Adipose Tissue Protein Research Articles

Increased ANGPTL3, 4 and ANGPTL8/betatrophin expression levels in obesity and T2D

BackgroundHypertriglyceridemia is associated with increased risk for cardiovascular diseases and type 2 diabetes (T2D). Angiopoietin like proteins particularly 3, 4 and recently 8 are well established regulators of plasma triglyceride level through regulating the activity of lipoprotein lipase. Plasma level and association between ANGPTL3, 4 and 8 is not well established in human subjects. This study was designed to establish the level of these proteins in plasma and adipose tissues and investigate the association between ANGPTL8 with ANGPTL3 and 4 in T2D and non-diabetics subjects.MethodsA total of 235 subjects were enrolled in this study, 144 non-diabetics and 91 T2D. ANGPTL 3, 4 and 8 levels were measured in plasma by ELISA and using real time RT-PCR in adipose tissues.ResultsIn this study, we showed that ANGPTL3, 4 and 8 were higher in T2D subjects. Dividing the non-diabetic subjects according to their BMI showed higher level of ANGPTL3, 4 and 8 in obese subjects compared to non-obese subjects. No significant difference was observed between the T2D subjects. ANGPTL8 was showed positive correlation with ANGPTL3 in the non-diabetic subjects in the non-obese (r = 0.2437, p-Value = 0.0543) and obese subjects (r = 0.418, p-Value = 0.0125). No association was observed in the T2D subjects. On the other hand, ANGPTL4 was positively associated with the obese subjects in both the non-diabetics (r = 0.3322, p-Value = 0.0316) and the obese T2D subjects (r = 0.3161, p-Value = 0.0211).ConclusionIn conclusion, our data shows that ANGPTL3, 4 and 8 are increased in obesity and T2D. ANGPTL8 associates with ANGPTL3 in the non-diabetic subjects while it associated more with ANGPTL4 in the obese and T2D subjects. Taken together, this data highlight the role of these proteins in metabolic diseases and how they interact with each other’s under different physiological and pathophysiological conditions.

Adipose inflammation at the heart of vascular disease.

Visceral adipose tissue is a primary site of chronic inflammation in obesity and may contribute to systemic inflammation and development of atherosclerotic vascular disease. Few studies identify molecular mechanisms and secretory pathways which mediate this process. In this edition of Clinical Science, Kwok et al. utilize a transgenic mouse in which dominant-negative c-Jun NH2 terminal kinase (dnJNK) expression is restricted to adipose tissue to implicate JNK-driven expression of adipocyte fatty acid binding protein (A-FABP) in visceral adipose tissue as a key secretory pathway to exacerbate development of atherosclerosis in ApoE-/- mice. They further demonstrate that ApoE-/- mice transplanted with visceral adipose tissue in which JNK has been inactivated display less systemic inflammation and develop significantly less atherosclerosis compared with control mice. Together, the findings of the present study reinforce our understanding of visceral adipose tissue as a secretory organ and the importance of the JNK/A-FABP pathway in mediating adipose vascular cross-talk and exacerbation of atherosclerosis.

1108 Proteomic analysis reveals increased abundance of inflammation-related proteins in adipose tissues from postpartum dairy cows treated with sodium salicylate

1108 Proteomic analysis reveals increased abundance of inflammation-related proteins in adipose tissues from postpartum dairy cows treated with sodium salicylate

P15 G-protein coupled receptor-55 plays a cardioprotective role in the response to myocardial ischemia/reperfusion injury in the setting of obesity

Activation of G-protein coupled receptor 55 (GPR55) by endogenous ligand lysophosphatidylinositol (LPI) stimulates numerous pathways, including intracellular calcium release and regulation of gene expression via ERK1/2 MAP kinase activation. The GPR55/LPI system is upregulated in the state of human obesity, as shown by increased adipose tissue mRNA and protein levels of GPR55 alongside elevated plasma concentrations of LPI. Our group has recently shown that exogenous administration of LPI prior to ischaemia/reperfusion (I/R) results in an increased infarct size through GPR55 activation of RhoA-ROCK, therefore we hypothesise that, obese individuals may suffer a worse outcome following myocardial infarction due to GPR55/LPI upregulation. In the present study, male GPR55-/- and C57Bl/6J mice were fed either a standard chow (SD) or high fat diet (HFD) for 12 weeks, after which mice were anaesthetised and the heart removed and retrogradely perfused using a Langendorff setup. Hearts were stabilised for 15 min followed by 30 min global ischaemia and 30 min reperfusion; hearts were then stained using triphenyltetrazolium chloride to determine infarct size. Hearts from wild type mice fed a HFD exhibited significantly smaller myocardial infarcts induced by I/R compared to SD fed controls. However, this effect was abrogated in the GPR55-/- mice, suggesting that rather than suffering a worse outcome as hypothesised, endogenous (unlike exogenous) LPI may play a protective role through GPR55. To gain insight into possible mechanisms underlying this protection, studies are currently underway to measure tissue levels of LPI and markers of the RISK pathway activation in infarcted myocardial tissue.

Effect of Intraoperative Glucose Infusion on Catabolism of Adipose Tissue and Muscle Protein in Patients Anesthetized With Remifentanil in Combination With Sevoflurane During Major Surgery: A Randomized Controlled Multicenter Trial.

A harmful effect of stress hormone secretion during surgery is lipolysis and proteolysis to maintain normal blood glucose levels. A well-titrated general anesthetic improves blood glucose control by suppressing secretion of these stress hormones. The aim of this study was to explore the effect of intraoperative glucose infusion on lipolysis and proteolysis in patients undergoing a general anesthetic consisting of sevoflurane and remifentanil during long (>6 hours) major surgery. In this prospective, single-blinded, randomized, multicenter trial, 80 patients with an expected duration of anesthesia of >6 hours were allocated to either the glucose group, consisting of 40 patients who were infused with acetated Ringer's solution with glucose (2 mg/kg/min), or the no glucose group, consisting of 40 patients who were infused with the same solution, but without glucose. After oxygenation, general anesthesia was induced with propofol, fentanyl, and rocuronium and was maintained with sevoflurane, oxygen, rocuronium, and remifentanil infusions. The rates of remifentanil infusion were titrated based on systolic arterial blood pressure, maintaining this parameter within 10% of its postanesthesia values. Seventy-four patients completed the study. Urinary 3-methylhistidine/creatinine (3-MH/Cre) ratio, acetoacetic acid, 3-hydroxybutyric acid, blood glucose, insulin, and cortisol were measured 3 times: at anesthesia induction (0 hour) and at 3 and 6 hours after anesthesia induction. Urinary 3-MH/Cre ratio was the primary study outcome. In the no glucose group, the urinary 3-MH/Cre ratio at 6 hours was increased compared with that at 0 hour (213 [range, 42-1903] vs 124 [18-672] nmol/μmol; the difference in medians, 89; the 95% confidence interval [CI] of the difference, 82-252; P = .0002). Acetoacetic acid and 3-hydroxybutyric acid levels in the no glucose group were greater than those in the glucose group at 6 hours (110 [8-1036] vs 11 [2-238] μmol/L; the difference in medians, 99; the 95% CI of the difference, 92-196; P < .0001 and 481 [15-2783] vs 19 [4-555] μmol/L; the difference in medians, 462; the 95% CI of the difference, 367-675; P < 0.0001, respectively). Blood glucose and insulin levels in the glucose group were greater than those in the no glucose group at 3 hours (146 [103-190] vs 93 [72-124] mg/dL; the difference in medians, 53; the 95% CI of the difference, 47-55; P < .0001 and 9.8 [1.2-25.4] vs 3.2 [0.4-15.0] μU/mL; the difference in medians, 6.5; the 95% CI of the difference, 4.8-6.8; P < .0001) and 6 hours (139 [92-189] vs 87 [68-126] mg/dL; the difference in medians, 52; the 95% CI of the difference, 44-58; P < .0001 and 8.1 [1.2-22.3] vs 3.2 [0.4-10.1] μU/mL; the difference in medians, 4.9; the 95% CI of the difference, 4.0-5.9; P < .0001). Cortisol levels in both groups were similarly within normal levels at 0, 3, and 6 hours. The study showed that intraoperative glucose infusion suppressed lipolysis and proteolysis in patients anesthetized with remifentanil in combination with sevoflurane during surgery of >6 hours in length.

Microarray analysis of gene expression in liver, adipose tissue and skeletal muscle in response to chronic dietary administration of NDGA to high-fructose fed dyslipidemic rats.

Nordihydroguaiaretic acid (NDGA), the main metabolite of Creosote Bush, has been shown to have profound effects on the core components of metabolic syndrome, including lowering of blood glucose, free fatty acids and triglyceride levels, attenuating elevated blood pressure in several rodent models of dyslipidemia, and improving body weight, insulin resistance, diabetes and hypertension. In the present study, a high-fructose diet fed rat model of hypertriglyceridemia, dyslipidemia, insulin resistance and hepatic steatosis was employed to investigate the global transcriptional changes in the lipid metabolizing pathways in three insulin sensitive tissues: liver, skeletal muscle and adipose tissue in response to chronic dietary administration of NDGA. Sprague-Dawley male rats (SD) were fed a chow (control) diet, high-fructose diet (HFrD) or HFrD supplemented with NDGA (2.5 g/kg diet) for eight weeks. Dietary administration of NDGA decreased plasma levels of TG, glucose, and insulin, and attenuated hepatic TG accumulation. DNA microarray expression profiling indicated that dietary administration of NDGA upregulated the expression of certain genes involved in fatty acid oxidation and their transcription regulator, PPARα, decreased the expression of a number of lipogenic genes and relevant transcription factors, and differentially impacted the genes of fatty acid transporters, acetyl CoA synthetases, elongases, fatty acid desaturases and lipid clearance proteins in liver, skeletal muscle and adipose tissues. These findings suggest that NDGA ameliorates hypertriglyceridemia and steatosis primarily by inhibiting lipogenesis and enhancing fatty acid catabolism in three major insulin responsive tissues by altering the expression of key enzyme genes and transcription factors involved in de novo lipogenesis and fatty acid oxidation.

WNT5A-JNK regulation of vascular insulin resistance in human obesity.

Obesity is associated with the development of vascular insulin resistance; however, pathophysiological mechanisms are poorly understood. We sought to investigate the role of WNT5A-JNK in the regulation of insulin-mediated vasodilator responses in human adipose tissue arterioles prone to endothelial dysfunction. In 43 severely obese (BMI 44±11 kg/m2) and five metabolically normal non-obese (BMI 26±2 kg/m2) subjects, we isolated arterioles from subcutaneous and visceral fat during planned surgeries. Using videomicroscopy, we examined insulin-mediated, endothelium-dependent vasodilator responses and characterized adipose tissue gene and protein expression using real-time polymerase chain reaction and Western blot analyses. Immunofluorescence was used to quantify endothelial nitric oxide synthase (eNOS) phosphorylation. Insulin-mediated vasodilation was markedly impaired in visceral compared to subcutaneous vessels from obese subjects (p<0.001), but preserved in non-obese individuals. Visceral adiposity was associated with increased JNK activation and elevated expression of WNT5A and its non-canonical receptors, which correlated negatively with insulin signaling. Pharmacological JNK antagonism with SP600125 markedly improved insulin-mediated vasodilation by sixfold (p<0.001), while endothelial cells exposed to recombinant WNT5A developed insulin resistance and impaired eNOS phosphorylation (p<0.05). We observed profound vascular insulin resistance in the visceral adipose tissue arterioles of obese subjects that was associated with up-regulated WNT5A-JNK signaling and impaired endothelial eNOS activation. Pharmacological JNK antagonism markedly improved vascular endothelial function, and may represent a potential therapeutic target in obesity-related vascular disease.

The Cancer Drug Dasatinib Increases PGC-1α in Adipose Tissue but Has Adverse Effects on Glucose Tolerance in Obese Mice

Dasatinib (Sprycel) is a tyrosine kinase inhibitor approved for treatment of chronic myeloid leukemia. In this study, we identify dasatinib as a potent inducer of Peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α mRNA. Dasatinib increased PGC-1α mRNA expression up to 6-fold in 3T3-F442A adipocytes, primary adipocytes, and epididymal white adipose tissue from lean and diet-induced obese mice. Importantly, gene expression translated into increased PGC-1α protein content analyzed in melanoma cells and isolated mitochondria from adipocytes. However, dasatinib treatment had adverse effect on glucose tolerance in diet-induced obese and Ob/Ob mice. This correlated with increased hepatic PGC-1α expression and the gluconeogenesis genes phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. In conclusion, we show that dasatinib is a potent inducer of PGC-1α mRNA and protein in adipose tissue. However, despite beneficial effects of increased PGC-1α content in adipose tissue, dasatinib significantly impaired glucose tolerance in obese but not lean mice. As far as we are aware, this is the first study to show that dasatinib regulates PGC-1α and causes glucose intolerance in obese mice. This should be considered in the treatment of chronic myeloid leukemia.

Comparative proteome analysis of abdominal adipose tissues between fat and lean broilers.

BackgroundThe molecular mechanism underlying broiler fat deposition is still poorly understood.MethodCurrently, we used two-dimensional gel electrophoresis (2DE) to identify differentially expressed proteins in abdominal adipose tissues of birds at 4 week of age derived from Northeast Agricultural University broiler lines divergently selected for abdominal fat content (NEAUHLF).ResultsThirteen differentially expressed protein spots were screened out and identified by matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF-MS). The protein spots were matched to thirteen proteins by searching against the NCBInr database. These identified proteins were apolipoprotein A-I (Apo A-I), cytokeratin otokeratin, ATP synthase subunit alpha, peptidyl-prolyl cis-trans isomerase FKBP4 (PPIase FKBP4), aspartate aminotransferase, carbonic anhydrase II (CA-II), prostaglandin-H2 D-isomerase precursor, fibrinogen alpha chain, lamin-A (LMNA), superoxide dismutase [Mn] (MnSOD), heat shock protein beta-1 (HSPβ1) and two predicted proteins. These differentially expressed proteins are involved mainly in lipid metabolism, amino acid metabolism, signal transduction, energy conversion, antioxidant, and cytoskeleton. Differential expression of Apo A-I, PPIase FKBP4, and cytokeratin otokeratin proteins were further confirmed by Western blot analysis. Quantitative real-time RT-PCR analyses showed that, of these 13 differentially expressed proteins, only PPIase FKBP4 and cytokeratin otokeratin were differentially expressed at mRNA level between the two lines.ConclusionsOur results have provided further information for understanding the basic genetics control of growth and development of broiler adipose tissue.

Association of Single Nucleotide Polymorphisms of Adiponectin Gene with Type 2 Diabetes Mellitus, and Their Influence on Cardiovascular Risk Markers.

Type 2 diabetes mellitus is a genetically heterogeneous condition, characterized by insulin deficiency and/or insulin resistance. The etiology of type 2 diabetes is complex, with involvement of genetic and environmental factors. The adipose tissue protein 'adiponectin' is known to increase insulin sensitivity with decreased risk of type 2 diabetes mellitus. The gene for adiponectin is present on chromosome 3q27, the association of number of single nucleotide polymorphisms of adiponectin gene with type 2 diabetes and its complications have been reported. In the present study the two most common SNPs +45T/G & +276G/T, and their association with type 2 diabetes mellitus and cardiovascular markers were studied. The significant difference in genotype frequencies of +45T/G & +276G/T was found in type 2 diabetic patients and controls, with odds ratio of 1.13 & 1.26 respectively. BMI, Fasting blood glucose, fasting insulin, HOMA IR, triglyceride and VLDL cholesterol levels were increased, and HDL cholesterol level was decreased in patients carrier for +45T/G SNP than the wild type. While only decrease in the HDL cholesterol was reported in carriers for SNP +276G/T than the wild type. The logistic regression analysis revealed the positive association of SNP +45T/G with total cholesterol & LDL cholesterol. And negative association of HDL cholesterol was found with SNPs +45T/G and +276G/T. The haplotype analysis shows the alterations in means of biochemical markers in the patients having haplotype (GG) for mutant allele of SNP +45T/G and wild allele for SNP +276G/T.

Prior exercise training blunts short-term high-fat diet-induced weight gain.

High-fat diets rapidly cause weight gain and glucose intolerance. We sought to determine whether these changes could be mitigated with prior exercise training. Male C57BL/6J mice were exercise-trained by treadmill running (1 h/day, 5 days/wk) for 4 wk. Twenty-four hours after the final bout of exercise, mice were provided with a high-fat diet (HFD; 60% kcal from lard) for 4 days, with no further exercise. In mice fed the HFD prior to exercise training, the results were blunted weight gain, reduced fat mass, and a slight attenuation in glucose intolerance that was mirrored by greater insulin-induced Akt phosphorylation in skeletal muscle compared with sedentary mice fed the HFD. When ad libitum-fed sedentary mice were compared with sedentary high-fat fed mice that were calorie restricted (-30%) to match the weight gain of the previously trained high-fat fed mice, the same attenuated impairments in glucose tolerance were found. Blunted weight gain was associated with a greater capacity to increase energy expenditure in trained compared with sedentary mice when challenged with a HFD. Although mitochondrial enzymes in white adipose tissue and UCP-1 protein content in brown adipose tissue were increased in previously exercised compared with sedentary mice fed a HFD, ex vivo mitochondrial respiration was not increased in either tissue. Our data suggest that prior exercise training attenuates high-fat diet-induced weight gain and glucose intolerance and is associated with a greater ability to increase energy expenditure in response to a high-fat diet.

Pronounced expression of the lipolytic inhibitor G0/G1 Switch Gene 2 (G0S2) in adipose tissue from brown bears (Ursus arctos) prior to hibernation

Prior to hibernation, the brown bear (Ursus arctos) exhibits unparalleled weight gain. Unlike humans, weight gain in bears is associated with lower levels of circulating free fatty acids (FFA) and increased insulin sensitivity. Understanding how free‐ranging brown bears suppress lipolysis when gaining weight may therefore provide novel insight toward the development of human therapies. Blood and subcutaneous adipose tissue were collected from immobilized free‐ranging brown bears (fitted with GPS‐collars) during hibernation in winter and from the same bears during the active period in summer in Dalarna, Sweden. The expression of lipid droplet‐associated proteins in adipose tissue was examined under the hypothesis that bears suppress lipolysis during summer while gaining weight by increased expression of negative regulators of lipolysis. Adipose triglyceride lipase (ATGL) expression did not differ between seasons, but in contrast, the expression of ATGL coactivator Comparative gene identification‐58 (CGI‐58) was lower in summer. In addition, the expression of the negative regulators of lipolysis, G0S2 and cell‐death inducing DNA fragmentation factor‐a‐like effector (CIDE)C markedly increased during summer. Free‐ranging brown bears display potent upregulation of inhibitors of lipolysis in adipose tissue during summer. This is a potential mechanism for increased insulin sensitivity during weight gain and G0S2 may serve as a target to modulate insulin sensitivity.

Gestational Exposure to Maternal Obesity Influences β3‐Adrenergic Agonist Induced Beiging of White Adipose Tissue in Offspring

Maternal obesity is now recognized as an important contributing factor to the currently unfolding epidemic of obesity. In animal models, maternal obesity and exposure to high‐fat diets in utero, unequivocally predisposes the offspring to greater weight gain, metabolic dysfunction and a host of other related comorbidities, such as fatty liver disease. Our previous work in both rat and mouse models of obesity showed that offspring of obese dams are hyper‐responsive to an obesogenic challenge post‐weaning, and gain greater weight and fat mass. In part this is associated with decreased energy expenditure, impaired expression of mitochondrial OXPHOS and lipid oxidative genes and lower expression uncoupling proteins in liver, skeletal muscle and white adipose tissue. Nonetheless, the consequences of maternal obesity on programming of adipose tissue development, especially brown/beige adipose tissue development are unknown. In this report, we investigated role of maternal obesity on beige fat development in offspring following β3‐adrenergic agonist. Female C57BL6/J mice were fed diets with either low (10%) or HFD (45% of calories) for 12 wk starting at 5 wk of age. Dams were mated with males on control diets and provided access to respective diets during pregnancy and lactation. At weaning, offspring were weaned onto control and HFD, creating four groups (CC, CH, HC, HH, denoting maternal and offspring diets respectively). Male offspring from the four groups were followed till 20 wk of age. HFD‐fed offspring from HF dams (HH) gained significantly (p&lt;0.05) greater body weights than offspring from lean dams (CH). At 20 wk of age, offspring were treated with either vehicle or β3‐adrenergic receptor agonist CL‐316,243 (1 mg/kg, ip) for one week (N=4–5 each). CL‐316,243 is a well established activator of beige adipocyte formation. Twenty weeks of diet intervention lead to significantly consistent increased weight gain in HH compared to other groups. One week of CL injection towards to end of study did not affect the weight gain. There were no significant differences in overall body weight between vehicle and CL treated animals. Gene expression analysis of inguinal adipose tissue depot (iWAT) revealed significant differences in vehicle and CL treated groups. Expression of brown‐fat specific genes such as Ucp1, Cidea and Pgc1a was affected by maternal HF diet feeding in both vehicle and CL treated group. Moreover, maternal obesity hampered the response to CL‐316,243 consistent with programming defect in adipose tissue. Further analysis of developmental aspects of beiging of adipose tissue is under investigation. Our findings indicate that maternal obesity influences beige cell formation in response to classical beiging inducers which might influence modulation of energy expenditure, metabolism and overall risk of obesity.Support or Funding InformationSupport USDA CRIS 6206‐51000‐010‐05S

Cissus quadrangularis Extracts Decreases Body Fat Through Regulation of Fatty acid Synthesis in High-fat Diet-induced Obese Mice

The current study investigated the anti-obesity effect of Cissus quadrangularsis extracts (CQR-300) and its molecular action mechanism on obese mice induced high-fat diet (HFD). To induce the obesity, mice were fed a HFD for 6 weeks and then fed HFD only or HFD with CQR-300 at 50 and 200 mg/kg. Then, body weight gain and white adipose tissue weights were measured. We investigated the reduction in body fat and the regulation of fatty acid synthesis was measured by dual energy X-ray absorptiometry and real-time PCR with Western blot, respectively. In vitro study, CQR-300 inhibited pancreatic lipase activity. The CQR-300 treatment was significantly decreased the body weight gain and adipocytes size as well as white adipose tissues weights in HFD-induced obese mice. Furthermore, CQR-300 reduced the body fat and fat mass with regulating of adipose tissue hormones as leptin. Treatment with 50 mg/kg CQR-300 showed effectively lower expression levels of adipogenesis/lipogenesis related genes and proteins such as CCAAT/enhancer binding protein α (C/EBPα), peroxisome proliferator-activated receptor γ (PPARγ), Sterol regulatory element binding protein-1c (SREBP-1c), and fatty acid synthase (FAS) in white adipose tissue (WAT) as compared with the HFD fed only mice. These results suggest that the CQR-300 has an anti-obesity effect via inhibition of lipase activity, decrease the body fat mass by regulating the adipogenesis and lipogenesis related genes and proteins in epididymal adipose tissue with evaluate body fat reduce in the HFD-induced obese mice.

Cell-autonomous programming of rat adipose tissue insulin signalling proteins by maternal nutrition.

Aims/hypothesisIndividuals with a low birthweight have an increased risk of developing type 2 diabetes mellitus in adulthood. This is associated with peripheral insulin resistance. Here, we aimed to determine whether changes in insulin signalling proteins in white adipose tissue (WAT) can be detected prior to the onset of impaired glucose tolerance, determine whether these changes are cell-autonomous and identify the underlying mechanisms involved.MethodsFourteen-month-old male rat offspring born to dams fed a standard protein (20%) diet or a low (8%) protein diet throughout gestation and lactation were studied. Fat distribution and adipocyte size were determined. Protein content and mRNA expression of key insulin signalling molecules were analysed in epididymal WAT and in pre-adipocytes that had undergone in vitro differentiation.ResultsThe offspring of low protein fed dams (LP offspring) had reduced visceral WAT mass, altered fat distribution and a higher percentage of small adipocytes in epididymal WAT. This was associated with reduced levels of IRS1, PI3K p110β, Akt1 and PKCζ proteins and of phospho-Akt Ser473. Corresponding mRNA transcript levels were unchanged. Similarly, in vitro differentiated adipocytes from LP offspring showed reduced protein levels of IRβ, IRS1, PI3K p85α and p110β subunits, and Akt1. Levels of Akt Ser473 and IRS1 Tyr612 phosphorylation were reduced, while IRS1 Ser307 phosphorylation was increased.Conclusions/interpretationMaternal protein restriction during gestation and lactation changes the distribution and morphology of WAT and reduces the levels of key insulin signalling proteins in the male offspring. This phenotype is retained in in vitro differentiated adipocytes, suggesting that programming occurs via cell-autonomous mechanism(s).

Pharmacological inhibition of galectin-1 by lactulose alleviates weight gain in diet-induced obese rats

AimsGalectin-1 (GAL1) is an important member of the lectin family with a carbohydrate recognition domain and has recently been demonstrated to be involved in adipose metabolism. In the present study, we investigated the effects of targeted inhibition of GAL1 by its binding inhibitor lactulose under high fat diet (HFD)-induced obesity. Main methodsEffects of targeted inhibition of GAL1 by lactulose on lipid metabolism were investigated in vitro and in vivo. Changes in lipogenic capacity in lactulose-treated adipocytes were demonstrated by Oil Red O staining, triglyceride quantification and major adipogenic marker expression patterns. After lactulose treatment in Sprague-Dawley rats, various important body weight parameters, food efficiency, plasma metabolic parameters (glucose, ALT, free fatty acid, triglycerides, leptin, and insulin) and metabolic protein expression patterns were evaluated. Key findingsLactulose treatment reduced adipogenesis and fat accumulation in vitro by down-regulation of major adipogenic transcription factors such as C/EBPα and PPARγ. In vivo treatment of lactulose to 5-week-old Sprague-Dawley male rats significantly alleviated HFD-induced body weight gain and food efficiency as well as improved plasma and other metabolic parameters. In addition, lactulose treatment down-regulated major adipogenic marker proteins (C/EBPα and PPARγ) in adipose tissue as well as stimulated expression of proteins involved in energy expenditure and lipolysis (ATP5B, COXIV, HSL, and CPT1). SignificanceIn conclusion, reduced adipogenesis and increased energy expenditure mediated by lactulose treatment synergistically contribute to alleviation of HFD-induced body weight gain. Therefore, pharmaceutical targeting of GAL1 using lactulose would be a novel therapeutic approach for the treatment of obesity.

Identification of a Novel Function of Adipocyte Plasma Membrane-Associated Protein (APMAP) in Gestational Diabetes Mellitus by Proteomic Analysis of Omental Adipose Tissue.

Gestational diabetes mellitus (GDM) is considered as an early stage of type 2 diabetes mellitus. In this study, we compared demographic and clinical data between six GDM subjects and six normal glucose tolerance (NGT; healthy controls) subjects and found that homeostasis model of assessment for insulin resistance index (HOMA-IR) increased in GDM. Many previous studies demonstrated that omental adipose tissue dysfunction could induce insulin resistance. Thus, to investigate the cause of insulin resistance in GDM, we used label-free proteomics to identify differentially expressed proteins in omental adipose tissues from GDM and NGT subjects (data are available via ProteomeXchange with identifier PXD003095). A total of 3528 proteins were identified, including 66 significantly changed proteins. Adipocyte plasma membrane-associated protein (APMAP, a.k.a. C20orf3), one of the differentially expressed proteins, was down-regulated in GDM omental adipose tissues. Furthermore, mature 3T3-L1 adipocytes were used to simulate omental adipocytes. The inhibition of APMAP expression by RNAi impaired insulin signaling and activated NFκB signaling in these adipocytes. Our study revealed that the down-regulation of APMAP in omental adipose tissue may play an important role in insulin resistance in the pathophysiology of GDM.

Korean Pine Nut Oil Attenuated Hepatic Triacylglycerol Accumulation in High-Fat Diet-Induced Obese Mice.

Korean pine nut oil (PNO) has been reported to influence weight gain and lipid metabolism. We examined whether PNO replacement in a high-fat diet (HFD) can ameliorate HFD-induced hepatic steatosis. Five-week-old male C57BL mice were fed control diets containing 10% of the energy from fat from PNO or soybean oil (SBO) (PC, SC) or HFDs with 45% of the energy from fat, with 10% from PNO or SBO and 35% from lard (PHFD, SHFD), for 12 weeks. Body weight gain and amount of white adipose tissue were lower in PHFD (10% and 18% lower, respectively) compared with SHFD. Hepatic triacylglycerol (TG) level was significantly lower in PHFD than the SHFD (26% lower). PNO consumption upregulated hepatic ACADL mRNA levels. The hepatic PPARG mRNA level was lower in the PC than in the SC. Expression of the sirtuin (SIRT) 3 protein in white adipose tissue was down-regulated in the SHFD and restored in the PHFD to the level in the lean control mice. SIRT 3 was reported to be upregulated under conditions of caloric restriction (CR) and plays a role in regulating mitochondrial function. PNO consumption resulted in lower body fat and hepatic TG accumulation in HFD-induced obesity, which seemed to be associated with the CR-mimetic response.

Pre-germinated brown rice prevented high fat diet induced hyperlipidemia through ameliorating lipid synthesis and metabolism in C57BL/6J mice.

Pre-germinated brown rice (PGBR) can ameliorate hyperlipidemia, but the action mechanism is not clear. We focus the mechanisms of PGBR prevented hyperlipidemia. Six-week-old mice were divided into: standard-regular diet (SRD), high-fat diet (HFD) and HFD with PGBR (HFD + PGBR) groups for 16 weeks. The HFD group has higher concentrations of TG, TC, HDL and Non-HDL in the blood, and a higher atherosclerosis index (AI). The TG levels in the liver, and TG, bile acid levels in the feces were enhanced; and the total adipocytokines level in adipose tissue was reduced. The HFD group had higher protein expressions of SREBP-1, SCD-1, FAS, LDLR, and CYP7α1 in the liver. Moreover, the greater expressions of SREBP-1, SCD-1, FAS and the less expressions of PPAR-α and adiponectin were in adipose tissue. In the HFD + PGBR group, the PGBR regulated the levels of TG, TC, HDL, Non-HDL, AI and adipocytokines. PGBR increased more cholesterol and bile acid exhaust in feces. The SREBP-1, SCD-1, FAS, HMGCR, LDLR, CYP7α1 and PPAR-α proteins in the liver; and the SREBP-1, SCD-1, FAS, PPAR-α and adiponectin proteins in adipose tissue were reversed by PGBR. Taken together, PGBR can improve lipid synthesis and metabolism, and we suggest PGBR is a recommendable food for controlling hyperlipidemia.

CISD1 in association with obesity-associated dysfunctional adipogenesis in human visceral adipose tissue.

To investigate CISD1 mRNA and protein in human adipose tissue in association with obesity and adipogenesis. Subcutaneous (SAT) and visceral (VAT) adipose tissue CISD1 gene expression (real-time PCR) and protein (Western blot) levels were investigated in human adipose tissue and during human adipocyte differentiation. SAT and VAT CISD1 mRNA and protein levels were significantly decreased in subjects with obesity and negatively correlated with BMI after controlling for age and sex. In participants with morbid obesity, VAT CISD1 gene expression was positively correlated with insulin sensitivity (r = 0.47, P = 0.01), and bariatric surgery-induced weight loss led to increased SAT CISD1 mRNA levels. In both VAT and SAT, CISD1 gene expression was significantly associated with SIRT1, ISCA2, and mitochondrial biogenesis-related (PPARGC1A, TFAM, and MT-CO3) and browning-related (PRDM16 and UCP1) gene expression. In addition, VAT CISD1 gene expression was significantly associated with adipogenic and iron metabolism-related genes. Importantly, these correlations were replicated in a second cohort. At the cellular level, CISD1 gene expression increased during human adipocyte differentiation in correlation with adipogenic genes (r > 0.60, P < 0.005). These data suggest a possible role of CISD1 in obesity-associated dysfunctional adipogenesis in human VAT.