Function In Obesity Research Articles

The impact of the metabolic phenotype on thyroid function in obesity.

BackgroundObesity is known to promote mild hyperthyrotropinaemia by unknown metabolic mechanisms. This investigation aimed to explore the association between thyroid function and metabolic phenotype in euthyroid obese individuals. Retrospective, cross-sectional study. Tertiary care center.Methods952 euthyroid obese individuals referred to our Institution for obesity. Serum levels of TSH, FT4, glucose, insulin and HbA1c levels, lipid profile, liver function and proinflammatory indices were measured. Resting energy expenditure was assessed by indirect calorimetry and body composition by bioimpedance analysis.ResultsOn admission, 306 patients had previously diagnosed diabetes mellitus on treatment with metformin, while 113 patients were diagnosed with incident diabetes mellitus. Serum TSH levels were similar between metformin-treated diabetic subjects and metformin-untreated subjects, while FT4 was slightly but significantly higher in the former. Analysis stratified by TSH categories found no effect of metformin-treated diabetes mellitus on TSH levels. Interestingly, obese patients with incident diabetes showed lower TSH levels than normoglycaemic ones. In correlation studies on the whole dataset, an association related TSH to BMI and total cholesterol levels, which was lost upon adjustment for individual confounders. FT4 levels were found to be inversely related to BMI, insulin resistance and triglycerides, while being directly associated with HDL-cholesterol levels. These correlations remained unaltered after controlling for individual confounders. In multivariate linear regression analysis, TSH was associated with FT4, total cholesterol and BMI values. Significant predictors of FT4 were constituted by previously diagnosed diabetes mellitus, BMI, TSH and age.ConclusionsIn euthyroid obese subjects, FT4 seems more closely related than TSH levels to parameters of cardiometabolic risk. TSH levels did not differ between metformin-treated and untreated subjects, while they were lower in patients with incident diabetes mellitus compared to normoglycaemic ones.

Functional and Molecular Adaptations of Enteroendocrine L-Cells in Male Obese Mice Are Associated With Preservation of Pancreatic α-Cell Function and Prevention of Hyperglycemia.

Glucose homeostasis depends on the coordinated secretion of glucagon, insulin, and Glucagon-like peptide (GLP)-1 by pancreas and intestine. Obesity, which is associated with an increased risk of developing insulin resistance and type 2 diabetes, affects the function of these organs. Here, we investigate the functional and molecular adaptations of proglucagon-producing cells in obese mice to better define their involvement in type 2 diabetes development. We used GLU-Venus transgenic male mice specifically expressing Venus fluorochrome in proglucagon-producing cells. Mice were subjected to 16 weeks of low-fat diet or high-fat diet (HFD) and then subdivided by measuring glycated hemoglobin (HbA1c) in 3 groups: low-fat diet mice and I-HFD (glucose-intolerant) mice with similar HbA1c and H-HFD (hyperglycemic) mice, which exhibited higher HbA1c. At 16 weeks, both HFD groups exhibited similar weight gain, hyperinsulinemia, and insulin resistance. However, I-HFD mice exhibited better glucose tolerance compared with H-HFD mice. I-HFD mice displayed functional and molecular adaptations of enteroendocrine L-cells resulting in increased intestinal GLP-1 biosynthesis and release as well as maintained pancreatic α- and β-cell functions. By contrast, H-HFD mice exhibited dysfunctional L, α- and β-cells with increased β- and L-cell numbers. Administration of the GLP-1R antagonist Exendin9-39 in I-HFD mice led to hyperglycemia and alterations of glucagon secretion without changes in insulin secretion. Our results highlight the cross-talk between islet and intestine endocrine cells and indicate that a compensatory adaptation of L-cell function in obesity plays an important role in preserving glucose homeostasis through the control of pancreatic α-cell functions.

Beneficial Effects of Bariatric Surgery on Cardiac Structure and Function in Obesity.

Bariatric surgery is being considered as a therapeutic option for morbidly obese patients. Data are accumulating showing that this surgical intervention may improve in major cardiovascular morbidity and mortality. We evaluated the effects of bariatric surgery on left ventricular (LV) structure and function including LV mechanics in obese patients. Thirty-seven patients (age=36±10years; male:female=11:26) undergoing bariatric surgery were enrolled. Echocardiography was performed before and after at least 1year of bariatric surgery. Conventional echocardiographic parameters, including tissue Doppler measurements, were measured. LV global longitudinal, circumferential, and radial deformations were assessed utilizing 2D speckle tracking software. Patients decreased body mass index by 11.8±4.7 over 15.6±5.5months. Bariatric surgery led to significant decreases in left ventricular (LV) size and mass (51.0±3.3 to 49.1±3.4mm, p<0.001 for LV end-diastolic dimension; 192.6±33.5 to 146.2±29.1g, p<0.001 for LV mass), and increases were noted in the ratio of early-to-late diastolic mitral inflow (E/A), early diastolic tissue Doppler velocity (Em), and LV longitudinal strain (1.42±0.52 to 1.59±0.56, p=0.04 for E/A ratio; 9.7±2.0 to 11.0±2.4cm/s, p<0.001 for Em; 14.1±1.9 to 16.2±1.4%, p<0.001 for longitudinal strain). Changes of LV longitudinal strain were related to LV mass reduction (p=0.04). However, LV ejection fraction, LV circumferential, and radial strains were all comparable at follow-up. Significant weight loss by bariatric surgery was associated with improved LV structure and function in obese patients, suggesting potential favorable effects of bariatric surgery to prevent future cardiovascular events.

Platelet hyperaggregability in obesity: is there a role for nitric oxide impairment and oxidative stress?

Epidemiological evidence has shown that platelet activation markers are consistently elevated in obesity, contributing to its prothrombotic state. In order to improve the understanding of the regulation of platelet function in obesity, the aim of this study was to investigate the l-arginine-nitric oxide (NO) pathway in obese adults without other cardiovascular risk factor. Seventeen obese (body mass index [BMI] 35.9±1.0kg/m(2) ) and eighteen age-matched normal weight subjects (BMI 22.0±0.6kg/m(2) ) were included in this study. l-arginine influx was measured with incubation of l-[(3) H]-arginine. NO synthase (NOS) and arginase activities were determined by the citrulline assay and the conversion of l-[(14) C]-arginine to [(14) C]-urea, respectively. Cyclic guanosine monophosphate (cGMP) content was evaluated by enzyme-linked immunosorbent assay. In addition, the study analyzed: platelet aggregation; intraplatelet antioxidant enzymes, via superoxide dismutase (SOD) and catalase activities; and systemic levels of l-arginine, fibrinogen, and C-reactive protein (CRP). Obese patients presented a significant decrease of platelet l-arginine influx, NOS activity, and cGMP levels, along with platelet hyperaggregability. On the presence of NO donor, platelet aggregation was similar between the groups. The fibrinogen and CRP systemic levels were significantly higher and SOD activity was reduced in obesity. No significant differences were observed in plasma levels of l-arginine and intraplatelet arginase and catalase activities between groups. The diminished NO bioavailability associated with inflammatory status and impaired enzymatic antioxidant defence may contribute to future cardiovascular complications in obesity.

Effects of an High-Fat Diet Enriched in Lard or in Fish Oil on the Hypothalamic Amp-Activated Protein Kinase and Inflammatory Mediators.

The high fat diet (HFD) rich in lard induces obesity, inflammation and oxidative stress, and the deregulation of hypothalamic nuclei plays an important role in this mechanism. One important factor involved in the food intake and inflammation is adenosine monophosphate-dependent kinase (AMPK), a serine/threonine kinase activated by phosphorylation. Omega (ω)3-polyunsaturated fatty acids (PUFA) are dietary compounds known to attenuate the obesity-related diseases, although the molecular mechanisms underlying their actions in the hypothalamus are not completely understood. We hypothesized that the beneficial effects of PUFA may be mediated by AMPK in the hypothalamus. To this aim, rats were fed a control diet (CD), or isocaloric HFD containing either fish oil (FD; rich in ω3-PUFA) or lard for 6 weeks, and the activation of AMPK, inflammatory state (IKKβ, TNF-α) and oxidative stress were analyzed in the hypothalamus. In addition, we also studied serum lipid profile, homeostatic model assessment (HOMA) index, and pro-inflammatory parameters. Our results showed, at the hypothalamic level of LD-fed rats, an increase of AMPK activation, inflammation and oxidative stress, while no modifications were detected in FD-fed animals compared to CD. In addition body weight gain, serum lipid profile, pro-inflammatory parameters and insulin resistance were reduced in FD animals compared to LD. In conclusion, our data indicate that the substitution of saturated by unsaturated fatty acids in the diet has beneficial effects on modulation of hypothalamic inflammation and function in obesity, underlying, at hypothalamic level, the interaction among insulin and/or leptin resistance, AMPK activation and hyperphagia.

Increasing Muscle Mass Improves Cavernosal Function in Obesity

Obesity is a known risk factor for erectile dysfunction but the causal mechanisms remain poorly understood. Moreover, exercise is known to improve erectile function but the components of exercise (weight loss, aerobic capacity, or muscle mass) that contribute are unclear. The purpose of our study was to investigate whether increased muscle mass in an obese mouse model improves the erectile function of the corpus cavernosum.Lean mice heterozygous for db, the leptin receptor, were bred to mice lacking myostatin, a myokine the limits muscle growth. Four groups were studied. Lean controls, lean myostatin‐null mice, obese control and obese myostatin‐null mice. All mice were phenotyped using metabolic cages and analysis of plasma chemistry. Responses of cavernosal strips were assessed in vitro in response to phenylephrine and acetylcholine.Obese mice compared to lean were characterized by a two‐fold increase in body weight, marked adiposity, low oxygen consumption, muscle atrophy, dyslipidemia and hyperglycemia. Deletion of myostatin in lean mice markedly increased muscle mass (35%, p&lt;0.05) but otherwise produced no phenotypic alterations. Deletion of myostatin increased muscle mass to a similar degree as lean mice and improved glucose control in obese mice with no effect on lipids, body weight or body composition.Despite similar cavernosal mass, obese mice showed increased vasoconstrictor force generation (which would restrain erection) to phenylephrine when compared to the lean controls (102%, p&lt;0.05). Deletion of myostatin had no effect in lean mice but reduced constriction to normal values in obese mice. Vasodilation to acetylcholine tended to be reduced in obese mice but no significant differences emerged among the four groups.Overall, these results support the hypothesis that increased muscle tone can improve erectile function in obese mice. This effect, potentially due to improved glucose tolerance by the larger muscle mass, may explain to some degree how exercise improves erectile function in obesity.Support or Funding InformationWork supported by NHLBI 092446 and 124773 and the Dean's Summer Research Program

Abstract A75: An analysis of the interaction between obesity and measures predicting prostate cancer-free survival

Abstract Introduction: Obesity has been associated with recurrence of prostate cancer for treated patients in past research. The Kattan nomogram and the CaPSURE/CPDR recurrence equation have been developed to approximate the probability that prostate cancer will recur in a patient after radical prostatectomy. Although these are commonly used algorithms, it is not clear how well they predict disease recurrence in obese patients. The purpose of this project is to examine whether obesity modifies the association between prostate cancer outcomes and the two prediction scores. We hypothesized that there will be differences among BMI groups in associations between prediction scores and prostate cancer recurrence. This would suggest varying accuracy in post-operative prognoses for radical prostatectomy patients by obesity status. Methods: Our sample included 1576 radical prostatectomy patients. Patients' obesity was classified using BMI as per conventional standards. The Kattan score was calculated using preoperative clinical variables and post-treatment pathologic variables, and the CaPSURE/CPDR score was calculated using a subset of these variables in addition to race. Cutoff points were defined for each score, and patients were categorized into low, medium, and high risk groups. Time to prostate cancer recurrence was modeled using Cox proportional hazard models as a function of obesity, the predictive score risk group, and their interaction. The models were adjusted for patients' age in addition to other measures associated with failure but not used to calculate the score. Results: As expected for the Kattan score, estimated hazard ratios (95% CI) indicated higher rates of recurrence for the medium (2.99 (2.29, 3.88)) and high (8.84 (5.91, 13.2)) risk groups compared to the low risk group. The associations were not statistically different across obesity groups. However, we noticed within our sample that the association between obesity and prostate cancer was strong in the low risk group and weak in the high risk group. Results were consistent for the CaPSURE/CPDR score. Conclusion: We observed no difference in the association between cancer recurrence and prediction scores across different obesity groups. However, we did observe that the relationship between obesity and cancer recurrence was stronger for low risk patients than for high risk patients, with obese men in the low risk group having poorer outcomes. This suggests that when men are at a high risk of cancer recurrence, obesity is a less effective predictor of recurrence, but obesity should be taken into account when predicting prostate cancer outcomes for moderate to low risk men. These results are not statistically significant. Our study suffered from a small sample of high risk patients, so there is not sufficient evidence that our findings are generalizable to all radical prostatectomy patients. Citation Format: Aaron Hudson, Charnita Zeigler-Johnson, Karen Glanz, Elaine Spangler, Timothy R. Rebbeck, Knashawn H. Morales. An analysis of the interaction between obesity and measures predicting prostate cancer-free survival. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr A75.

Effects of Obesity on Perivascular Adipose Tissue Vasorelaxant Function: Nitric Oxide, Inflammation and Elevated Systemic Blood Pressure

Introduction: Perivascular adipose tissue (PVAT) surrounds most vessels in the human body. Healthy PVAT has a vasorelaxant effect which is not observed in obesity. We assessed the contribution of nitric oxide (NO), inflammation and endothelium to obesity-induced PVAT damage. Methods: Rats were fed a high-fat diet or normal chow. PVAT function was assessed using wire myography. Skeletonised and PVAT-intact mesenteric vessels were prepared with and without endothelium. Vessels were incubated with <smlcap>L</smlcap>-NNA or superoxide dismutase (SOD) and catalase. Gluteal fat biopsies were performed on 10 obese and 10 control individuals, and adipose tissue was assessed using proteomic analysis. Results: In the animals, there were significant correlations between weight and blood pressure (BP; r = 0.5, p = 0.02), weight and PVAT function (r = 0.51, p = 0.02), and PVAT function and BP (r = 0.53, p = 0.01). PVAT-intact vessel segments from healthy animals constricted significantly less than segments from obese animals (p < 0.05). In a healthy state, there was preservation of the PVAT vasorelaxant function after endothelium removal (p < 0.05). In endothelium-denuded vessels, <smlcap>L</smlcap>-NNA attenuated the PVAT vasorelaxant function in control vessels (p < 0.0001). In obesity, incubation with SOD and catalase attenuated PVAT-intact vessel contractility in the presence and absence of endothelium (p < 0.001). In obese humans, SOD [Cu-Zn] (SOD1; fold change -2.4), peroxiredoxin-1 (fold change -2.15) and adiponectin (fold change -2.1) were present in lower abundances than in healthy controls. Conclusions: Incubation with SOD and catalase restores PVAT vasorelaxant function in animal obesity. In the rodent model, obesity-induced PVAT damage is independent of endothelium and is in part due to reduced NO bioavailability within PVAT. Loss of PVAT function correlates with rising BP in our animal obesity model. In keeping with our hypothesis of inflammation-induced damage to PVAT function in obesity, there are lower levels of SOD1, peroxiredoxin-1 and adiponectin in obese human PVAT.

Obesity decreases B cell responses in young and elderly individuals.

To evaluate the effects of obesity-associated inflammation on influenza vaccine responses. In young and elderly individuals, both lean and with obesity, antibody responses to influenza vaccination were measured. A decrease in in vivo vaccine responses, circulating switched memory, and transitional B cells and an increase in pro-inflammatory late/exhausted memory B cells were found. In vitro B cell function was measured by activation-induced cytidine deaminase and E47, markers of optimal antibody responses. Moreover, IL-6 production was increased, whereas IL-10 production was decreased in cultures of B cells from individuals with obesity. Markers of immune activation (TNF-α, TLR4, micro-RNAs) in unstimulated B cells were also found increased and were negatively correlated with B cell function. In order to reveal potential mechanisms, we stimulated B cells from lean individuals in vitro with leptin, the adipokine increased in obesity. Leptin increased phospho-STAT3, crucial for TNF-α production, and decreased phospho-AMPK, the energy sensing enzyme upstream of phospho-p38 MAPK and E47. Leptin-induced phospho-STAT3 and phospho-AMPK levels were similar to those in B cells from individuals with obesity. These results demonstrate that leptin can be responsible for decreased B cell function in obesity.

Inhibition of Inflammation and iNOS Improves Lymphatic Function in Obesity.

Although recent studies have shown that obesity decreases lymphatic function, the cellular mechanisms regulating this response remain unknown. In the current study, we show that obesity results in perilymphatic accumulation of inflammatory cells and that local inhibition of this response with topical tacrolimus, an inhibitor of T cell differentiation, increases lymphatic vessel density, decreases perilymphatic iNOS expression, increases lymphatic vessel pumping frequency, and restores lymphatic clearance of interstitial fluid to normal levels. Although treatment of obese mice with 1400W, a selective inhibitor of iNOS, also improved lymphatic collecting vessel contractile function, it did not completely reverse lymphatic defects. Mice deficient in CD4+ cells fed a high fat diet also gained weight relative to controls but were protected from lymphatic dysfunction. Taken together, our findings suggest that obesity-mediated lymphatic dysfunction is regulated by perilymphatic accumulation of inflammatory cells and that T cell inflammatory responses are necessary to initiate this effect.

Vitamins C, E, and NADH on &amp;lt;i&amp;gt;in Vitro&amp;lt;/i&amp;gt; Lymphocyte Proliferation and Redox Status among Obese Patients

Background: The prevalence of overweight and obesity associated with oxidative stress and immune abnormalities is continuously increasing. Antioxidant supplementations might counteract potential damage caused by ROS to cellular tissues. Objective: To determine the role of vitamins on immune improvement during obesity, we investigated in vitro effects of vitamins C, E, and NADH on mitogen-stimulated proliferation, Th1- and Th2-type cytokine production, and oxidant/antioxidant status of lymphocytes isolated from obese patients. Methods: Peripheral blood lymphocytes were isolated using a density gradient of Histopaque. They were in vitro cultured and stimulated by Con A in the presence or absence of vitamins. Cell proliferation was determined by MTT assay and interleukin-2, interleukin-4 and interferon-γ (INFγ) secretions. Cell oxidant/antioxidant balance was studied by assaying glutathione (GSH), malondialdehyde (MDA), carbonyl protein levels, catalase activity and micronucli frequency. Results: Obesity is associated with enhanced oxidative stress response. Indeed, vitamin C, E and NADH improved significantly lymphocyte proliferation and diminished cellular oxidative stress. Conclusion: Treatments of lymphocytes with vitamins had beneficial effects on lymphocyte proliferation, cytokines secretions and redox status, generating an anti-inflammatory profile and should be considered in therapeutic approaches for normalizing immune cell function in obesity.

Association of Waist Circumference with Pulmonary Function in Obesity

Obesity is a global health hazard and the prevalence of obesity is increasing. There is evidence that obesity, particularly abdominal obesity is negatively associated with pulmonary function. Obesity-related health risks are better explained by waist circumference (WC) than BMI as it provides information on fat distribution that cannot be obtained from BMI. We aimed to evaluate the association of WC with pulmonary function in adults with or without obesity. Pulmonary function was assessed by spirometry in 40 non-obese and obese adults between 20–60 years. Their height, weight and waist circumference were recorded. Student's t-test was done and Pearson's correlation was used to show a relationship between WC and the spirometric variables. Significant differences were observed in forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), expiratory reserve volume (ERV), inspiratory reserve volume (IRV) and maximum voluntary ventilation (MVV) between the obese and non-obese groups. WC showed a significant negative association with FEV1, FVC, ERV and MVV. The mechanisms underlying this association need to be further explored.

Altered Methylation Profile of Lymphocytes Is Concordant with Perturbation of Lipids Metabolism and Inflammatory Response in Obesity.

Obesity is associated with immunological perturbations that contribute to insulin resistance. Epigenetic mechanisms can control immune functions and have been linked to metabolic complications, although their contribution to insulin resistance still remains unclear. In this study, we investigated the link between metabolic dysfunction and immune alterations with the epigenetic signature in leukocytes in a porcine model of obesity. Global DNA methylation of circulating leukocytes, adipose tissue leukocyte trafficking, and macrophage polarisation were established by flow cytometry. Adipose tissue inflammation and metabolic function were further characterised by quantification of metabolites and expression levels of genes associated with obesity and inflammation. Here we show that obese pigs showed bigger visceral fat pads, higher levels of circulating LDL cholesterol, and impaired glucose tolerance. These changes coincided with impaired metabolism, sustained macrophages infiltration, and increased inflammation in the adipose tissue. Those immune alterations were linked to global DNA hypermethylation in both B-cells and T-cells. Our results provide novel insight into the possible contribution of immune cell epigenetics into the immunological disturbances observed in obesity. The dramatic changes in the transcriptomic and epigenetic signature of circulating lymphocytes reinforce the concept that epigenetic processes participate in the increased immune cell activation and impaired metabolic functions in obesity.

Metabolic Effects of Long-Term Reduction in Free Fatty Acids With Acipimox in Obesity: A Randomized Trial.

Increased circulating free fatty acids (FFAs) have been proposed to contribute to insulin resistance in obesity. Short-term studies have investigated the effects of acipimox, an inhibitor of hormone-sensitive lipase, on glucose homeostasis, but longer-term studies have not been performed. To test the hypothesis that long-term treatment with acipimox would reduce FFA and improve insulin sensitivity among nondiabetic, insulin-resistant, obese subjects. At an academic medical center, 39 obese men and women were randomized to acipimox 250 mg thrice-daily vs identical placebo for 6 months. Plasma lipids, insulin sensitivity, adiponectin, and mitochondrial function via assessment of the rate of post-exercise phosphocreatine recovery on (31)P-magnetic resonance spectroscopy as well as muscle mitochondrial density and relevant muscle gene expression. Fasting glucose decreased significantly in acipimox-treated individuals (effect size, -6 mg/dL; P = .02), in parallel with trends for reduced fasting insulin (effect size, -6.8 μU/mL; P = .07) and HOMA-IR (effect size, -1.96; P = .06), and significantly increased adiponectin (effect size, +668 ng/mL; P = .02). Acipimox did not affect insulin-stimulated glucose uptake, as assessed by euglycemic, hyperinsulinemic clamp. Effects on muscle mitochondrial function and density and on relevant gene expression were not seen. These data shed light on the long-term effects of FFA reduction on insulin sensitivity, other metabolic parameters, and muscle mitochondrial function in obesity. Reduced FFA achieved by acipimox improved fasting measures of glucose homeostasis, lipids, and adiponectin but had no effect on mitochondrial function, mitochondrial density, or muscle insulin sensitivity.

The effects of high-fat feeding on physical function and skeletal muscle extracellular matrix.

Skeletal muscle extracellular matrix (ECM) remodelling has been proposed as a feature of the pathogenic milieu associated with obesity and metabolic dysfunction. Whether muscle ECM is associated with impaired physical function in obese conditions is unknown. C57BL/6 mice were fed a high-fat diet (HFD) or chow for 5, 10 and 25 weeks. Non-invasive physiological tests (hang wire, hang mesh and grip strength) to assess neuromuscular function and motor co-ordination were performed. Genes related to ECM structure (COL1, COL3, COL6A2, SPARC), growth factors (TGFB1, TGFB2, CTGF, VEGF) and muscle function (DMD (Dp147), CPN3, DAG1) were measured in gastrocnemius muscle using real-time PCR and COL1, 3 and 6 protein were measured by western immunoblot. Compared with chow, HFD mice had two to six-fold lower muscle strength (hang wire test; raw data and multiplied by body weight) at all time-points (P<0.001) and two-fold lower hang mesh and grip strength at 10 weeks (P<0.05). At 5 weeks, COL1, COL3 and COL6 gene expression, but not protein levels were three to eight-fold lower in HFD compared with chow. In the HFD group at 5 weeks, greater COL3 and 6 gene expression were associated with poorer hang wire performance. For the first time, our results demonstrate links between muscle ECM structure and physical function in obesity.

Biotin-dependent functions in adiposity: a study of monozygotic twin pairs.

Biotin acts as a coenzyme for carboxylases regulating lipid and amino-acid metabolism. We investigated alterations of the biotin-dependent functions in obesity and the downstream effects of biotin restriction in adipocytes in vitro. Twenty-four monozygotic twin pairs discordant for body mass index (BMI). Mean within-pair difference (heavy-lean co-twin, Δ) of BMI was 6.0 kg m(-2) (range 3.1-15.2 kg m(-)(2)). Adipose tissue (AT) DNA methylation, gene expression of AT and adipocytes, and leukocytes (real-time quantitative PCR), serum biotin, C-reactive protein (CRP) and triglycerides were measured in the twins. Human adipocytes were cultured in low and control biotin concentrations and analyzed for lipid droplet content, mitochondrial morphology and mitochondrial respiration. The gene expression levels of carboxylases, PCCB and MCCC1, were upregulated in the heavier co-twins' leukocytes. ΔPCCB (r=0.91, P=0.0046) and ΔMCCC1 (r=0.79, P=0.036) correlated with ΔCRP within-pairs. Serum biotin levels were lower in the heavier (274 ng l(-1)) than in the lean co-twins (390 ng l(-1), P=0.034). ΔBiotin correlated negatively with Δtriglycerides (r=-0.56, P=0.045) within-pairs. In AT, HLCS and ACACB were hypermethylated and biotin cycle genes HLCS and BTD were downregulated (P<0.05). Biotin-dependent carboxylases were downregulated (ACACA, ACACB, PCCB, MCCC2 and PC; P<0.05) in both AT and adipocytes of the heavier co-twins. Adipocytes cultured in low biotin had decreased lipid accumulation, altered mitochondrial morphology and deficient mitochondrial respiration. Biotin-dependent functions are modified by adiposity independent of genetic effects, and correlate with inflammation and hypertriglyceridemia. Biotin restriction decreases lipid accumulation and respiration, and alters mitochondrial morphology in adipocytes.

Stigma and the etiology of depression among the obese: An agent-based exploration

BackgroundObesity and depression are comorbid more often than chance predicts. However, depression among the obese is more common in settings where obesity is less common. This suggests that body habitus norms and social stigmatization may play a role in the etiology of depression among the obese. MethodsWe developed an agent-based social network model to explore mechanisms by which deviance from normative body habitus may contribute to social isolation in the obese. At each of 240 simulated months (20 years), each agent updated its body mass index based on environmental, peer influence, and stochastic factors. At each month, each agent was subject to social ostracization and consequent depression if its body mass index deviated from that of its peers and the network-wide mean. We compared risk of depression as a function of obesity and obesity norms through simulations of a high-obesity context simulating the US state of Mississippi and a low-obesity context simulating the US state of Colorado, then explored the relationship between global obesogenic forces and agent-specific resistance to the forces. ResultsOver 1000 simulations in each context, 25 percent of obese agents in simulated Colorado were ever-depressed as compared to 21 percent in simulated Mississippi, although 10 percent overall were ever-depressed in both settings. High and low levels of resistance to obesogeneity prevented the most depression, whereas medium resistance levels were more depressogenic. ConclusionsSocial stigma and ostracization that occur as a consequence of deviance from body habitus norms may be a plausible mechanism by which weight stigma may influence depression in the obese. Public health interventions targeting individuals rather than obesogenic environments may modify body habitus norms with the unintended consequence of increasing stigma-based social isolation among those who remain obese.

Circulating Endocannabinoids and the Polymorphism 385C>A in Fatty Acid Amide Hydrolase (FAAH) Gene May Identify the Obesity Phenotype Related to Cardiometabolic Risk: A Study Conducted in a Brazilian Population of Complex Interethnic Admixture.

The dysregulation of the endocannabinoid system is associated with cardiometabolic complications of obesity. Allelic variants in coding genes for this system components may contribute to differences in the susceptibility to obesity and related health hazards. These data have mostly been shown in Caucasian populations and in severely obese individuals. We investigated a multiethnic Brazilian population to study the relationships among the polymorphism 385C>A in an endocannabinoid degrading enzyme gene (FAAH), endocannabinoid levels and markers of cardiometabolic risk. Fasting plasma levels of endocannabinoids and congeners (anandamide, 2-arachidonoylglycerol, N-oleoylethanolamide and N-palmitoylethanolamide) were measured by liquid chromatography-mass spectrometry in 200 apparently healthy individuals of both genders with body mass indices from 22.5 ± 1.8 to 35.9 ± 5.5 kg/m2 (mean ± 1 SD) and ages between 18 and 60 years. All were evaluated for anthropometric parameters, blood pressure, metabolic variables, homeostatic model assessment of insulin resistance (HOMA-IR), adiponectin, leptin, C-reactive protein, and genotyping. The endocannabinoid levels increased as a function of obesity and insulin resistance. The homozygous genotype AA was associated with higher levels of anandamide and lower levels of adiponectin versus wild homozygous CC and heterozygotes combined. The levels of anandamide were independent and positively associated with the genotype AA position 385 of FAAH, C-reactive protein levels and body mass index. Our findings provide evidence for an endocannabinoid-related phenotype that may be identified by the combination of circulating anandamide levels with genotyping of the FAAH 385C>A; this phenotype is not exclusive to mono-ethnoracial populations nor to individuals with severe obesity.

Abstract 12631: Peripheral Gamma-aminobutyric Acid(gaba) Signaling in Brown Adipose Tissue Induces Metabolic Dysfunction in Obesity

Accumulating evidence suggests that adult humans possess active brown adipose tissue (BAT) that may contribute significantly to systemic metabolism because of its high energy consumption capacity. Recently, we demonstrated that metabolic stress induced BAT hypoxia and impaired mitochondrial function, leading to the development of BAT “whitening” and systemic metabolic dysfunction in murine obese models. Various neurotransmitters are known to be involved in the maintenance of BAT homeostasis. Among them, the gamma-aminobutyric acid (GABA) signaling in the central nervous system is well accepted to have anti-obesity effects through the activation of the sympathetic nervous system. Here we show the previously unknown role of peripheral GABA signaling in the development of systemic metabolic dysfunction in obesity. We generated an obese model by imposing a high fat/high sucrose (HFHS) diet on C57BL/6NCr mice. Mass spectrometry analysis demonstrated a significant increase in GABA level in BAT of the dietary obese model. Addition of GABA into drinking water induced BAT whitening, reduced the thermogenic response upon cold tolerance test, and promoted systemic metabolic dysfunction in the obese mice. Mitochondrial calcium is important for the maintenance of mitochondrial homeostasis, whereas calcium overload is reported to inhibit mitochondrial function. Treatment of BAT cells with GABA markedly increased mitochondrial calcium level, promoted the production of reactive oxygen species (ROS), and inhibited mitochondrial respiration. These results indicate that peripheral GABA contributes to the development of systemic metabolic dysfunction by inhibiting BAT function in obesity. The inhibition of peripheral GABA signaling would become a new therapeutic target for obesity and diabetes.

A possible link between hepatic mitochondrial dysfunction and diet-induced insulin resistance

Mitochondria are the main cellular sites devoted to ATP production and lipid oxidation. Therefore, the mitochondrial dysfunction could be an important determinant of cellular fate of circulating lipids, that accumulate in the cytoplasm, if they are not oxidized. The ectopic fat accumulation is associated with the development of insulin resistance, and a link between mitochondrial dysfunction and insulin resistance has been proposed. Recent data on the possible link existing between mitochondrial dysfunction in the liver and diet induced obesity will be summarized, focusing on the three factors that affect the mitochondrial oxidation of metabolic fuels, i.e. organelle number, organelle activity, and energetic efficiency of the mitochondrial machinery in synthesizing ATP. Search in PubMed relevant articles from 2003 to 2014 was conducted, by using query “liver mitochondria and obesity” “hepatic mitochondria and obesity” “liver mitochondria and high fat diet” and “hepatic mitochondria and high fat diet” and including related articles by the same groups. Several works, by using different physiological approaches, have dealt with alteration in mitochondrial function in obesity and diabetes. Most results show that hepatic mitochondrial function is impaired in models of obesity and insulin resistance induced by high-fat or highfructose feeding. Since mitochondria are the main producers of both cellular energy and free radicals, dysfunctional mitochondria could play an important role in the development of insulin resistance and ectopic fat storage in the liver, thus supporting the emerging idea that mitochondrial dysfunction is closely related to the development of obesity, type 2 diabetes mellitus and non-alcoholic steatohepatitis.