Obesity-associated Morbidities Research Articles

Lower adiponectin is associated with higher anthropometry and insulin resistance but not with low cardiorespiratory fitness in adolescents.

The aim of this study was to analyze the relationship between adiposity, cardiometabolic risk and cardiorespiratory fitness (CRF) according to different groups of adiponectin concentration. 255 adolescents of both sexes, aged 11-17years old, participated. Anthropometric and biochemical parameters such as body mass, height, abdominal circumference (AC), waist circumference (WC), fat mass, fat-free mass, total cholesterol (TC), high-density lipoprotein (HDL-c), low-density lipoprotein (LDL-c), triglycerides (TG), glucose, insulin, adiponectin, blood pressure, peak oxygen consumption (VO2peak) were measured. Body mass index (BMI), z-score BMI (BMI-z), triponderal mass index (TMI), waist-to-height ratio (WHtR), homeostasis model to assessment insulin resistance (HOMA-IR), and quantitative insulin sensitivity check index (QUICKI) were calculated. Adiponectin was categorized: low adiponectin concentration (LAC ≤ 5.18µg/mL-1), intermediate (IAC = 5.18 and 7.63µg/mL-1) and high (HAC ≥ 7.63µg/ml-1). LAC showed higher BMI, BMI-z and TMI than the other groups (p < 0.05) and higher AC, WC and WHtR that the HAC (p < 0.05). IAC showed lower values of TC, LDL-c and TG, and the LAC presented the highest values of insulin, HOMA-IR and QUICKI (p < 0.05) to the IAC and HAC. HAC presented the lower VO2peak than the other groups (p < 0.01). BMI, TMI, glucose, insulin, HOMA-IR showed inverse, and QUICKI a direct and weak correlation with adiponectin (p < 0.05). No significant association was found between adiponectin and VO2peak (p > 0.05). The LAC group had higher means in the anthropometric variables and the worst results related to insulin resistance and sensitivity. Thus, adiponectin may play an important role in obesity and reduced concentration may be a factor in the development of obesity-associated morbidities.

NOD-like Receptors-Emerging Links to Obesity and Associated Morbidities.

Obesity and its associated metabolic morbidities have been and still are on the rise, posing a major challenge to health care systems worldwide. It has become evident over the last decades that a low-grade inflammatory response, primarily proceeding from the adipose tissue (AT), essentially contributes to adiposity-associated comorbidities, most prominently insulin resistance (IR), atherosclerosis and liver diseases. In mouse models, the release of pro-inflammatory cytokines such as TNF-alpha (TNF-α) and interleukin (IL)-1β and the imprinting of immune cells to a pro-inflammatory phenotype in AT play an important role. However, the underlying genetic and molecular determinants are not yet understood in detail. Recent evidence demonstrates that nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family proteins, a group of cytosolic pattern recognition receptors (PRR), contribute to the development and control of obesity and obesity-associated inflammatory responses. In this article, we review the current state of research on the role of NLR proteins in obesity and discuss the possible mechanisms leading to and the outcomes of NLR activation in the obesity-associated morbidities IR, type 2 diabetes mellitus (T2DM), atherosclerosis and non-alcoholic fatty liver disease (NAFLD) and discuss emerging ideas about possibilities for NLR-based therapeutic interventions of metabolic diseases.

Maternal Obesity-Associated Neonatal Morbidities in Early Newborn Period.

Maternal obesity has been associated with pregnancy-related complications and neonatal morbidities. The primary aim of this study was to evaluate early neonatal morbidities associated with maternal obesity from the infant-mother dyad data set at a single, large Regional Perinatal Center (RPC) in NY. A retrospective chart review of all mother-infant dyads born from January 2009 to December 2019 was done. Maternal obesity was defined using the NIH definition of pre-pregnancy body mass index (BMI) ≥ 30 Kg/m2. Maternal data included pre-pregnancy BMI, gestational diabetes, hypertension, and mode of delivery. Neonatal data recorded the birth weight, gestational age, respiratory support after delivery, diagnosis of transient tachypnea of the newborn (TTN), respiratory distress syndrome (RDS), neonatal hypoglycemia (NH), and hypoxic-ischemic encephalopathy (HIE). Diagnosis of TTN, RDS, NH, and HIE was defined by the service neonatologist and cross-checked by the data system review neonatologist. Medical records of 22,198 infant-mother dyads included in the study had 7,200 infants (32.4%) born to obese mothers and 14,998 infants (67.6%) born to non-obese women. There was a statistically significant increase in the diagnosis of gestational diabetes, gestational hypertension, and cesarean deliveries in obese mothers. Diagnosis of TTN, RDS, and NH was significantly higher in infants born to obese mothers, while HIE incidence was similar in both the groups. Infants born to obese mothers are more likely to be delivered by cesarean section and are at a higher risk of diagnosis of transient tachypnea of newborn, respiratory distress syndrome, and hypoglycemia in the early neonatal period.

Suture pattern does not influence outcomes of endoscopic sleeve gastroplasty in obese patients.

Background and study aims ESG is an effective and safe medium-term procedure for obesity treatment. A variety of suture patterns have been reported. We aimed to compare whether there are differences in efficacy depending on suture pattern used. Patients and methods Retrospective and comparative review of 5 years of prospectively collected data, including consecutive obese patients undergoing ESG at two collaborative centers. Primary outcomes included weight loss (mainly % total body weight loss [TBWL] and % exces weight loss [EWL]) at 12 months and safety profile. We compared them according to three suture patterns (transverse bilinear [TBp], longitudinal [Lp] and transverse monolinear [TMp]), and number of sutures (4 – 7) and stitches (< 25, 25 to 30 and > 30) applied. Evolution of major obesity-associated morbidities (hypertension, dyslipidemia, Type 2 diabetes mellitus (T2DM), sleep obstructive apnea syndrome, and arthropathy) were also described. Results 88 patients (mean age 46.1±12.3 years, 69.3 % female) underwent ESG. Mean body mass index (BMI) at baseline was 39.40 ± 4.69 kg/m². At 1 year, %TBWL was 17.36 ± 6.09 % (%EWL 46.41±20.6 %) with TBWL > 10 % in 95.5 % of patients (EWL > 25 % in 94.3 % of patients). According to pattern, there were no differences in %TBWL but there were in %EWL (43.7 ± 20.4 %, 59.8 ± 18.9 % and 45.4 ± 14.9 % in TBp, Lp and TMp patterns, respectively) ( P = 0.034). No differences were found related to number of sutures (mean 5.2 ± 0.73, r = 4 – 7) or stitches (mean 27.4 ± 6.50, r = 18 – 50) applied. Forty-three of 72 (59.7 %) major comorbidities were resolved. No serious adverse events were observed with any pattern. Conclusions ESG is an effective procedure at 12-month follow-up for weight loss and comorbidity resolution. All three analyzed patterns are safe and effective without differences in %TBWL, but there was a slight increase in %EWL in Lp, regardless of the number of sutures or stitches applied.

Childhood Obesity, Endothelial Cell Activation, and Critical Illness.

Pediatric obesity is increasing in prevalence and is frequently an antecedent to adult obesity and adult obesity-associated morbidities such as atherosclerosis, type II diabetes, and chronic metabolic syndrome. Endothelial cell activation, one aspect of inflammation, is present in the early stages of atherosclerosis, often prior to the onset of symptoms. Endothelial activation is a pathological condition in which vasoconstricting, pro-thrombotic, and proliferative mediators predominate protective vasodilating, anti-thrombogenic, and anti-mitogenic mediators. Many studies report poor outcomes among obese children with systemic endothelial activation. Likewise, the link between childhood obesity and poor outcomes in critical illness is well-established. However, the link between obesity and severity of endothelial activation specifically in the setting of critical illness is largely unstudied. Although endothelial cell activation is believed to worsen disease in critically ill children, the nature and extent of this response is poorly understood due to the difficulty in measuring endothelial cell dysfunction and destruction. Based on the data available for the obese, asymptomatic population and the obese, critically ill population, the authors posit that obesity, and obesity-associated chronic inflammation, including oxidative stress and insulin resistance, may contribute to endothelial activation and associated worse outcomes among critically ill children. A research agenda to examine this hypothesis is suggested.

Integrated Transcriptome Analysis of Human Visceral Adipocytes Unravels Dysregulated microRNA-Long Non-coding RNA-mRNA Networks in Obesity and Colorectal Cancer.

Obesity, and the obesity-associated inflammation, represents a major risk factor for the development of chronic diseases, including colorectal cancer (CRC). Dysfunctional visceral adipose tissue (AT) is now recognized as key player in obesity-associated morbidities, although the biological processes underpinning the increased CRC risk in obese subjects are still a matter of debate. Recent findings have pointed to specific alterations in the expression pattern of non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), and long non-coding RNAs (lncRNAs), as mechanisms underlying dysfunctional adipocyte phenotype in obesity. Nevertheless, the regulatory networks and interrelated processes relevant for adipocyte functions, that may contribute to a tumor-promoting microenvironment, are poorly known yet. To this end, based on RNA sequencing data, we identified lncRNAs and miRNAs, which are aberrantly expressed in visceral adipocytes from obese and CRC subjects, as compared to healthy lean control, and validated a panel of modulated ncRNAs by real-time qPCR. Furthermore, by combining the differentially expressed lncRNA and miRNA profiles with the transcriptome analysis dataset of adipocytes from lean and obese subjects affected or not by CRC, lncRNA–miRNA–mRNA adipocyte networks were defined for obese and CRC subjects. This analysis highlighted several ncRNAs modulation that are common to both obesity and CRC or unique of each disorder. Functional enrichment analysis of network-related mRNA targets, revealed dysregulated pathways associated with metabolic processes, lipid and energy metabolism, inflammation, and cancer. Moreover, adipocytes from obese subjects affected by CRC exhibited a higher complexity, in terms of number of genes, lncRNAs, miRNAs, and biological processes found to be dysregulated, providing evidence that the transcriptional and post-transcriptional program of adipocytes from CRC patients is deeply affected by obesity. Overall, this study adds further evidence for a central role of visceral adipocyte dysfunctions in the obesity–cancer relationship.

Proteoglycans in Obesity-Associated Metabolic Dysfunction and Meta-Inflammation.

Proteoglycans are a specific subset of glycoproteins found at the cell surface and in the extracellular matrix, where they interact with a plethora of proteins involved in metabolic homeostasis and meta-inflammation. Over the last decade, new insights have emerged on the mechanism and biological significance of these interactions in the context of diet-induced disorders such as obesity and type-2 diabetes. Complications of energy metabolism drive most diet-induced metabolic disorders, which results in low-grade chronic inflammation, thereby affecting proper function of many vital organs involved in energy homeostasis, such as the brain, liver, kidney, heart and adipose tissue. Here, we discuss how heparan, chondroitin and keratan sulfate proteoglycans modulate obesity-induced metabolic dysfunction and low-grade inflammation that impact the initiation and progression of obesity-associated morbidities.

A Carbohydrate Beverage Reduces Monocytes Expressing TLR4 in Children with Overweight or Obesity

Background:Childhood obesity is increasing, with about one-third of children overweight or obese. Obesity is characterized by a state of chronic low-grade inflammation that is related to cardiometabolic comorbidities. Inflammatory monocytes, which are classified into 3 different groups—classical, intermediate, and nonclassical monocytes, with Toll-like receptor 4 (TLR4+) expression indicating a proinflammatory state—underlie several obesity-associated morbidities. Objectives:This study aimed to assess the responses of monocyte populations to beverages of differing macronutrient composition in children with healthy weight (HW) or overweight/obesity (OW/OB). Methods:Ten HW children (5th to 84.9th percentile; mean age 12.29±2.5 y) and 7 children with OW/OB (85th to 99.99th percentile; mean age 11.96±3.8 y) completed the study. Adiposity was determined via DXA. Using a double-blinded, randomized, crossover design, participants consumed either a high-carbohydrate (CHO; 210 kcal; 0g fat/56g carbohydrates/0g protein) or a whole-eggbased high-protein/fat (EGG; 210 kcal; 15g fat/0g carbohydrates/18g protein) beverage. Venous blood was collected at baseline and 2 h postprandially for evaluation of metabolic and inflammatory responses. Repeated measures ANOVA and Pearson correlations were conducted. Results:Consuming the CHO beverage significantly reduced the primary outcome: TLR4+expression on classical monocytes in children with OW/OB only (25.60% decrease from baseline in OW/OB compared with 1.61% increase in HW). Children with OW/OB had significantly less percentages of TLR4+nonclassical monocytes than HW (47.66% lower after CHO). Insulin and glucose (secondary outcomes), were significantly higher after the CHO condition compared with baseline (230.61% and 9.93% increase, respectively). Changes in glucose were significantly and negatively related to changes in monocyte populations in the CHO condition. Conclusions:These data suggest that high-carbohydrate beverages alter monocyte populations in the blood in children with OW/OB, which is related to glucose metabolism. These findings have implications for nutritional recommendations in children with overweight/obesity. National Clinical Trial registry trial number: NCT03597542.

The role of LCPUFA-ω3 on the obesity-associated hyperandrogenemia of pubertal girls: secondary analysis of a randomized clinical trial.

Introduction Hyperandrogenism (HA), either clinical or biochemical, is associated with obesity in adolescent girls. Long chain polyunsaturated fatty acids ω3 (LCPUFA-ω3) play protective roles in some obesity-associated morbidities, but their contribution to preventing HA is unclear. Our aim was to examine the potential positive relationships between erythrocyte LCPUFA-ω3, with or without supplementation, and hyperandrogenemia. Methods Secondary analysis of a clinical trial that was conducted previously to analyze the effect of LCPUFA-ω3 on insulin resistance and body weight. Here, we present a cross-sectional analysis of 180 girls with obesity, and a longitudinal analysis of 117 girls who completed a 3-month supplementation period (57 LCPUFA-ω3 [DO3] and 60 placebo [DP)]). Dehydroepiandrosterone sulfate (DHEAS), total testosterone (TT) and steroid hormone binding globulin (SHBG) were measured with chemiluminescence; free testosterone (FT) was calculated. Erythrocyte fatty acids were determined by gas chromatography. Non-parametric statistics was used for analysis. Results In cross-sectional analysis, age (odds ratio [OR] = 1.35; 95% confidence interval [CI] = 1.03, 1.78; p = 0.027), insulin (OR = 1.05; 95% CI: 1.00, 1.10; p = 0.018), and erythrocytes eicosapentaenoic acid (EPA) (OR = 0.04; 95% CI: 0.01, 0.65; p = 0.012) were predictors of hyperandrogenemia (FT >0.63 ng/mL). In longitudinal analysis, EPA, adiponectin and SHBG increased, while FT decreased, in the DO3 group (p < 0.05). The risk of hyperandrogenemia at the end of follow-up was predicted by basal hyperandrogenemia (OR = 18.16, 95% CI: 5.37, 61.4; p < 0.001) and by increases in EPA (OR = 0.40; 95% CI: 0.01, 0.65; p = 0.06 marginal significance). Conclusions Our results suggest a preventive role of EPA on the risk for hyperandrogenemia in girls with obesity, but further studies are needed to demonstrate a benefit.

How does exercise support dietary approaches to weight loss and better health?

The rapid global rise of obesity incurs a heavy personal and healthcare burden due to obesity-associated morbidities and shortening of life. The purpose of this review is to provide evidence-based strategies for prevention, reversal, and mitigation of obesity and its sequelae. To that end, this review highlights the features of human physiology that favor fat accretion and interfere with fat loss. Strategies for prevention of obesity include understanding the basis for the strong motivating properties of palatable food, for human inability to consciously detect calories eaten or calories expended through exercise, for metabolic and hormonal adaptations to negative energy balance that drive weight regain, and for evolutionary natural selection which likely led to high human capacity for fat storage. Reversal of obesity is difficult primarily due to metabolic, hormonal, and behavioral reactions to body fat loss. Reduced resting metabolic rate presents a physiological challenge whether the weight loss is achieved through dietary restriction or energy expenditure of exercise. Increased insulin sensitivity after body fat loss drives resynthesis of storage substrates including triglycerides in the adipose tissue, muscle glycogen, and proteins, thus contributing to weight regain. Reduced basal plasma leptin concentration elicits a strong hunger drive. Mitigation of obesity-associated morbidities involves adding exercise energy expenditure to deliberate control of the quantity of food eaten, reducing postprandial hyperinsulinemia by lowering the carbohydrate load of the diet, and exercising after, rather than before, the meals to facilitate improved glucose tolerance.

Inhibition of soluble epoxide hydrolase attenuates a high-fat diet-mediated renal injury by activating PAX2 and AMPK

A high-fat diet (HFD) causes obesity-associated morbidities involved in macroautophagy and chaperone-mediated autophagy (CMA). AMPK, the mediator of macroautophage, has been reported to be inactivated in HFD-caused renal injury. However, PAX2, the mediator for CMA, has not been reported in HFD-caused renal injury. Here we report that HFD-caused renal injury involved the inactivation of Pax2 and Ampk, and the activation of soluble epoxide hydrolase (sEH), in a murine model. Specifically, mice fed on an HFD for 2, 4, and 8 wk showed time-dependent renal injury, the significant decrease in renal Pax2 and Ampk at both mRNA and protein levels, and a significant increase in renal sEH at mRNA, protein, and molecular levels. Also, administration of an sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea, significantly attenuated the HFD-caused renal injury, decreased renal sEH consistently at mRNA and protein levels, modified the renal levels of sEH-mediated epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DHETs) as expected, and increased renal Pax2 and Ampk at mRNA and/or protein levels. Furthermore, palmitic acid (PA) treatment caused significant increase in Mcp-1, and decrease in both Pax2 and Ampk in murine renal mesangial cells (mRMCs) time- and dose-dependently. Also, 14(15)-EET (a major substrate of sEH), but not its sEH-mediated metabolite 14,15-DHET, significantly reversed PA-induced increase in Mcp-1, and PA-induced decrease in Pax2 and Ampk. In addition, plasmid construction revealed that Pax2 may positively regulate Ampk transcriptionally in mRMCs. This study provides insights into and therapeutic target for the HFD-mediated renal injury.

Transcriptome Profiles of Human Visceral Adipocytes in Obesity and Colorectal Cancer Unravel the Effects of Body Mass Index and Polyunsaturated Fatty Acids on Genes and Biological Processes Related to Tumorigenesis.

Obesity, a low-grade inflammatory condition, represents a major risk factor for the development of several pathologies including colorectal cancer (CRC). Although the adipose tissue inflammatory state is now recognized as a key player in obesity-associated morbidities, the underlying biological processes are complex and not yet precisely defined. To this end, we analyzed transcriptome profiles of human visceral adipocytes from lean and obese subjects affected or not by CRC by RNA sequencing (n = 6 subjects/category), and validated selected modulated genes by real-time qPCR. We report that obesity and CRC, conditions characterized by the common denominator of inflammation, promote changes in the transcriptional program of adipocytes mostly involving pathways and biological processes linked to extracellular matrix remodeling, and metabolism of pyruvate, lipids and glucose. Interestingly, although the transcriptome of adipocytes shows several alterations that are common to both disorders, some modifications are unique under obesity (e.g., pathways associated with inflammation) and CRC (e.g., TGFβ signaling and extracellular matrix remodeling) and are influenced by the body mass index (e.g., processes related to cell adhesion, angiogenesis, as well as metabolism). Indeed, cancer-induced transcriptional program is deeply affected by obesity, with adipocytes from obese individuals exhibiting a more complex response to the tumor. We also report that in vitro exposure of adipocytes to ω3 and ω6 polyunsaturated fatty acids (PUFA) endowed with either anti- or pro-inflammatory properties, respectively, modulates the expression of genes involved in processes potentially relevant to carcinogenesis, as assessed by real-time qPCR. All together our results suggest that genes involved in pyruvate, glucose and lipid metabolism, fibrosis and inflammation are central in the transcriptional reprogramming of adipocytes occurring in obese and CRC-affected individuals, as well as in their response to PUFA exposure. Moreover, our results indicate that the transcriptional program of adipocytes is strongly influenced by the BMI status in CRC subjects. The dysregulation of these interrelated processes relevant for adipocyte functions may contribute to create more favorable conditions to tumor establishment or favor tumor progression, thus linking obesity and colorectal cancer.

Effects of an Intensive Inpatient Rehabilitation Program in Elderly Patients with Obesity

Objective: The aim of this study was to assess the short-term effectiveness of an intensive inpatient multidimensional rehabilitation program (MRP), including diet, exercise, and behavioral therapy, in elderly patients with severe obesity. Methods: Forty-four elderly patients (old; age 69.3 ± 3.5 years, BMI 41.9 ± 14.9) were analyzed against 215 younger patients (young; age 48.2 ± 18.5 years, BMI 43.9 ± 9.4), who were used as controls. All patients underwent MRP, based on group therapy guided by a multidisciplinary team (physicians, dietitians, exercise trainers, psychologists). We evaluated changes in anthropometry, cardiovascular risk factors, physical fitness, quality of life, and eating behavior. Results: After 3 weeks of MRP, we observed a reduction in body weight (old –3.8%, young –4.3%), BMI (old –3.9%, young –4.4%), waist circumference (old –3.4%, young –4.1%), total cholesterol (old –14.0%, young –15.0%), and fasting glucose (old –8.3%, young –8.1%), as well as improved performance in the Six-Minute-Walk Test (old +28.7%, young +15.3%), chair-stand test (old +24.8%, young +26.9%), and arm-curl test (old +15.2%, young +27.3%). Significant improvement was registered in all other analyzed domains. Conclusion: Our 3-week MRP provided significant clinical and functional improvement, which was similar between elderly and younger patients with severe obesity. In the long-term, this may be translated into better quality of life, through better management of obesity-associated morbidities and reduced frailty.

Psoas major cross-sectional area: A potential marker of cardiorespiratory fitness

Background and Aim: Cardiorespiratory fitness is an important marker for overall health that significantly correlates with obesity-associated morbidities and mortality. Maximal oxygen uptake (VO2max) recorded during an incremental exercise test is the gold standard assessment for aerobic fitness. However, its cost, chronic illness, and frailty often preclude its application. The cross-sectional area (CSA) of the abdominal psoas major muscle is a predictor of sarcopenia and surgery outcomes and represents a promising biomarker for cardiorespiratory health. Therefore, in the present study, we have planned to assess the relationship between psoas major CSA, anthropometry, and body composition in a UK-based cohort of 210 men and women. Methods: Body mass (kg), height (cm), waist circumference (cm), VO2max, and blood pressure were measured in each participant. The CSA of psoas major, rectus abdominus, and another abdominal muscle of the core muscle group were assessed. Results: Following adjustment for height, psoas major CSA was found to be a significant predictor of percentage body fat (P = 0.02) in men, and body mass index (BMI) in both men (P = 0.015) and women (P = 0.004). We found psoas major CSA correlated more strongly with VO2max (r = 0.74, P < 0.01) than any other study outcome, including age and BMI. Conclusion: Psoas major muscle CSA represents an accurate, reproducible, and time-efficient surrogate for cardiorespiratory fitness and body composition.

Parallel Profiles of Inflammatory and Effector Memory T Cells in Visceral Fat and Liver of Obesity-Associated Cancer Patients.

In the midst of a worsening obesity epidemic, the incidence of obesity-associated morbidities, including cancer, diabetes, cardiac and liver disease is increasing. Insights into mechanisms underlying pathological obesity-associated inflammation are lacking. Both the omentum, the principal component of visceral fat, and liver of obese individuals are sites of excessive inflammation, but to date the T cell profiles of both compartments have not been assessed or compared in a patient cohort with obesity-associated disease. We have previously identified that omentum is enriched with inflammatory cytokines, chemokines and T cells. Here, we compared the inflammatory profile of T cells in the omentum and liver of patients with the obesity-associated malignancy oesophageal adenocarcinoma (OAC). Furthermore, we assessed the secreted cytokine profile in OAC patient serum, omentum and liver to assess systemic and local inflammation. We observed parallel T cell cytokine profiles and phenotypes in the omentum and liver of OAC patients, in particular CD69(+) and inflammatory effector memory T cells. This study reflects similar processes of inflammation and T cell activation in the omentum and liver, and may suggest common targets to modulate pathological inflammation at these sites.

Hepatic Aryl Hydrocarbon Receptor Attenuates Fibroblast Growth Factor 21 Expression

The Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor involved in many physiological processes. Several studies indicate that AHR is also involved in energy homeostasis. Fibroblast growth factor 21 (FGF21) is an important regulator of the fasting and feeding responses. When administered to various genetic and diet-induced mouse models of obesity, FGF21 can attenuate obesity-associated morbidities. Here, we explore the role of AHR in hepatic Fgf21 expression through the use of a conditional, hepatocyte-targeted AHR knock-out mouse model (Cre(Alb)Ahr(Fx/Fx)). Compared with the congenic parental strain (Ahr(Fx/Fx)), non-fasted Cre(Alb)Ahr(Fx/Fx) mice exhibit a 4-fold increase in hepatic Fgf21 expression, as well as elevated expression of the FGF21-target gene Igfbp1 Furthermore, in vivo agonist activation of AHR reduces hepatic Fgf21 expression during a fast. The Fgf21 promoter contains several putative dioxin response elements (DREs). Using EMSA, we demonstrate that the AHR-ARNT heterodimer binds to a specific DRE that overlaps binding sequences for peroxisome proliferator-activated receptor α (PPARα), carbohydrate response element-binding protein (ChREBP), and cAMP response element-binding protein, hepatocyte specific (CREBH). In addition, we reveal that agonist-activated AHR impairs PPARα-, ChREBP-, and CREBH-mediated promoter activity in Hepa-1 cells. Accordingly, agonist treatment in Hepa-1 cells ablates potent ER stress-driven Fgf21 expression, and pre-treatment with AHR antagonist blocks this effect. Finally, we show that pre-treatment of primary human hepatocytes with AHR agonist diminishes PPARα-, glucose-, and ER stress-driven induction of FGF21 expression, indicating the effect is not mouse-specific. Together, our data show that AHR contributes to hepatic energy homeostasis, partly through the regulation of FGF21 expression and signaling.

Intracellular lipid dysregulation interferes with leukocyte function in the ovaries of meat-type hens under unrestricted feed intake

Meat-type Red-feather country hens fed ad libitum (AD-hens) exhibit obesity-associated morbidities and a number of ovarian irregularities. Leukocyte participations in ovarian activities are unstudied in AD-hens. In contrast to feed-restricted hens (R-hens), ovulatory process of the F1 follicle appeared delayed in AD-hens in association with reduced F1 follicle progesterone content, gelatinase A (MMP-2) and collagenase-3 (MMP-13) activities coincident with elevated IL-1β and no production (P<0.05), and increased leukocyte infiltration of inflamed necrotic follicle walls. Extracts of AD-hen F1 follicle walls induced greater leukocyte migration than extracts from F1 follicle wall extracts of R-hens (P<0.05). Co-cultures of granulosa cells with increasing numbers of leukocytes from either AD-hens or R-hens exhibited dose dependent reductions in progesterone production and increases in cell death. AD-hen leukocytes were less proapoptotic than their R counterparts (P<0.05). Granulosa MMP-13 and MMP-2 activities were also suppressed in the co-cultures with heterophils or monocytes in a dose-dependent manner (P<0.05). AD heterophils and R monocytes had a greater inhibitory effect on MMP activities in the co-cultures than their respective counterparts (P<0.05). Both basal and LPS-induced IL-1β secretion and MMP-22 or MMP-2 activities in freshly isolated AD-hen leukocytes were reduced (P<0.05). Exposure of AD or R leukocytes to 0.5mM palmitate impaired IL-1β secretion and MMP-22 or MMP-2 activity. Inhibition of ceramide synthesis with FB1 and ROS production with n-MPG scavenging rescued MMP activity and IL-1β production in palmitate treated heterophils, but exacerbated monocyte suppression. These latter findings suggest that intracellular lipid dysregulation in leukocytes contributes to ovarian dysfunction in AD-hens.

Cardiovascular risk and metabolic syndrome in obese youth enrolled in a multidisciplinary medical weight management program: implications of musculoskeletal pain, cardiorespiratory fitness, and health-related quality of life.

Obese youth demonstrate the same obesity-associated morbidities observed in obese adults, including poor cardiorespiratory fitness, poor quality of life, and reports of musculoskeletal pain. The purposes of this study were to compare the prevalence of cardiovascular risk factors and evaluate the odds of metabolic syndrome in obese youth based on measures of cardiorespiratory fitness, quality of life, and pain. A medical chart review of 183 obese youth in a medical weight management program was conducted. Measures of cardiovascular risk and metabolic syndrome were recorded. Groups were categorized based on Progressive Aerobic Cardiovascular Endurance Run (PACER) score, Pediatric Quality of Life (PedsQL)-Physical Function score, PedsQL-Psychosocial Health score, and reports of musculoskeletal pain. Statistical analysis included independent t-tests, Mann-Whitney U-test, chi-squared test, and logistic regression. Thirty-three percent of the entire sample had C-reactive protein (CRP) levels >3.0 mg/dL and 30% were categorized as having metabolic syndrome. Patients with lower PACER scores demonstrated a greater prevalence of CRP levels >3.0 mg/dL versus those with higher PACER scores (45% vs. 12%; P=0.01). There were no other differences in the prevalence of cardiovascular risk factors or metabolic syndrome when categorized by PACER, PedsQL, or pain. Those with CRP levels >3.0 mg/dL demonstrated increased odds of metabolic syndrome-[odds (95% confidence interval, CI): 4.93 (1.24-19.61); P=0.02]. Overall, results do not show differences in cardiovascular risk in obese youth when categorized by PACER, PedsQL, or reports of MSK pain. Elevated CRP may be a useful predictor of metabolic syndrome in obese youth and warrants further investigation.

Obesity – the continuously growing threat

The continuous increase in body weight observed inmost of the so-called ‘ civilised ’ countries worldwide over the last few decades is contributing to a health economics problem of immense dimensions. Obesity-associated morbidities, with type 2 diabetes mellitus being the most prominent, are responsible for a continuously growing financial burden to every social and health care system. The main reason for this problem is the observed increase of overconsumption of food due to a lack of appetite control and a mainly passive (sedentary) lifestyle based on steadily decreasing physical activity which leads to a pathological energy balance and obesity. This development causes a situation where one out of every five American dollars spent on health care in the United States of America is for the treatment of obesity. Therefore, this issue of Hamdan Medical Journal is focusing on this immense health problem and offers its readers the latest state-of-the-art reviews dealing with the pathophysiology as well as the newest treatment options.

Bariatric surgery rapidly improves mitochondrial respiration in morbidly obese patients

Obesity and its attendant comorbidities are an emerging epidemic. Chronic metabolic inflammation (metainflammation) is thought to precipitate obesity-associated morbidities; however, its mechanistic progression is poorly understood. Moreover, although interventions such as diet, exercise, and bariatric surgery can control body weight, their effects on metainflammation are also poorly understood. Recently, metainflammation and the pathobiology of obesity have been linked to mitochondrial dysfunction. Herein we examined the effects of bariatric surgery on mitochondrial respiration as an index of resolving metainflammation in morbidly obese patients. This institutional review board-approved study involved morbidly obese patients (body mass index > 35 kg/m(2)) undergoing sleeve gastrectomy or Roux-en-Y gastric bypass. Mitochondrial respiration was assessed in peripheral blood monocytes and in skeletal muscle samples before surgery and at 12 weeks after surgery. Patient biometrics, homeostasis model assessment-estimated insulin resistance (HOMA-IR) score, C-reactive protein, and lipid profile were analyzed. Twenty patients were enrolled and showed an average percent excess body weight loss of 30.3% weight loss at 12 weeks after surgery. Average HOMA-IR score decreased from 3.0 to 1.2 in insulin-resistant patients. C-reactive protein, an index of metainflammation, showed a modest decrease. Lipid profile remained stable. Intriguingly, mitochondrial basal and maximal respiration rates in peripheral blood monocytes increased after surgery. Basal rates of skeletal muscle mitochondrial respiration were unchanged, but the maximal respiration rate trended toward an increase after surgery. Cellular and tissue mitochondrial respiration increased in a morbidly obese patient cohort after laparoscopic bariatric surgery. These changes were consistent in patients with postsurgical weight loss. Importantly, no significant changes or improvements occurred in canonical indices used to assess recovery after bariatric surgery over this short time course. Thus, increased mitochondrial respiration may represent a novel biomarker of early improvement and positive outcome after surgery in morbidly obese patients.