Function In Obesity Research Articles

A gene expression network analysis of the pancreatic islets from lean and obese mice identifies complement 1q\xa0like-3 secreted protein as a regulator of \u03b2-cell function

Secreted proteins are important metabolic regulators. Identifying and characterizing the role of secreted proteins from small tissue depots such as islets of Langerhans, which are required for the proper control of whole-body energy metabolism, remains challenging. Our objective was to identify islet-derived secreted proteins that affect islet function in obesity. Lean and obese mouse islet expression data were analyzed by weighted gene co-expression network analysis (WGCNA) to identify trait-associated modules. Subsequently, genes within these modules were filtered for transcripts that encode for secreted proteins based on intramodular connectivity, module membership, and differential expression. Complement 1q like-3 (C1ql3) secreted protein was identified as a hub gene affecting islet function in obesity. Co-expression network, hierarchal clustering, and gene-ontology based approaches identified a putative role for C1ql3 in regulating β-cell insulin secretion. Biological validation shows that C1ql3 is expressed in β-cells, it inhibits insulin secretion and key genes that are involved in β-cell function. Moreover, the increased expression of C1ql3 is correlated with the reduced insulin secretion in islets of obese mice. Herein, we demonstrate a streamlined approach to effectively screen and determine the function of secreted proteins in islets, and identified C1ql3 as a putative contributor to reduced insulin secretion in obesity, linking C1ql3 to an increased susceptibility to type 2 diabetes.

Pulmonary Function in Obese individuals

This review tries to discuss the researches that are related to pulmonary function in obesity, its mechanisms and consequences. Abdominal adiposity could be considered as a better predictor of pulmonary function than weight or BMI. Obesity has important effects on respiratory function, which add considerably to the load of respiratory disease. Weigh loss is found to improve lung function in patients with respiratory disorders especially with asthma.

2169-P: A Gene Expression Network Analysis of the Pancreatic Islets from Lean and Obese Mice Identifies Complement 1q-Like-3 Secreted Protein as a Regulator of Beta-Cell Function

Secreted proteins are important metabolic regulators that function in healthy and disease states. Our objective was to identify those secreted proteins that are important regulators of pancreatic islet function in obesity. To facilitate this, we used Weighted Gene Co-Expression Network Analysis-based approach on the expression data that was obtained from the pancreatic islets of lean and obese mice to identify gene modules that enriched with obesity. Subsequently, filtering the data for transcripts expressing secreted protein based on the intramodular connectivity, module membership, and differential expression identified complement-1q-like-3 (C1ql3) secreted protein as a top candidate to affect islet function. Co-expression network, hierarchal clustering, and gene-ontology based approaches identified C1ql3 to affect ‘secretory processes’ in islets. Biological validation showed that C1ql3 is expressed in human and mouse islets, and inhibits insulin secretion from pancreatic β-cells. Its expression in islets is increased by >32-fold with obesity. Moreover, C1ql3 in the islet β-cells specifically reduced the expression of genes that are critical for regulating insulin secretion. These findings demonstrate a streamlined approach to screen for the putative novel secreted protein regulators that function in an autocrine/paracrine manner to affect islet function in obesity. Herein, we have identified a critical role of C1ql3 in β-cells and propose that the increased secretion of C1ql3 from islets during obesity contributes to the reduced β-cell function in a paracrine/autocrine-dependent pathway to increase the susceptibility to type 2 diabetes. Disclosure J. Koltes: None. I. Arora: None. R. Gupta: None. D.C. Nguyen: None. S. Bhatnagar: None. Funding American Diabetes Association (1-18-PDF-103 to R.G.)

2095-P: Association between Markers of Neuro and Systemic Inflammation and Cognitive Function in Obesity

Obesity is associated with alterations in brain structure and cognitive impairment. The mechanisms underlying obesity related decline in cognitive function are not well understood. Obesity related chronic systemic inflammation is postulated to be one of the potential mechanisms leading to cognitive dysfunction. It is unknown whether inflammation impacts brain areas important for higher level cognition such as the anterior cingulate cortex (ACC). Elevated myo-inositol (Ins), as measured by magnetic resonance spectroscopy (MRS), may be a marker of neuroinflammation and reflects activated astrocytes and microglia. We hypothesized that obese subjects (OB) will have higher ACC Ins compared to normal weight controls (CON) and that higher Ins will be associated with elevated blood inflammatory markers and reduced cognitive performance. We examined neurochemical profile from a 24x24x12mm3 voxel over the ACC using 1H MRS at 3 and 7 Tesla (T), in 5 nondiabetic OB (age 33 ± 5 years, BMI 43 ± 6 kg/m2) and 4 CON (age 36 ± 3 years, BMI 23 ± 3 kg/m2). Subjects also underwent cognitive testing and measurement of blood inflammatory markers. MR spectra were quantified using LCModel and the concentrations are expressed as a ratio to total creatine (tCr). There was a strong trend of higher Ins/tCr in ACC in OB compared to CON both at 3T (0.96 ± 0.06 vs. 0.88 ± 0.05, p =0.07) and 7T (0.91 ± 0.07 vs. 0.83 ± 0.08, p =0.17). Pearson correlations were used to test the relationship between Ins/tCr and markers of inflammation among all subjects. Higher blood inflammatory markers were associated with higher Ins/tCr (3T) in ACC (CRP, r=.74, p= 0.04; TNF α, r=.89, p=0.003) and with low levels of crystallized ability as measured by the NIH Toolbox Cognition Battery (CRP, r=-.73, p=0.03). Higher ACC Ins/tCr was also associated with poorer performance on a measure of fine motor coordination (r=.93, p=0.001). These data support the hypothesis that inflammation may contribute to the pathogenesis of brain and cognitive alterations in obesity. Disclosure A. Khan: None. J.M. Joers: None. M. Luciana: None. N. Rubin: None. Y. Siddiqui: None. S. Mangia: None. L.E. Eberly: None. S. Ikramuddin: Research Support; Self; Medtronic. E.R. Seaquist: Advisory Panel; Self; Eli Lilly and Company, Zucara Therapeutics Inc. Consultant; Self; 360 Consulting, MannKind Corporation. Research Support; Self; Eli Lilly and Company, JDRF, National Institutes of Health. Other Relationship; Self; American Diabetes Association, Sanofi, WebMD. G. Oz: None. A. Moheet: None. Funding National Institutes of Health

Positive Effects of Heme Oxygenase Upregulation on Adiposity and Vascular Dysfunction: Gene Targeting vs. Pharmacologic Therapy.

Objective: Heme oxygenase (HO-1) plays a critical role in adipogenesis and it is important to understand its function in obesity. Many studies have shown that upregulation of HO-1 can affect the biologic parameters in obesity-mediated diabetes, hypertension and vascular endothelial cell function. Thus, we aimed to explore the hypothesis that upregulation of HO-1, using a pharmacologic approach as well as gene targeting, would improve both adiposity and endothelial cell dysfunction by direct targeting of endothelial cells. Our second aim was to compare the short-term effect of a HO-1 inducer, cobalt-protoporphrin IX (CoPP), with the long-term effects of gene targeted therapy on vascular and adipocyte stem cells in obese mice. Method: We examined the effect of CoPP on fat pre-adipocytes and mesenchymal stem cells (MSC) in mice fed a high-fat diet (HFD). We also used a lentiviral construct that expressed heme oxygenase (HO-1) that was under the control of an endothelium specific promoter, vascular endothelium cadherin (VECAD) heme oxygenase (VECAD-HO-1). We targeted endothelial cells using vascular endothelium cadherin/green fluorescent protein fusion construct (VECAD-GFP) as the control. Conditioned media (CM) from endothelial cells (EC) was added to fat derived adipocytes. Additionally, we treated renal interlobar arteries with phenylephrine and dosed cumulative increments of acetylcholine both with and without exposure to CoPP. We did the same vascular reactivity experiments with VECAD-HO-1 lentiviral construct compared to the control. Results: CoPP improved vascular reactivity and decreased adipogenesis compared to the control. MSCs exposed to CM from EC transfected with VECAD-HO-1 showed decreased adipogenesis, smaller lipid droplet size and decreased PPAR-γ, C/EBP and increased Wnt 10b compared to the control. HO-1 upregulation had a direct effect on reducing adipogenesis. This effect was blocked by tin mesoporphrin (SnMP). EC treated with VECAD-HO-1 expressed lower levels of ICAM and VCAM compared to the control, suggesting improved EC function. This also improved ACH induced vascular reactivity. These effects were also reversed by SnMP. The effect of viral transfection was much more specific and sustained than the effects of pharmacologic therapy, CoPP. Conclusion: This study demonstrates that a pharmacological inducer of HO-1 such as CoPP improves endothelial cell function while dampening adipogenesis, but long-term HO-1 expression by direct targeting of endothelial cells by gene transfer therapy may offer a more specific and ideal solution. This was evidenced by smaller healthier adipocytes that had improved insulin sensitivity, suggesting increased adiponectin levels. HO-1 upregulation reestablished the “crosstalk” between perivascular adipose tissue and the vascular system that was lost in the chronic inflammatory state of obesity. This study demonstrates that gene targeting of EC may well be the future direction in treating obesity induced EC dysfunction, with the finding that targeting the vasculature had a direct and sustained effect on adipogenesis.

431 – Activation of Nrf2 Attenuates Delayed Gastric Emptying by Restoring Impaired Gastric Estrogen Receptors, Bh4 (Cofactor of NNOS) Biosynthesis Enzyme GCH-1 & Neuronal Nitric Oxide Synthase Function in Obesity Induced Diabetic (T2DM) Female Mice

431 – Activation of Nrf2 Attenuates Delayed Gastric Emptying by Restoring Impaired Gastric Estrogen Receptors, Bh4 (Cofactor of NNOS) Biosynthesis Enzyme GCH-1 & Neuronal Nitric Oxide Synthase Function in Obesity Induced Diabetic (T2DM) Female Mice

Dietary cholesterol is essential to mast cell activation and associated obesity and diabetes in mice

Mast cell (MC) deficiency in KitW-sh/W-sh mice and inhibition with disodium chromoglycate (DSCG) or ketotifen reduced obesity and diabetes in mice on a high-cholesterol (1.25%) Western diet. Yet, Kit-independent MC-deficient mice and mice treated with DSCG disproved MC function in obesity and diabetes when mice are fed a high-fat diet (HFD) that contains no cholesterol. This study reproduced the obesity and diabetes inhibitory activities of DSCG and ketotifen from mice on a Western diet. Yet, such inhibitory effects were diminished in mice on the HFD. DSCG and ketotifen MC inhibitory activities were recovered from mice on the HFD supplemented with the same amount of cholesterol (1.25%) as that in the Western diet. DSCG and ketotifen effectively blunted the high-cholesterol diet-induced elevations of blood histamine and adipose tissue MC degranulation. Pearson's correlation test demonstrated significant and positive correlations between plasma histamine and total cholesterol or low-density lipoprotein-cholesterol (LDL). In cultured bone marrow-derived MCs, plasma from mice following a Western diet or a cholesterol-supplemented HFD, but not those from HFD-fed mice, induced MC degranulation and the release of β-hexosaminidase, histamine, and serotonin. IgE, LDL, very low-density lipoprotein, and high-density lipoprotein also induced MC activation, which can be inhibited by DSCG and ketotifen depending on the doses and types of MC inhibitors and cholesterol, and also the MC granule molecules of interest. DSCG or ketotifen lost their activities in inhibiting LDL-induced activation of MCs from LDL receptor-deficient mice. These results indicate that dietary cholesterol critically influences the function of mouse MCs.

Abstract P335: Greater Frequency of Olive Oil Consumption is Associated with Lower Platelet Activation in Obesity

Healthy lifestyle behaviors, including maintenance of normal weight, are associated with lower risk of atherothrombotic events. In the general population, consumption of olive oil and a Mediterranean diet are associated with reduced risk of cardiovascular disease (CVD). However, less is known about how this affects individuals with obesity. We investigated whether olive oil intake is associated with reduced platelet activation in a cohort of obese, non-smoking, non-diabetic subjects without known CVD. As part of a larger prospective study of platelet function in obesity, we assessed platelet activation (surface P-selectin and PAC1 MFI) with and without agonist (0.025U thrombin, 0.1uM ADP, 0.4uM epinephrine) exposure via flow cytometry. Food frequency surveys were used to estimate diet composition. Subjects were stratified by food intake frequency and platelet activation was compared using ANOVA, with post-hoc independent samples t-testing. Among 63 subjects, the mean age was 32.2 ± 8.0 years and BMI 44.1 ± 8.5 kg/m 2 . Olive oil intake frequency was stratified into 3 groups: ≤ 1 time/wk, n=21; 1 - 3 times/wk, n=18; ≥ 4 times/wk, n=24. The groups did not differ by age, weight, BMI, waist and hip circumferences, platelet count or mean platelet volume. Subjects with more frequent olive oil intake showed lower platelet activation to agonists than those consuming olive oil ≤ 1 time/wk (Figure). Non-agonized platelet activity did not differ significantly by olive oil intake frequency. Notably, we did not observe associations between platelet activity and consumption of red meat, eggs, butter, or margarine. In metabolically healthy obese individuals, more frequent olive oil intake is associated with suppressed platelet activation. We hypothesize that phenolic compounds in olive oil may alter platelet membrane phospholipid content, making platelets less susceptible to activation. For obese individuals, olive oil intake may lower risk of cardiovascular events.

Saturated Fatty Acid Activates T Cell Inflammation Through a Nicotinamide Nucleotide Transhydrogenase (NNT)-Dependent Mechanism.

Circulating fatty acids (FAs) increase with obesity and can drive mitochondrial damage and inflammation. Nicotinamide nucleotide transhydrogenase (NNT) is a mitochondrial protein that positively regulates nicotinamide adenine dinucleotide phosphate (NADPH), a key mediator of energy transduction and redox homeostasis. The role that NNT-regulated bioenergetics play in the inflammatory response of immune cells in obesity is untested. Our objective was to determine how free fatty acids (FFAs) regulate inflammation through impacts on mitochondria and redox homeostasis of peripheral blood mononuclear cells (PBMCs). PBMCs from lean subjects were activated with a T cell-specific stimulus in the presence or absence of generally pro-inflammatory palmitate and/or non-inflammatory oleate. Palmitate decreased immune cell expression of NNT, NADPH, and anti-oxidant glutathione, but increased reactive oxygen and proinflammatory Th17 cytokines. Oleate had no effect on these outcomes. Genetic inhibition of NNT recapitulated the effects of palmitate. PBMCs from obese (BMI >30) compared to lean subjects had lower NNT and glutathione expression, and higher Th17 cytokine expression, none of which were changed by exogenous palmitate. Our data identify NNT as a palmitate-regulated rheostat of redox balance that regulates immune cell function in obesity and suggest that dietary or therapeutic strategies aimed at increasing NNT expression may restore redox balance to ameliorate obesity-associated inflammation.

MYOCARDIAL FUNCTIONS IN OBESE CHILDREN WITH SUBCLINICAL HYPOTHYROIDISM

Ponte Academic JournalFeb 2019, Volume 75, Issue 2 MYOCARDIAL FUNCTIONS IN OBESE CHILDREN WITH SUBCLINICAL HYPOTHYROIDISMAuthor(s): Atilla Cifci ,Mehmet BoyrazJ. Ponte - Feb 2019 - Volume 75 - Issue 2 doi: 10.21506/j.ponte.2019.2.11 Abstract:Childhood obesity is an important health problem representing a major public health concern worldwide. An isolated elevation of Thyroid Stimulating Hormone (TSH) with normal levels of thyroid hormones is frequently found in obese children. It has been named Isolated Hyperthyreotropinemia or Subclinical Hypothyroidism (SCH) and may be considered a consequence of obesity. SCH is related to impairment of both systolic and diastolic myocardial function in the adult population. Objective: Aim of this study is to evaluate whether SCH affects myocardial function in childhood obesity. Material and Methods: We examined 48 obese children and adolescents with SCH and 70 obese children and adolescents with normal TSH. Doppler echocardiography was performed in order to evaluate myocardial function to all cases in both groups. Results: Global systolic function was evaluated with, ejection fraction (EF) and compared between groups. Right ventricular global systolic function and pressure were significantly decreased in SCH group. LV mass index was significantly higher in SCH group (p=0.041). Global systolic function was evaluated as EF and no difference was found among the groups. RV global longitudinal function was evaluated with TAPSE measurement and a significant decrease was observed for this value in SCH group compared to the other group (p=0.0015). MAPSE lateral and MAPSE septum which are important for showing LV longitudinal function in SCH group decreased significantly (p=0.004 and p=0.002). Similarly, tissue Doppler imaging (TDI) and peak systolic movement were decreased in SCH group (9,6±1,8 cm/s vs 11.5±1.7 cm/sn; p=0.03). In addition, significant changes were observed in both systolic and diastolic functions in the left ventricle in SCH group. Conclusions: These results suggest the possible involvement of cardiac functions in obese children with SCH. Download full text:Check if you have access through your login credentials or your institution Username Password

Netrin-1 Alters Adipose Tissue Macrophage Fate and Function in Obesity.

Macrophages accumulate prominently in the visceral adipose tissue (VAT) of obese humans and high fat diet (HFD) fed mice, and this is linked to insulin resistance and type II diabetes. While the mechanisms regulating macrophage recruitment in obesity have been delineated, the signals directing macrophage persistence in VAT are poorly understood. We previously showed that the neuroimmune guidance cue netrin-1 is expressed in the VAT of obese mice and humans, where it promotes macrophage accumulation. To better understand the source of netrin-1 and its effects on adipose tissue macrophage (ATM) fate and function in obesity, we generated mice with myeloid-specific deletion of netrin-1 (Ntn1fl/fl LysMCre+/–; Ntn1Δmac). Interestingly, Ntn1Δmac mice showed a modest decrease in HFD-induced adiposity and adipocyte size, in the absence of changes in food intake or leptin, that was accompanied by an increase in markers of adipocyte beiging (Prdm16, UCP-1). Using single cell RNA-seq, combined with conventional histological and flow cytometry techniques, we show that myeloid-specific deletion of netrin-1 caused a 50% attrition of ATMs in HFD-fed mice, particularly of the resident macrophage subset, and altered the phenotype of residual ATMs to enhance lipid handling. Pseudotime analysis of single cell transcriptomes showed that in the absence of netrin-1, macrophages in the obese VAT underwent a phenotypic switch with the majority of ATMs activating a program of genes specialized in lipid handling, including fatty acid uptake and intracellular transport, lipid droplet formation and lipolysis, and regulation of lipid localization. Furthermore, Ntn1Δmac macrophages had reduced expression of genes involved in arachidonic acid metabolism, and targeted LCMS/MS metabololipidomics analysis revealed decreases in proinflammatory eicosanoids (5-HETE, 6-trans LTB4, TXB2, PGD2) in the obese VAT. Collectively, our data show that targeted deletion of netrin-1 in macrophages reprograms the ATM phenotype in obesity, leading to reduced adipose inflammation, and improved lipid handling and metabolic function.

Impact of obesity and gender differences on electrodermal activities.

The widespread use of electrodermal activity (EDA) as a measuring tool in sympathetic nervous system activity researches has resulted in a wide variety of publications on EDA. Yet, the influences of obesity and gender differences in the responses and levels of EDA have not been studied carefully. This study aims to investigate the impacts of obesity and gender differences on EDA parameters. To this end, EDA responses and levels were recorded from 36 (18 males and18 females) apparently healthy adult subjects nearly half of them are obese. EDA measures were induced by three different stimuli and the EDA responses and levels were compared as a function of obesity and gender differences for all stimuli. It was found that EDA parameters, in particular, skin conductance responses (SCRs) were significantly different between obese and non-obese subjects for both genders. In addition, it was found that the change in skin susceptance levels (SSLs) was statistically significant only among females. The investigation also showed that the gender difference has a crucial role in skin potential levels (SPLs) for obese subjects. The outcome results led to the conclusion that the phasic SCRs were strongly related to BMI, while tonic SPLs were related to gender differences.

MR (Mineralocorticoid Receptor) Induces Adipose Tissue Senescence and Mitochondrial Dysfunction Leading to Vascular Dysfunction in Obesity.

Adipose tissue (AT) senescence and mitochondrial dysfunction are associated with obesity. Studies in obese patients and animals demonstrate that the MR (mineralocorticoid receptor) contributes to obesity-associated cardiovascular complications through its specific role in AT. However, underlying mechanisms remain unclear. This study aims to elucidate whether MR regulates mitochondrial function in obesity, resulting in AT premature aging and vascular dysfunction. Obese (db/db) and lean (db/+) mice were treated with an MR antagonist or a specific mitochondria-targeted antioxidant. Mitochondrial and vascular functions were determined by respirometry and myography, respectively. Molecular mechanisms were probed by Western immunoblotting and real-time polymerase chain reaction in visceral AT and arteries and focused on senescence markers and redox-sensitive pathways. db/db mice displayed AT senescence with activation of the p53-p21 pathway and decreased SIRT (sirtuin) levels, as well as mitochondrial dysfunction. Furthermore, the beneficial anticontractile effects of perivascular AT were lost in db/db via ROCK (Rho kinase) activation. MR blockade prevented these effects. Thus, MR activation in obesity induces mitochondrial dysfunction and AT senescence and dysfunction, which consequently increases vascular contractility. In conclusion, our study identifies novel mechanistic insights involving MR, adipose mitochondria, and vascular function that may be of importance to develop new therapeutic strategies to limit obesity-associated cardiovascular complications.

Expansion of Islet-Resident Macrophages Leads to Inflammation Affecting β Cell Proliferation and Function in Obesity

The nature of obesity-associated islet inflammation and its impact on β cell abnormalities remains poorly defined. Here, we explore immune cell components of islet inflammation and define their roles in regulating β cell function and proliferation. Islet inflammation in obese mice is dominated by macrophages. We identify two islet-resident macrophage populations, characterized by their anatomical distributions, distinct phenotypes, and functional properties. Obesity induces the local expansion of resident intra-islet macrophages, independent of recruitment from circulating monocytes. Functionally, intra-islet macrophages impair β cell function in a cell-cell contact-dependent manner. Increased engulfment of βcell insulin secretory granules by intra-islet macrophages in obese mice may contribute to restricting insulin secretion. In contrast, both intra- and peri-islet macrophage populations from obese mice promote β cell proliferation in a PDGFR signaling-dependent manner. Together, these data define distinct roles and mechanisms for islet macrophages in the regulation of islet β cells.

T Cells in Adipose Tissue in Aging.

Similar to obesity, aging is associated with visceral adiposity and insulin resistance. Inflammation in adipose tissue, mainly evidenced by increased accumulation and proinflammatory polarization of T cells and macrophages, has been well-documented in obesity and may contribute to the associated metabolic dysfunctions including insulin resistance. Studies show that increased inflammation, including inflammation in adipose tissue, also occurs in aging, so-called “inflamm-aging.” Aging-associated inflammation in adipose tissue has some similarities but also differences compared to obesity-related inflammation. In particular, conventional T cells are elevated in adipose tissue in both obesity and aging and have been implicated in metabolic functions in obesity. However, the changes and also possibly functions of regulatory T cells (Treg) in adipose tissue are different in aging and obesity. In this review, we will summarize recent advances in research on the changes of these immune cells in adipose tissue with aging and obesity and discuss their possible contributions to metabolism and the potential of these immune cells as novel therapeutic targets for prevention and treatment of metabolic diseases associated with aging or obesity.

Performance of prostate cancer recurrence nomograms by obesity status: a retrospective analysis of a radical prostatectomy cohort

BackgroundObesity has been associated with aggressive prostate cancer and poor outcomes. It is important to understand how prognostic tools for that guide prostate cancer treatment may be impacted by obesity. The goal of this study was to evaluate the predicting abilities of two prostate cancer (PCa) nomograms by obesity status.MethodsWe examined 1576 radical prostatectomy patients categorized into standard body mass index (BMI) groups. Patients were categorized into low, medium, and high risk groups for the Kattan and CaPSURE/CPDR scores, which are based on PSA value, Gleason score, tumor stage, and other patient data. Time to PCa recurrence was modeled as a function of obesity, risk group, and interactions.ResultsAs expected for the Kattan score, estimated hazard ratios (95% CI) indicated higher risk of recurrence for medium (HR = 2.99, 95% CI = 2.29, 3.88) and high (HR = 8.84, 95% CI = 5.91, 13.2) risk groups compared to low risk group. The associations were not statistically different across BMI groups. Results were consistent for the CaPSURE/CPDR score. However, the difference in risk of recurrence in the high risk versus low risk groups was larger for normal weight patients than the same estimate in the obese patients.ConclusionsWe observed no statistically significant difference in the association between PCa recurrence and prediction scores across BMI groups. However, our study indicates that there may be a stronger association between high risk status and PCa recurrence among normal weight patients compared to obese patients. This suggests that high risk status based on PCa nomogram scores may be most predictive among normal weight patients. Additional research in this area is needed.

A17398 Nitric oxide synthase regulates of the anti-contractile functions of perivascular adipose tissue

Objectives: Perivascular adipose tissue (PVAT) plays a crucial role in the modulation of vascular tone. Loss of function in obesity leads to an increase in arterial tone, and may contribute to development of hypertension. Activation of nitric oxide synthase (NOS) has been implicated in the anti-contractile effect of PVAT. Accordingly, we have examined the roles of NOS in healthy and obese PVAT. Methods: Electrical field stimulation profiles or noradrenaline concentration response curves were generated in healthy, obese, and eNOS−/− mouse mesenteric resistance arteries. Pharmacological manipulation of NOS was conducted using the non-specific inhibitor; L-NMMA, and activator; histamine. The role of β3-adrenoceptors was investigated using the agonist CL-316,243. Immunohistochemistry was use to examine expression of the endothelial NOS isoform (eNOS) in PVAT. Results: Stimulation of PVAT induced an anti-contractile effect on healthy mouse arteries, which was absent in obese and eNOS−/− mouse arteries. Inhibition of NOS in healthy mouse PVAT abolished the anti-contractile effect, and activation of NOS in obese PVAT restored the anti-contractile effect. Using immunohistochemistry, eNOS is the isoform present in mesenteric PVAT, and expression is unchanged in obesity. The β3-adrenoceptor agonist enhanced the anti-contractile effect, and this enhancement was abolished using the NOS inhibitor. Conclusion: These results demonstrate that the β3-adrenoceptor mediated anti-contractile effect of PVAT is dependent upon NOS. In obesity, the anti-contractile effect is lost which may contribute to development of hypertension. However, function can be rescued using activation of NOS; presenting a potential pharmacological target for intervention in obesity-related hypertension.

Microparticle miRNAs as Biomarkers of Vascular Function and Inflammation Response to Aerobic Exercise in Obesity?

This study aimed to explore the role of nine microRNAs (miRNAs) in microparticles (MPs) on the efficacy of aerobic exercise in the regulation of inflammation and vascular function in obesity. Sedentary women with normal weight (n = 6, BMI < 25 kg/m2 ) and women with obesity (n = 9, BMI > 30 kg/m2 ) were recruited at F. Hached Hospital (Sousse, Tunisia) and enrolled in an 8-week aerobic program. Vascular function was assessed using laser Doppler flowmetry/iontophoresis, circulating MPs by flow cytometry, miRNAs by real-time polymerase chain reaction, and inflammation by ELISA, before and after exercise. Women with obesity presented with high prevalence of cardiovascular risk factors and a higher circulating MP level compared with healthy subjects. The MP miRNA profile was significantly different in the two groups. Exercise reduced BMI and inflammation in both groups and significantly improved endothelial-dependent response (acetylcholine cutaneous vascular conductance) for healthy subjects, with a trend for women with obesity. Circulating MP level was increased after exercise, and miRNA expression was differentially modulated in both populations. Pearson analysis revealed a correlation between MPs miR-124a and miR150 and adiponectin, TNFα, or IL-6 levels. The relation between MPs and miRNA profile, inflammation, vascular function, and exercise is of particular interest for defining "miRNA biomarker signature" in patients with cardiovascular disease who are potentially susceptible to respond to exercise.

Neurobehavioral correlates of obesity are largely heritable

Recent molecular genetic studies have shown that the majority of genes associated with obesity are expressed in the central nervous system. Obesity has also been associated with neurobehavioral factors such as brain morphology, cognitive performance, and personality. Here, we tested whether these neurobehavioral factors were associated with the heritable variance in obesity measured by body mass index (BMI) in the Human Connectome Project (n = 895 siblings). Phenotypically, cortical thickness findings supported the "right brain hypothesis" for obesity. Namely, increased BMI is associated with decreased cortical thickness in right frontal lobe and increased thickness in the left frontal lobe, notably in lateral prefrontal cortex. In addition, lower thickness and volume in entorhinal-parahippocampal structures and increased thickness in parietal-occipital structures in participants with higher BMI supported the role of visuospatial function in obesity. Brain morphometry results were supported by cognitive tests, which outlined a negative association between BMI and visuospatial function, verbal episodic memory, impulsivity, and cognitive flexibility. Personality-BMI correlations were inconsistent. We then aggregated the effects for each neurobehavioral factor for a behavioral genetics analysis and estimated each factor's genetic overlap with BMI. Cognitive test scores and brain morphometry had 0.25-0.45 genetic correlations with BMI, and the phenotypic correlations with BMI were 77-89% explained by genetic factors. Neurobehavioral factors also had some genetic overlap with each other. In summary, obesity as measured by BMI has considerable genetic overlap with brain and cognitive measures. This supports the theory that obesity is inherited via brain function and may inform intervention strategies.

Dietary fats modify vascular fat composition, eNOS localization within lipid rafts and vascular function in obesity.

We tested whether dietary fatty acids alter membrane composition shifting localization of signaling pathways within caveolae to determine their role in vascular function. Wild type (WT) and caveolin‐1‐deficient mice (cav‐1 KO), required for vascular caveolae formation, were fed low fat (LF), high saturated fat (HF, 60% kcal from lard), or high‐fat diet with 50:50 lard and n‐3 polyunsaturated fatty acid‐enriched menhaden oil (MO). HF and MO increased body weight and fat in WT but had less effect in cav‐1 KO. MO increased unsaturated fatty acids and the unsaturation index of aorta from WT and cav‐1 KO. In LF WT aorta, endothelial nitric oxide synthase (eNOS) was localized to cav‐1‐enriched low‐density fractions which shifted to actin‐enriched high‐density fractions with acetylcholine (ACh). HF and MO shifted eNOS to high‐density fractions in WT aorta which was not affected by ACh. In cav‐1 KO aorta, eNOS was localized in low‐density non‐caveolar fractions but not shifted by ACh or diet. Inducible NOS and cyclooxygenase 1/2 were not localized in low‐density fractions or affected by diet, ACh or genotype. ACh‐induced dilation of gracilis arteries from HF WT was similar to dilation in LF but the NOS component was reduced. In WT and cav‐1 KO, dilation to ACh was enhanced by MO through increased role for NOS and cyclooxygenase. We conclude that dietary fats affect vascular fatty acid composition and membrane localization of eNOS but the contribution of eNOS and cyclooxygenase in ACh‐mediated vascular responses is independent of lipid rafts.