Leptin Expression Research Articles

SUCNR1 signaling in adipocytes controls energy metabolism by modulating circadian clock and leptin expression

SUCNR1 signaling in adipocytes controls energy metabolism by modulating circadian clock and leptin expression

Oral probiotics increased the proportion of Treg, Tfr, and Breg cells to inhibit the inflammatory response and impede gestational diabetes mellitus

BackgroundChildren of mothers with gestational diabetes mellitus (GDM) are more prone to acquire type 2 diabetes and obesity as adults. Due to this link, early intervention strategies that alter the gut microbiome may benefit the mother and kid long-term. This work uses metagenomic and transcriptome sequencing to investigate how probiotics affect gut microbiota dysbiosis and inflammation in GDM.MethodsGDM and control metagenomic sequencing data were obtained from the SRA database. This metagenomic data helped us understand gut microbiota abundance and function. KEGG detected and extracted functional pathway genes. Transcriptome sequencing data evaluated GDM-related gene expression. Finally, GDM animal models were given probiotics orally to evaluate inflammatory response, regulatory immune cell fractions, and leptin protein levels.ResultsGDM patients had more Fusobacteria and Firmicutes, while healthy people had more Bacteroidetes. Gut microbiota composition may affect GDM by altering the L-aspartate and L-asparagine super pathways. Mannan degradation and the super pathway of L-aspartate and L-asparagine synthesis enhanced in GDM mice with leptin protein overexpression. Oral probiotics prevent GDM by lowering leptin. Oral probiotics increased Treg, Tfr, and Breg cells, which decreased TNF-α and IL-6 and increased TGF-β and IL-10, preventing inflammation and preserving mouse pregnancy.ConclusionDysbiosis of the gut microbiota may increase leptin expression and cause GDM. Oral probiotics enhance Treg, Tfr, and Breg cells, which limit the inflammatory response and assist mice in sustaining normal pregnancy. Thus, oral probiotics may prevent GDM, enabling targeted gut microbiota modulation and maternal and fetal health.

High Gamma-Aminobutyric Acid (GABA) Oolong Tea Alleviates High-Fat Diet-Induced Metabolic Disorders in Mice.

Obesity and overweight are associated with an increasing risk of developing health conditions and chronic non-communicable diseases, including cardiovascular diseases, cancer, musculoskeletal problems, respiratory problems, and mental health, and its prevalence is rising. Diet is one of three primary lifestyle interventions. Many bioactive components in tea especially oolong tea, including flavonoids, gamma-aminobutyric acid (GABA), and caffeine were reported to show related effects in reducing the risk of obesity. However, the effects of GABA oolong tea extracts (OTEs) on high-fat diet (HFD)-induced obesity are still unclear. Therefore, this study aims to explore whether the intervention of GABA OTEs can prevent HFD-induced obesity and decipher its underlying mechanisms using male C57BL/6 J mice. The result indicated that GABA OTEs reduced leptin expression in epididymal adipose tissue and showed a protective effect on nonalcoholic fatty liver disease. It promoted thermogenesis-related protein of uncoupling protein-1 and peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α), boosted lipid metabolism, and promoted fatty acid oxidation. It also reduced lipogenesis-related protein levels of sterol regulatory element binding protein, acetyl-CoA carboxylase, and fatty acid synthase and inhibited hepatic triglyceride (TG) levels. These data suggest that regular drinking of GABA oolong tea has the potential to reduce the risk of being overweight, preventing obesity development through thermogenesis, lipogenesis, and lipolysis.

Regulation of adipocyte leptin expression by signaling metabolite

Regulation of adipocyte leptin expression by signaling metabolite

Regulation and function of adiponectin in the intestinal epithelial cells in response to Trichinella spiralis infection

Besides metabolic homeostasis regulation, adipokines are recently emerged as important players in regulating immunity and inflammation. Helminth infection has known to modulate circulating adipokine secretion; however, the regulation and function of adipokines in response to helminth infection is still unclear. Here, we investigated the regulation and function of adiponectin during T. spiralis infection. While there was no change in circulating level of adiponectin, we found an increased adiponectin, but not leptin expression in the small intestine. Interestingly, the intestinal adiponectin expression was strongly associated with the expression of epithelial cell-derived cytokines IL-25, IL-33, and TSLP following infection. Indeed, mice deficiency of IL-25 receptor exhibited no intestinal adiponectin induction upon helminth infection. Interestingly, IL-25-induced adiponectin modulated intestinal epithelial cell responses by enhancing occludin and CCL17 expression. Using LPS-induced intestinal epithelial barrier dysfunctions in a Caco-2 cell monolayer model, adiponectin pretreatment enhanced a Transepithelial electrical resistance (TEER) and occludin expression. More importantly, adiponectin pretreatment of Caco2 cells prevented T. spiralis larval invasion in vitro and its administration during infection enhanced intestinal IL-13 secretion and worm expulsion in vivo. Altogether, our data suggest that intestinal adiponectin expression induced by helminth infection through the regulation of IL-25 promotes worm clearance and intestinal barrier function.

커피발효물의 발효특성 및 항비만 효과

This study was conducted to investigate the fermentation characteristics and anti-obesity effects of acetic acid fermentation products of coffee wine. The live cell counts, soluble solids, pH and total acidity of the acetic acid unfermented coffee wine (AUFCW; day 0, before fermentation) were 6.35 log CFU/mL, 8.10 °Brix, 3.88, and 1.29%, respectively, while the acetic acid fermented coffee wine (AFCW; day 15, after fermentation) were 4.40 log CFU/mL, 8.57 °Brix, 3.07, and 7.45%, respectively. Pancreatic lipase inhibitory activity tended to increase as the acetic acid fermentation period increased. The anti-obesity effects of AFCW on 3T3-L1 cells, which was induced by MDI, were evaluated based on the lipid accumulation rate, leptin expression, and fat production-related gene expression (PPAR-γ and SREBP-1c) at the mRNA level. In the case of AFCW, the lipid accumulation rate and leptin expression were decreased to 69.37% and 50.20% at a concentration of 200 μg/mL, respectively, and the expression levels of PPAR-γ and SREBP-1c at the mRNA level were decreased to 79.89% and 48.81%, respectively. These results indicate that anti-obesity effect of acetic acid fermentation products could be increased by acetic acid fermentation of coffee wine.

Paternal developmental thyrotoxicosis disrupts neonatal leptin leading to increased adiposity and altered physiology of the melanocortin system.

The genetic code does not fully explain individual variability and inheritance of susceptibility to endocrine conditions, suggesting the contribution of epigenetic factors acting across generations. We used a mouse model of developmental thyrotoxicosis (Dio3-/- mouse) to analyze endocrine outcomes in the adult offspring of Dio3-/- males using standard methods for body composition, and baseline and fasting hormonal and gene expression determinations in serum and tissues of relevance to the control of energy balance. Compared to controls, adult females with an exposed father (EF females) exhibited higher body weight and fat mass, but not lean mass, a phenotype that was much milder in EF males. After fasting, both EF females and males exhibited a more pronounced decrease in body weight than controls. EF females also showed markedly elevated serum leptin, increased white adipose tissue mRNA expression of leptin and mesoderm-specific transcript but decreased expression of type 2 deiodinase. EF females exhibited decreased serum ghrelin, which showed more pronounced post-fasting changes in EF females than in control females. EF female hypothalami also revealed significant decreases in the expression of pro-opiomelanocortin, agouti-related peptide, neuropeptide Y and melanocortin receptor 4. These markers also showed larger changes in response to fasting in EF females than in control females. Adult EF females showed no abnormalities in serum thyroid hormones, but pituitary expression of thyrotropin-releasing hormone receptor 1 and thyroid gland expression of thyroid-stimulating hormone receptor, thyroid peroxidase and iodotyrosine deiodinase were increased at baseline and showed differential regulation after fasting, with no increase in Trhr1 expression and more pronounced reductions in Tshr, Tpo and Iyd. In EF males, these abnormalities were generally milder. In addition, postnatal day 14 (P14) serum leptin was markedly reduced in EF pups. A paternal excess of thyroid hormone during development modifies the endocrine programming and energy balance in the offspring in a sexually dimorphic manner, with baseline and dynamic range alterations in the leptin-melanocortin system and thyroid gland, and consequences for adiposity phenotypes. We conclude that thyroid hormone overexposure may have important implications for the non-genetic, inherited etiology of endocrine and metabolic pathologies.

Baicalein enhances immune response in TNBC by inhibiting leptin expression of adipocytes.

Triple-negative breast cancer (TNBC) is a special pathological type of breast cancer (BC) with poor prognosis. Obesity is shown to be involved in TNBC tumor progression. The interaction between obesity and BC has generated great attention in recent years, however, the mechanism is still unclear. Here, we showed that leptin secreted by adipocytes upregulated PD-L1 expression in TNBC through the p-STAT3 signaling pathway and that baicalein inhibited PD-L1 expression in tumor microenvironment by suppressing leptin transcription of adipocytes. Collectively, our findings suggest that leptin may be the key factor participating in obesity-related tumor progression and that baicalein can break through the dilemma to boost the anti-tumor immune response.

Immunometabolism mRNA expression phenotypes and reprogramming of CD14 in T2DM with or without CVD

Background/AimType 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD) have a significant impact on the expression of genes in peripheral blood mononuclear cells (PBMCs). The primary objective of this study was to investigate the role of two signaling pathways, STAT1/6, and two important modulators of immunometabolism, leptin and PPARs, in the development of T2DM with and without CVD. Furthermore, the study aimed to assess the correlation between these factors and the dynamics of CD14 in PBMCs. This research was conducted within the context of a growing body of literature on the complex pathophysiology of T2DM and its association with CVD. Prior studies have indicated that T2DM is characterized by an imbalance in immunometabolism and the involvement of various signaling pathways. Materials and methodsBlood samples were collected from a total of 47 subjects, including 7 healthy volunteers, 20 individuals diagnosed with diabetes and cardiovascular disease (D.CVD) and another 20 individuals diagnosed with diabetes only (D). PBMCs were isolated from these samples, and the expression levels of leptin, PPARγ, PPARα, and CD14 genes were measured using Real-Time PCR. ResultsThe most relevant result showed that diabetic patients with CVD had significantly higher levels of leptin expression, which was positively correlated with STAT1 (r = 0.7497, p = 0.0001). On the other hand, diabetic patients without CVD had elevated PPARγ expression, which was strongly correlated with STAT6 (r = 0.8437, p = 0.0001). Interestingly, we found a significant increase in the PPARγ/ PPARα ratio in the D.CVD group compared to the D group (4.273 ± 0.9531; 7.52 ± 3.556, p = 0.0479). Moreover, CD14 expression was significantly reduced in this group compared to diabetic patients without CVD. ConclusionThese findings suggested that the immunometabolic imbalance in T2DM was driven by a STAT1/Leptin phenotype in diabetic patients with CVD and by a STAT6/PPARγ phenotype in diabetic patients without CVD. Taking into account STAT1/Leptin and STAT6/PPARγ profiling could help clinicians identify novel therapeutic targets for T2DM and other related diseases.

Liraglutide ameliorates diabetic-induced testicular dysfunction in male rats: role of GLP-1/Kiss1/GnRH and TGF-β/Smad signaling pathways.

Introduction: Glucagon-like peptide -1 (GLP-1) is released by intestinal cells to stimulate glucose-dependent insulin release from the pancreas. GLP-1 has been linked to ameliorating obesity and/or diabetic complications as well as controlling reproductive function. Liraglutide is a GLP-1 receptor agonist (GLP-1RA) with 97% homology with GLP-1. The main objective of this study was to investigate the ameliorative role of liraglutide in diabetic-induced reproductive dysfunction in male rats. Methods: Rats were randomly allocated into 3 groups; a control group, a diabetic group, and a liraglutide-treated diabetic group. Results: In the diabetic group, a significant increase in BMI, FBG, HbA1c, HOMA-IR, TC, TAG, LDL, IL6, TNFα, and MDA, as well as decreased serum insulin, HDL, GSH, total testosterone, LH, and FSH, were shown compared to the control group. Furthermore, A significant downregulation in relative hypothalamic gene expression of GLP-1R, PPAR-α, PGC-1α, kiss, kiss1R, leptin, leptin R, GnRH GLP-1R, testicular PGC-1α, PPARα, kiss1, kiss1R, STAR, CYP17A1, HSD17B3, CYP19A, CYP11A1, and Smad7, as well as upregulation in hypothalamic GnIH and testicular TGF- β and Smad2 expression, were noticed compared to the control group. Liraglutide treatment significantly improved such functional and structural reproductive disturbance in diabetic rats. Conclusion: GLP-1RAs ameliorated the deleterious effects of diabetes on reproductive function by targeting GLP-1/leptin/kiss1/GnRH, steroidogenesis, and TGF- β/Smad pathways.

Dry heat whole Sorghum BRS 305 flour modulate satiety and improves antioxidant response in brain of Wistar rats fed with high-fat high-fructose diet

Sorghum BRS 305 (Sorghum bicolor L. Moench) is a cereal with high tannins and anthocyanins content and keep better the resistant starch when submitted to dry heat treatment. Our objective was to investigate the effects of BRS 305 dry heat treatment whole sorghum flour on satiety and antioxidant response in brain and adipose tissue of Wistar rats fed with a high fat high fructose diet (HFHF). Male Wistar rats were divided in two groups: control (n = 8) and HFHF (n = 16) for eight weeks. After, animals of HFHF group were divided: HFHF (n = 8) and HFHF + BRS 305 sorghum whole flour (n = 8), for 10 weeks. Sorghum consumption reduced gene expression of leptin, resistin, and endocannabinoid receptor 1 type (CB1) in adipose and brain tissues compared to HFHF group. In brain, sorghum consumption also promotes reduction in neuropeptide Y (NPY) gene expression. BRS305 sorghum consumption improved gene expression of sirtuin-1 (SIRT1) in adipose tissue, and in the brain increased heat shock protein 72 (HSP72), erythroid-derived nuclear factor 2 (NRF2), peroxisome proliferator-activated receptor alpha (PPARα), superoxide dismutase (SOD) and catalase activity compared to HFHF. In silicoanalysis showed interaction with PPARα, CB1, and leptin receptors. Advanced glycation end products (AGEs) concentrations in group HFHF + sorghum did not differ from HFHF group. Advanced glycation end products receptors (RAGEs) concentrations did not differ among experimental groups. Then, BRS 305 sorghum submitted to dry treatment was able to modulate gene expression of markers related to satiety and improve antioxidant capacity of rats fed with HFHF diet.

Hepatocellular carcinoma induced by hepatocyte Pten deletion reduces BAT UCP-1 and thermogenic capacity in mice, despite increasing serum FGF-21 and iWAT browning.

Hepatocellular carcinoma (HCC) markedly enhances liver secretion of fibroblast growth factor 21 (FGF-21), a hepatokine that increases brown and subcutaneous inguinal white adipose tissues (BAT and iWAT, respectively) uncoupling protein 1 (UCP-1) content, thermogenesis and energy expenditure. Herein, we tested the hypothesis that an enhanced BAT and iWAT UCP-1-mediated thermogenesis induced by high levels of FGF-21 is involved in HCC-associated catabolic state and fat mass reduction. For this, we evaluated body weight and composition, liver mass and morphology, serum and tissue levels of FGF-21, BAT and iWAT UCP-1 content, and thermogenic capacity in mice with Pten deletion in hepatocytes that display a well-defined progression from steatosis to steatohepatitis (NASH) and HCC upon aging. Hepatocyte Pten deficiency promoted a progressive increase in liver lipid deposition, mass, and inflammation, culminating with NASH at 24 weeks and hepatomegaly and HCC at 48 weeks of age. NASH and HCC were associated with elevated liver and serum FGF-21 content and iWAT UCP-1 expression (browning), but reduced serum insulin, leptin, and adiponectin levelsand BAT UCP-1 content and expression of sympathetically regulated gene glycerol kinase (GyK), lipoprotein lipase (LPL), and fatty acid transporter protein 1 (FATP-1), which altogether resulted in an impaired whole-body thermogenic capacity in response to CL-316,243. In conclusion, FGF-21 pro-thermogenic actions in BAT are context-dependent, not occurring in NASH and HCC, and UCP-1-mediated thermogenesis is not a major energy-expending process involved in the catabolic state associated with HCC induced by Pten deletion in hepatocytes.

Distinct inflammatory signatures of upper and lower body adipose tissue and adipocytes in women with normal weight or obesity.

Upper and lower body fat accumulation poses an opposing obesity-related cardiometabolic disease risk. Depot-differences in subcutaneous adipose tissue (SAT) function may underlie these associations. We aimed to investigate the inflammatory signatures of abdominal (ABD) and femoral (FEM) SAT in postmenopausal women with normal weight or obesity. We included 23 postmenopausal women with normal weight (n = 13) or obesity (n = 10). In vivo secretion of adipokines from ABD and FEM SAT was measured using the arterio-venous balance technique. Adipokine gene expression and adipocyte morphology were examined in ABD and FEM SAT. Furthermore, adipokine expression and secretion were investigated in vitro using differentiated human primary ABD and FEM subcutaneous adipocytes derived from the study participants. Plasma leptin and plasminogen activator inhibitor (PAI)-1 concentrations were higher, and ABD and FEM adipocytes were larger in women with obesity than normal weight. No differences in adipocyte size and blood flow were apparent between ABD and FEM SAT. We found significant release of leptin and monocyte chemoattractant protein (MCP)-1 from ABD and FEM SAT, with higher fractional release of MCP-1 from ABD than FEM SAT. Gene expression of leptin, PAI-1, and tumor necrosis factor-α was lower in ABD than FEM SAT and higher in women with obesity than normal weight. In ABD adipocytes, interleukin-6, PAI-1, and leptin gene expression were higher, while adiponectin and dipeptidyl-peptidase-4 gene expression were lower than in FEM adipocytes. Finally, ABD adipocytes secreted less MCP-1 compared to FEM adipocytes. These findings demonstrate that upper and lower body SAT and adipocytes are characterized by distinct inflammatory signatures in postmenopausal women, which seem independent of adipocyte size.

308-OR: Hippo-YAP/TAZ Signaling Coordinates Adipose Plasticity and Energy Balance by Uncoupling Leptin Expression from Fat Mass

Adipose tissue regulates systemic energy homeostasis by acting as an energy reservoir and endocrine organ. Coordinated regulation of these functions is essential for metabolic health, but the underlying mechanisms are unknown. Here we show that the transcriptional coregulators YAP and TAZ mediate the crosstalk between adipose tissue mass and leptin levels to maintain systemic energy balance. The activation of adipocyte-specific YAP/TAZ via genetic ablation of the upstream regulators LATS1 and LATS2 resulted in a profound reduction in fat mass due to the conversion of mature adipocytes into delipidated cells with progenitor-like features. Rosiglitazone treatment normalized fat mass, indicating that PPARG inhibition is a major contributor to YAP/TAZ-induced lipoatrophy. Surprisingly, LATS1/2 knockout mice did not exhibit lipodystrophy-related metabolic dysfunction. This phenotype was attributed to a paradoxical increase in circulating leptin levels, which was found to offset the energy storage deficit by increasing fat oxidation and energy expenditure. Mechanistically, we identify a YAP/TAZ-TEAD axis that upregulates leptin expression by direct binding to an upstream enhancer site of the leptin gene. Finally, we show that YAP/TAZ activity is associated with leptin regulation during fasting and refeeding, indicating that YAP/TAZ links nutrient status in adipose tissue to systemic energy homeostasis. Taken together, we reveal that adipocyte Hippo-YAP/TAZ functions as a nexus for coordinating nutrient storage capacity and systemic energy balance by regulating adipocyte plasticity and leptin gene transcription. Disclosure S.Choi: None. K.Park: None. H.Shin: None. J.Suh: None.

1523-P: A Leptin-Mediated Interoceptive Network between the Brain and Brown Adipose Tissue

Obesity is attributed to chronic disruption in energy homeostasis. This phenomenon is controlled by systemic and local signals such as leptin, a nutrient-sensitive signal secreted primarily by the white adipose tissue (WAT). Previously, interscapular brown adipose tissue (iBAT) has been shown to express undetectable or very low levels of leptin. Unexpectedly, in this study, we observed that iBAT leptin expression displayed a distinct circadian pattern and fluctuated with nutritional and ambient temperature. These observations suggest a vital role of iBAT leptin in the regulation of energy homeostasis. To explore this idea, we performed gain and loss of function experiments by overexpressing (LEPOE) or knocking down (LEPKD) leptin selectively in UCP1+ cells of iBAT, respectively. We found that LEPOE reduced food intake while LEPKD increased it in normal and fasting-induced feeding conditions. Notably, LEPOE/LEPKD selectively increased/decreased the mRNA expression of leptin in the iBAT without affecting circulating leptin levels, indicating a possible paracrine role of iBAT leptin. In supporting this point of view, we found that the leptin receptor is highly expressed in the iBAT-associated sensory nerve (iBAT-SN). Moreover, iBAT-specific leptin infusion activated leptin signaling in the iBAT-SN and subsequently stimulated proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus. Conversely, chemical ablation of iBAT-SN increased food intake and blunted hypothalamic POMC activation induced by iBAT-specific leptin infusion. These findings indicate that iBAT possesses a structural and functional basis for paracrine leptin signaling via iBAT-SN, which cross-talks with POMC neurons to modulate energy homeostasis. Our results support an unappreciated metabolic role of iBAT leptin in energy homeostasis. Disclosure M.D.Munoz: None. X.Yang: None. V.C.Torres irizarry: None. P.Luo: None. L.Carrillo-sáenz: None. N.Antony: None. C.Liew: None. P.Xu: None. Funding National Institutes of Health (R01DK123098); U.S. Department of Defense (W81XWH-19-PRMRP-DA); Diabetes Research and Training Center (DK020595)

Predictive Value of Nesfatin-1, Galectin-3, Ghrelin, and Leptin Expressions in Patients with Metabolic Syndrome Who Underwent Coronary Artery Bypass Graft (CABG) Surgery

Predictive Value of Nesfatin-1, Galectin-3, Ghrelin, and Leptin Expressions in Patients with Metabolic Syndrome Who Underwent Coronary Artery Bypass Graft (CABG) Surgery

Effect of reduced water intake on ovarian reserve, leptin immunoexpression and impact of leptin on the in vitro culture of sheep secondary follicles

This study evaluated the effect of reduced water intake on survival, apoptosis and immunoexpression of leptin in sheep preantral follicles, activation of primordial follicles, serum levels of leptin, estradiol (E2) and progesterone (P4), and in vitro maturation (IVM) of oocytes antral follicles, as well evaluated the effects of leptin on in vitro culture of secondary follicles isolated these animals. Ewes (n = 32) were divided into four groups: water ad libitum (Control – 100%), 80%; 60% and 40% of ad libitum intake. Blood was collected to determine, leptin, E2 and P4, before and after experiment. After the slaughter, ovarian cortex was used to histological and immunohistochemistry analysis and oocytes IVM. Moreover, isolated secondary follicles were cultured in vitro for 12 days in control medium (α-MEM+) or α-MEM+ with 10 or 25 ng/mL leptin. The reduction of water intake caused a linear decreasing effect on the percentages of normal preantral follicles, especially of primordial (P < 0.05), increased the apoptosis (P < 0.05) and decreased leptin expression in preantral follicles. The treatment with 60% of water intake showed greater total growth rate of isolated secondary follicles cultured with 25 ng/L leptin (P < 0.05), compared to those cultured in α-MEM+ . In conclusion, reduced water intake impaired the number of normal sheep preantral follicles, especially of primordial follicles, increased apoptosis and decreased leptin expression in preantral follicles. Moreover, secondary follicles from of ewes that receive 60% water intake increased follicular growth after in vitro culture with 25 ng/mL leptin.

Maresin 1 Exerts a Tissue-Specific Regulation of Adipo-Hepato-Myokines in Diet-Induced Obese Mice and Modulates Adipokine Expression in Cultured Human Adipocytes in Basal and Inflammatory Conditions.

This study analyses the effects of Maresin 1 (MaR1), a docosahexaenoic acid (DHA)-derived specialized proresolving lipid mediator with anti-inflammatory and insulin-sensitizing actions, on the expression of adipokines, including adiponectin, leptin, dipeptidyl peptidase 4 (DPP-4), cardiotrophin-1 (CT-1), and irisin (FNDC5), both in vitro and in in vivo models of obesity. The in vivo effects of MaR1 (50 μg/kg, 10 days, oral gavage) were evaluated in epididymal adipose tissue (eWAT), liver and muscle of diet-induced obese (DIO) mice. Moreover, two models of human differentiated primary adipocytes were incubated with MaR1 (1 and 10 nM, 24 h) or with a combination of tumor necrosis factor-α (TNF-α, 100 ng/mL) and MaR1 (1-200 nM, 24 h) and the expression and secretion of adipokines were measured in both models. MaR1-treated DIO mice exhibited an increased expression of adiponectin and Ct-1 in eWAT, increased expression of Fndc5 and Ct-1 in muscle and a decreased expression of hepatic Dpp-4. In human differentiated adipocytes, MaR1 increased the expression of ADIPONECTIN, LEPTIN, DPP4, CT-1 and FNDC5. Moreover, MaR1 counteracted the downregulation of ADIPONECTIN and the upregulation of DPP-4 and LEPTIN observed in adipocytes treated with TNF-α. Differential effects for TNF-α and MaR1 on the expression of CT-1 and FNDC5 were observed between both models of human adipocytes. In conclusion, MaR1 reverses the expression of specific adipomyokines and hepatokines altered in obese mice in a tissue-dependent manner. Moreover, MaR1 regulates the basal expression of adipokines in human adipocytes and counteracts the alterations of adipokines expression induced by TNF-α in vitro. These actions could contribute to the metabolic benefits of this lipid mediator.

Intrarenal Anti-Leptin Treatment Attenuates Ischemia and Reperfusion Injury

Introduction: Renal ischemia and reperfusion (IR) injury introduces cellular stress and is the main cause of acute kidney damage. Renal cells exposed to noxious stress induce the expression of the pleiotropic hormone leptin. As we have previously revealed a deleterious stress-related role for leptin expression, these results suggested that leptin is also involved in pathological renal remodeling. The systemic functions of leptin preclude the study of its local effects using conventional approaches. We have therefore designed a method to locally perturb leptin activity in specific tissues without affecting its systemic levels. This study explores whether local anti-leptin strategy is renoprotective in a post-IR porcine kidney model. Methods: We induced renal IR injury in pigs by exposing kidneys to ischemia and revascularization. Upon reperfusion, kidneys instantly received an intra-arterial bolus of either a leptin antagonist (LepA) or saline solution. Peripheral blood was sampled to assess systemic leptin, IL-6, creatinine, and BUN levels, and postoperative tissue samples were analyzed by hematoxylin and eosin histochemistry and immunohistochemistry. Results: Histology of IR/saline kidneys exhibited extensive necrosis of proximal tubular epithelial cells, as well as elevated levels of apoptosis markers and inflammation. In contrast, IR/LepA kidneys showed no signs of necrosis or inflammation with normal IL-6 and tall-like receptor 4 levels. LepA treatment led to upregulation in mRNA levels of leptin, leptin receptor, ERK1/2, STAT3, and transport molecule Na/H exchanger-3. Conclusions: Local, intrarenal postischemic LepA treatment at reperfusion prevented apoptosis and inflammation and was renoprotective. Selective intrarenal administration of LepA at reperfusion may provide a viable option for clinical implementation.

Effect of metformin on transcriptome and adipokinome of adipocytes of local fat deposts of patients with ischemic heart disease

BACKGROUND: The information available to date on the effect of metformin on the transcriptome and secretory capacity of adipocytes in human adipose tissue (AT) is scarce and contradictory. The study analyzed whether metformin in vitro modulates gene expression and secretion of adiponectin and leptin in the AT of subcutaneous (SAT), epicardial (EAT) and perivascular (PVAT) localization of patients with ischemic artery disease (IHD).AIM: To assess the effect of metformin at various concentrations (1 and 10 mmol / L) on the level of expression of adiponectin and leptin genes and their content in adipocytes of subcutaneous, epicardial and perivascular AT of patients with IHD.MATERIALS AND METHODS: The study included 134 patients with IHD and indications for direct myocardial revascularization by coronary artery bypass grafting (CABG). During the operation, biopsies of SAT, EAT and PVAT were obtained for 3–5 gram, which served as a source of adipocytes. Isolated adipocytes were cultured for 24 hours with and without metformin (1 and 10 mmol / L). After a day of incubation, the expression of the ADIPOQ and LEP genes and the level of secretion of adiponectin and leptin in the culture medium of adipocytes were determined. Statistical processing was performed using the GraphPad Prism 6 software package (GraphPad Software, La Jolla, CA, USA) and Statistica software, 6.1 (Dell Software, Inc., Round Rock, TX, USA).RESULTS: The adipocytes of the EAT and PVAT of patients with IHD were characterized by an imbalance in the adipokine system, manifested by a low level of ADIPOQ expression and a high LEP expression in comparison with adipocytes of the SAT. Metformin increased the level of ADIPOQ expression and its secretion by adipocytes regardless of their location, while a low concentration (1 mmol / L) in adipocytes of EAT had a stronger effect compared to 10 mmol / L. Metformin had a multidirectional effect on the level of leptin in adipocytes, which depended on their localization: both in low (1 mmol / L) and high concentrations (10 mmol / L), the drug reduced the level of LEP expression and protein secretion in the culture medium of adipocytes of the SAT. EAT had no significant effect on adipocytes. In PVAT, metformin increased the expression and secretion of leptin regardless of concentration.CONCLUSION: Metformin has a direct effect on adipocytes in SAT, EAT, and PVAT and is able to modulate their activity, which is a promising strategy for maintaining the balance of adipokines in AT, especially epicardial and perivascular localization.