HFD, or DHA (1% wt/wt) enriched HFD for 15 weeks. Both EPA and DHA supplements reverse hyperglycemia and IR but do not affect body weight in DIO mice while DHA exhibits a more pronounced ameliorative effect in male mice. Both EPA- and DHA-enriched Lactobacillus and short-chain fatty acids (SCFAs)-producing species from Lachnospiraceae while reduced lipopolysaccharide (LPS)-producing Bilophila and Escherichia/Shigella. Compared with EPA, DHA-supplemented mice have more abundant propionic/butyric acid-producing bacteria, including Coprococcus, Butyricimonas synergistica, Bacteroides acidifaciens, and Intestinimonas, and less-abundant LPS-correlated species Streptococcus and p-75-a5. The shifts in gut microbiome co-occurred with the changes in levels of propionic/butyric acid, circulating LPS, and serotonin. Additionally, EPA/DHA supplementation attenuates adipose inflammation with upregulated glucose transporter 4 and Akt phosphorylation, indicating the improvement of insulin signaling. CONCLUSION: EPA and DHA differentially reverse IR and relieve adipose inflammation while modulating gut microbiome and SCFAs/LPS production, underscoring the gut-adipose axis as a primary target of EPA/DHA.