Obesity in adults: a clinical practice guideline

Obesity is a complex chronic disease in which abnormal or excess body fat (adiposity) impairs health, increases the risk of long-term medical complications and reduces lifespan.1 Epidemiologic studies define obesity using the body mass index (BMI; weight/height2), which can stratify obesity-related health risks at the population level. Obesity is operationally defined as a BMI exceeding 30 kg/m2 and is subclassified into class 1 (30­34.9), class 2 (35­39.9) and class 3 (≥ 40). At the population level, health complications from excess body fat increase as BMI increases.2 At the individual level, complications occur because of excess adiposity, location and distribution of adiposity and many other factors, including environmental, genetic, biologic and socioeconomic factors.

Assessment of people living with obesity

Obesity is a chronic, progressive and relapsing disease, characterized by the presence of abnormal or excess adiposity that impairs health and social well-being. Screening for obesity should be performed regularly by mea­suring body mass index (BMI) and waist circumference. The clinical assessment of obesity should aim to establish the diagnosis and identify the causes and consequences of abnormal or excess adiposity on a patient's physical, mental and functional health. Providers participating in the assessment of obesity should focus on establishing values and goals of treatment, identi­fying which resources and tools may be needed and foster­ing self-efficacy with the patient in order to achieve long-term success. A non-judgmental, stigma-free environment is necessary for an effective assessment of a patient living with obesity.

Comparative effectiveness and safety of gastric bypass, sleeve gastrectomy and adjustable gastric banding in a population-based bariatric program: prospective cohort study.

BACKGROUND: Bariatric surgery in Canada is primarily delivered within publicly funded specialty clinics. Previous studies have demonstrated that bariatric surgery is superior to intensive medical management for reduction of weight and obesity-related comorbidities. Our objective was to compare the effectiveness and safety of laparoscopic Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (LSG) and adjustable gastric banding (LAGB) in a publicly funded, population-based bariatric treatment program. METHODS: We followed consecutive bariatric surgery patients for 2 years. The primary outcome was weight change (in kilograms). Between-group changes were analyzed using multivariable regression. Last-observation-carried-forward imputation was used for missing data. RESULTS: We included 150 consecutive patients (51 RYGB; 51 LSG; 48 LAGB) in our study. At baseline, mean age was 43.5 ± 9.5 years, 87.3% of patients were women, and preoperative body mass index (BMI) was 46.2 ± 7.4. Absolute and relative (% of baseline) weight loss at 2 years were 36.6 ± 19.5 kg (26.1 ± 12.2%) for RYGB, 21.4 ± 16.0 kg (16.4 ± 11.6%) for LSG and 7.0 ± 9.7 kg (5.8 ± 7.9%) for LAGB (p < 0.001). Change in BMI was greater for the RYGB (-13.0 ± 6.6) than both the LSG (-7.6 ± 5.7) and the LAGB (-2.6 ± 3.5) groups (p < 0.001). The reduction in diabetes, hypertension and dyslipidemia was greater after RYGB than after LAGB (all p < 0.05). There were no deaths. The anastomotic and staple leakage rate was 1.3%. CONCLUSION: In a publicly funded, population-based bariatric surgery program, RYGB and LSG demonstrated greater weight loss than the LAGB procedure. Bypass resulted in the greatest reduction in obesity-related comorbidities. All procedures were safe.

BACKGROUND: Au Canada, la chirurgie bariatrique est effectuée principalement dans des cliniques spécialisées financées par le secteur public. Des études ont démontré que les interventions de cette nature sont supérieures à la prise en charge médicale intensive pour la perte de poids et la réduction des affections comorbides liées à l'obésité. L'objectif de notre étude était de comparer l'efficacité et l'innocuité de la dérivation gastrique Roux-en-Y par laparoscopie (DGRY), de la gastrectomie longitudinale (GL) et de la gastroplastie par anneau gastrique modulable (GAGM) dans le cadre d'un programme de traitement bariatrique basé sur la population financé par les deniers publics. METHODS: Nous avons suivi pendant 2 ans des patients ayant subi une chirurgie bariatrique. Le résultat primaire à l'étude était la variation pondérale (en kilogrammes). Nous avons analysé la variation intergroupe au moyen d'une régression multivariable et utilisé la méthode d'imputation des données manquantes par report de la dernière observation. RESULTS: Nous avons retenu 150 patients consécutifs (51 DGRY; 51 GL; 48 GAGM). Au début de l'étude, l'âge moyen était de 43,5 ± 9,5 ans, 87,3 % des patients étaient des femmes, et leur indice de masse corporelle (IMC) avant l'opération était de 46,2 ± 7,4. Après 2 ans, la perte de poids moyenne (pourcentage du poids de départ) était de 36,6 ± 19,5 kg (26,1 ± 12,2 %) pour la DGRY, de 21,4 ± 16,0 kg (16,4 ± 11,6 %) pour la GL, et de 7,0 ± 9,7 kg (5,8 ± 7,9 %) pour la GAGM (p < 0,001). La variation de l'IMC était plus grande pour le groupe DGRY (13,0 ± 6,6) que pour les 2 autres groupes (7,6 ± 5,7 pour la GL et 2,6 ± 3,5 pour la GAGM; p < 0,001). L'incidence sur le diabète, l'hypertension et la dyslipidémie était également plus grande après la DGRY qu'après la GAGM (p < 0,05 pour tous). Il n'y a eu aucun décès. Le taux de fuites anastomotiques et liées aux sutures était de 1,3 %. CONCLUSION: Dans le cadre d'un programme de chirurgie bariatrique basé sur une population et financé par le secteur public, la DGRY et la GL ont entraîné une plus grande perte de poids que la GAGM. La dérivation a donné lieu à la plus forte réduction des affections comorbides liées à l'obésité. Toutes les interventions se sont avérées sécuritaires.

Health Benefits of Long-Term Weight-Loss Maintenance.

Obesity is a chronic and complex medical condition associated with a large number of complications affecting most organs and systems through multiple pathways. Strategies for weight management include behavioral, pharmacological, and surgical interventions, all of which can result in a reduction in obesity-related comorbidities and improvements in quality of life. However, subsequent weight regain often reduces the durability of these improvements. The objective of this article is to review evidence supporting the long-term effects of intentional weight loss on morbidity, mortality, quality of life, and health-care cost. Overall, considerable evidence suggests that intentional weight loss is associated with clinically relevant benefits for the majority of obesity-related comorbidities. However, the degree of weight loss that must be achieved and sustained to reap these benefits varies widely between comorbidities.

Socioeconomic status is positively associated with measures of adiposity and insulin resistance, but inversely associated with dyslipidaemia in Colombian children.

BACKGROUND: Low socioeconomic status (SES) has been associated with higher risk of cardiometabolic diseases in developed societies, but investigation of SES and cardiometabolic risk in children in less economically developed populations is sparse. We aimed to examine associations among SES and cardiometabolic risk factors in Colombian children. METHODS: We used data from a population-based study of 1282 children aged 6-10 years from Bucaramanga, Colombia. SES was classified according to household wealth, living conditions and access to public utilities. Anthropometric and biochemical parameters were measured at a clinic visit. Cardiometabolic risk factors were analysed continuously using linear regression and as binary outcomes-according to established paediatric cut points-using logistic regression to calculate OR and 95% CIs. RESULTS: Mean age of the children was 8.4 (SD 1.4) and 51.1% of the sample were boys. Odds of overweight/obesity, abdominal obesity and insulin resistance were greater among higher SES. Compared with the lowest SES stratum, children in the highest SES had higher odds of overweight/obesity (OR=3.25, 95% CI 1.89 to 5.57), abdominal obesity (OR=2.74, 95% CI 1.41 to 5.31) and insulin resistance (OR=2.60, 95% CI 1.81 to 3.71). In contrast, children in the highest SES had lower odds of hypertriglyceridaemia (triglycerides ≥90th centile; OR=0.28, 95% CI 0.14 to 0.54) and low (≤10th centile) high-density lipoprotein (HDL) cholesterol (OR=0.35, 95% CI 0.15 to 0.78). CONCLUSIONS: In Colombian children, SES is directly associated with obesity and insulin resistance, but inversely associated with dyslipidaemia (hypertriglyceridaemia and low HDL cholesterol). Our findings highlight the need to analyse cardiometabolic risk factors separately in children and to carefully consider a population's level of economic development when studying their social determinants of cardiometabolic disease.

Weight loss required by the severely obese to achieve clinically important differences in health-related quality of life: two-year prospective cohort study.

BACKGROUND: Guidelines and experts describe 5% to 10% reductions in body weight as 'clinically important'; however, it is not clear if 5% to 10% weight reductions correspond to clinically important improvements in health-related quality of life (HRQL). Our objective was to calculate the amount of weight loss required to attain established minimal clinically important differences (MCIDs) in HRQL, measured using three validated instruments. METHODS: Data from the Alberta Population-based Prospective Evaluation of Quality of Life Outcomes and Economic Impact of Bariatric Surgery (APPLES) study, a population-based, prospective Canadian cohort including 150 wait-listed, 200 medically managed and 150 surgically treated patients were examined. Two-year changes in weight and HRQL measures (Short-Form (SF)-12 physical (PCS; MCID = 5) and mental (MCS; MCID = 5) component summary score, EQ-5D Index (MCID = 0.03) and Visual Analog Scale (VAS; MCID = 10), Impact of Weight on Quality of Life (IWQOL)-Lite total score (MCID = 12)) were calculated. Separate multivariable linear regression models were constructed within medically and surgically treated patients to determine if weight changes achieved HRQL MCIDs. Pooled analysis in all 500 patients was performed to estimate the weight reductions required to achieve the pre-defined MCID for each HRQL instrument. RESULTS: Mean age was 43.7 (SD 9.6) years, 88% were women, 92% were white, and mean initial body mass index was 47.9 (SD 8.1) kg/m2. In surgically treated patients (two-year weight loss = 16%), HRQL MCIDs were reached for all instruments except the SF-12 MCS. In medically managed patients (two-year weight loss = 3%), MCIDs were attained in the EQ-index but not the other instruments. In all patients, percent weight reductions to achieve MCIDs were: 23% (95% confidence interval (CI): 17.5, 32.5) for PCS, 25% (17.5, 40.2) for MCS, 9% (6.2, 15.0) for EQ-Index, 23% (17.3, 36.1) for EQ-VAS, and 17% (14.1, 20.4) for IWQOL-Lite total score. CONCLUSIONS: Weight reductions to achieve MCIDs for most HRQL instruments are markedly higher than the conventional threshold of 5% to 10%. Surgical, but not medical treatment, consistently led to clinically important improvements in HRQL over two years. TRIAL REGISTRATION: Clinicaltrials.gov NCT00850356.

Implementation and evaluation of the 5As framework of obesity management in primary care: design of the 5As Team (5AsT) randomized control trial.

BACKGROUND: Obesity is a pressing public health concern, which frequently presents in primary care. With the explosive obesity epidemic, there is an urgent need to maximize effective management in primary care. The 5As of Obesity Management™ (5As) are a collection of knowledge tools developed by the Canadian Obesity Network. Low rates of obesity management visits in primary care suggest provider behaviour may be an important variable. The goal of the present study is to increase frequency and quality of obesity management in primary care using the 5As Team (5AsT) intervention to change provider behaviour. METHODS/DESIGN: The 5AsT trial is a theoretically informed, pragmatic randomized controlled trial with mixed methods evaluation. Clinic-based multidisciplinary teams (RN/NP, mental health, dietitians) will be randomized to control or the 5AsT intervention group, to participate in biweekly learning collaborative sessions supported by internal and external practice facilitation. The learning collaborative content addresses provider-identified barriers to effective obesity management in primary care. Evidence-based shared decision making tools will be co-developed and iteratively tested by practitioners. Evaluation will be informed by the RE-AIM framework. The primary outcome measure, to which participants are blinded, is number of weight management visits/full-time equivalent (FTE) position. Patient-level outcomes will also be assessed, through a longitudinal cohort study of patients from randomized practices. Patient outcomes include clinical (e.g., body mass index [BMI], blood pressure), health-related quality of life (SF-12, EQ5D), and satisfaction with care. Qualitative data collected from providers and patients will be evaluated using thematic analysis to understand the context, implementation and effectiveness of the 5AsT program. DISCUSSION: The 5AsT trial will provide a wide range of insights into current practices, knowledge gaps and barriers that limit obesity management in primary practice. The use of existing resources, collaborative design, practice facilitation, and integrated feedback loops cultivate an applicable, adaptable and sustainable approach to increasing the quantity and quality of weight management visits in primary care. TRIAL REGISTRATION: NCT01967797.

Predictors of health-related quality of life in 500 severely obese patients.

OBJECTIVE: To characterize health-related quality of life (HRQL) impairment in severely obese subjects, using several validated instruments. METHODS: A cross-sectional analysis of 500 severely obese subjects was completed. Short-Form (SF)-12 [Physical (PCS) and Mental (MCS) component summary scores], EuroQol (EQ)-5D [Index and Visual Analog Scale (VAS)], and Impact of Weight on Quality of Life (IWQOL)-Lite were administered. Multivariable linear regression models were performed to identify independent predictors of HRQL. RESULTS: Increasing BMI was associated with lower PCS (-1.33 points per 5 kg/m(2) heavier; P < 0.001), EQ-index (-0.02; P < 0.001), EQ-VAS (-1.71; P = 0.003), and IWQOL-Lite (-3.72; P = 0.002), but not MCS (P = 0.69). The strongest predictors (all P < 0.005) for impairment in each instrument were: fibromyalgia for PCS (-5.84 points), depression for MCS (-7.49 points), stroke for EQ-index (-0.17 points), less than full-time employment for EQ-VAS (-7.06 points), and coronary disease for IWQOL-Lite (-10.86 points). Chronic pain, depression, and sleep apnea were associated with reduced HRQL using all instruments. CONCLUSION: The clinical impact of BMI on physical and general HRQL was small, and mental health scores were not associated with BMI. Chronic pain, depression, and sleep apnea were consistently associated with lower HRQL.

Weight loss and outcomes in wait-listed, medically managed, and surgically treated patients enrolled in a population-based Bariatric program: prospective cohort study.

BACKGROUND: Multidisciplinary bariatric care is increasingly being delivered in Canada within publicly funded regional programs. Demand is high, wait lists are long, and clinical effectiveness is unknown. OBJECTIVE: To examine the "real-world" outcomes associated with a publicly funded, population-based regional bariatric (medical and surgical) program. RESEARCH DESIGN: Prospective observational cohort. SUBJECTS: Five hundred consecutive patients (150 wait-listed, 200 medically treated, 150 surgically treated) from the Edmonton Weight Wise program were enrolled. MEASURES: The primary outcome was weight change (kg). Between-group changes were analyzed using multivariable regression adjusted for age, sex, and baseline weight and "last-observation-carried-forward" was used for missing data. Subjects transitioning between groups (wait-list to medical or medical to surgery) were censored when crossing over. RESULTS: At baseline, mean age was 43.7 ± 9.6 years, mean body mass index was 47.9 ± 8.1 kg/m, and 88% were female. A total of 412 subjects (82%) completed 2-year follow-up and 143 (29%) subjects crossed over to the next treatment phase. Absolute and relative (% of baseline) mean weight reductions were 1.5 ± 8.5 kg (0.9 ± 6.1%) for wait-listed, 4.1 ± 11.6 kg (2.8 ± 8.1%) for medically treated, and 22.0 ± 19.7 kg (16.3 ± 13.5%) for surgically treated (P<0.001) subjects. For surgery, weight reductions were 7.0 ± 9.7 kg (5.8 ± 7.9%) with banding, 21.4 ± 16.0 kg (16.4 ± 11.6%) with sleeve gastrectomy, and 36.6 ± 19.5 kg (26.1 ± 12.2%) with gastric bypass (P<0.001). Rates of hypertension, diabetes, and dyslipidemia decreased to a significantly greater degree with surgery than medical management (P<0.001) and stayed the same or increased in wait-listed subjects. CONCLUSIONS: Population-based bariatric care, particularly bariatric surgery, was clinically effective. Weight and cardiometabolic risk was relatively stable wait-listed patients receiving "usual care."

Prevalence and predictors of self-reported sexual abuse in severely obese patients in a population-based bariatric program.

BACKGROUND: Sexual abuse may be associated with poorer weight loss outcomes following bariatric treatment. Identifying predictors of abuse would enable focused screening and may increase weight management success. METHODS: We analyzed data from 500 consecutively recruited obese subjects from a population-based, regional bariatric program. The prevalence of self-reported sexual abuse was ascertained using a single interview question. Health status was measured using a visual analogue scale (VAS). Multivariable logistic regression was performed to identify sexual abuse predictors. RESULTS: The mean age was 43.7 y (SD 9.6), 441 (88.2%) were females, 458 (91.8%) were white, and the mean body mass index (BMI) was 47.9 kg/m(2) (SD 8.1). The self-reported prevalence of past abuse was 21.8% (95% CI 18.4-25.4%). Abused subjects had worse health status (VAS score 53.1 (SD 21.2) versus 58.0 (SD 20.1), P = 0.03). BMI was not associated with abuse (P > 0.5). Age, sex, BMI, and covariate-adjusted independent predictors of abuse included alcohol addiction (adjusted odds ratio 15.8; 95% CI 4.0-62.8), posttraumatic stress disorder (4.9; 2.5-9.5), borderline personality (3.8; 1.0-13.8), depression (2.4; 1.3-4.3), and lower household income (3.4; 1.6-7.0). CONCLUSIONS: Abuse was common amongst obese patients managed in a population-based bariatric program; alcohol addiction, psychiatric comorbidities, and low-income status were highly associated with sexual abuse.

New pharmacological approaches for obesity management.

Obesity, which results from an imbalance between calorie intake and expenditure, now affects over 500 million individuals worldwide. Lifestyle and behavioural interventions aimed at reducing calorie intake and/or increasing energy expenditure have limited long-term effectiveness due to complex and persistent hormonal, metabolic and neurochemical adaptations that defend against weight loss and promote weight regain. Surgical treatments for obesity, although highly effective, are unavailable or unsuitable for the majority of individuals with excess adiposity. Accordingly, few effective treatment options are available to most individuals with obesity. In the past, the use of antiobesity drugs, seemingly the logical choice to fill this therapeutic gap, has been limited because of a lack of efficacy, poor long-term adherence rates and serious adverse effects. In 2012, the FDA approved two new medications-lorcaserin and phentermine-topiramate controlled release-and is currently reviewing the resubmission of naltrexone sustained release-bupropion sustained release. This Review presents the available data on the efficacy and safety of these three medications and discusses future perspectives and challenges related to pharmacological weight management.

Effects of resveratrol in pregnancy using murine models with reduced blood supply to the uterus.

Preeclampsia (PE) and fetal growth restriction (FGR) contribute significantly to fetal and maternal morbidity and mortality. Although the causes of PE and FGR are not fully understood, both conditions are known to be associated with impaired uterine artery blood flow. Resveratrol, a polyphenol found in a number of plants, has been shown to induce relaxation of uterine arteries in vitro as well as improve many pathological conditions associated with PE and FGR. We hypothesized that treatment of endothelial nitric oxide synthase knockout mice (eNOS⁻/⁻) and catechol-O-methyltransferase knockout mice (COMT⁻/⁻) with resveratrol during pregnancy would improve uterine artery blood flow and therefore ameliorate the PE-like phenotype and FGR in these murine models. Pregnant C57BL/6J, eNOS⁻/⁻ and COMT⁻/⁻ mice received either resveratrol supplemented diet (4 g/kg diet) or control diet between gestational day (GD) 0.5 and GD 18.5. Resveratrol supplementation significantly increased uterine artery blood flow velocity and fetal weight in COMT⁻/⁻ but not in eNOS⁻/⁻ mice. There were no effects of resveratrol on litter size and placental weight among the groups. In conclusion, resveratrol increased uterine artery blood flow velocity and fetal weight in COMT⁻/⁻ mice, suggesting potential as a therapeutic strategy for PE and FGR.

Adiposity indices in the prediction of insulin resistance in prepubertal Colombian children.

OBJECTIVE: To compare BMI with abdominal skinfold thickness (ASF), waist circumference and waist-to-height ratio in the prediction of insulin resistance (IR) in prepubertal Colombian children. DESIGN: We calculated age- and sex-specific Z-scores for BMI, ASF, waist circumference, waist-to-height ratio and three other skinfold-thickness sites. Logistic regression with stepwise selection (P = 0·80 for entry and P = 0·05 for retention) was performed to identify predictors of IR and extreme IR, which were determined by age- and sex-specific Z-scores to identify the ≥ 90th and ≥ 95th percentile of homeostasis model assessment (HOMAIR), respectively. We used receiver operating characteristic curves to compare the area under the curve between models. SETTING: Bucaramanga, Colombia. SUBJECTS: Children (n 1261) aged 6-10 years in Tanner stage 1 from a population-based study. RESULTS: A total of 127 children (seventy girls and fifty-seven boys) were classified with IR, including sixty-three children (thirty-three girls and thirty boys) classified with extreme IR. Only ASF and BMI Z-scores were retained as predictors of IR by stepwise selection. Adding ASF Z-score to BMI Z-score improved the area under the curve from 0·794 (95 % CI 0·752, 0·837) to 0·811 (95 % CI 0·770, 0·851; P for contrast = 0·01). In predicting extreme IR, the addition of ASF Z-score to BMI Z-score improved the area under the curve from 0·837 (95 % CI 0·790, 0·884) to 0·864 (95 % CI 0·823, 0·905; P for contrast = 0·01). CONCLUSIONS: ASF Z-score predicted IR independent of BMI Z-score in our population of prepubertal children. ASF and BMI Z-scores together improved IR risk stratification compared with BMI Z-score alone, opening new perspectives in the prediction of cardiometabolic risk in prepubertal children.

Synergistic effects of prenatal hypoxia and postnatal high-fat diet in the development of cardiovascular pathology in young rats.

We have previously shown that adult offspring exposed to a prenatal hypoxic insult leading to intrauterine growth restriction (IUGR) are more susceptible to cardiovascular pathologies. Our objectives were to evaluate the interaction between hypoxia-induced IUGR and postnatal diet in the early development of cardiovascular pathologies. Furthermore, we sought to determine whether the postnatal administration of resveratrol could prevent the development of cardiovascular disorders associated with hypoxia-induced IUGR. On day 15 of pregnancy, Sprague-Dawley rats were randomly assigned to hypoxia (11.5% oxygen), to induce IUGR, or normal oxygen (control) groups. For study A, male offspring (3 wk of age) were randomly assigned a low-fat (LF, <10% fat) or a high-fat (HF, 45% fat) diet. For study B, offspring were randomized to either HF or HF+resveratrol diets. After 9 wk, cardiac and vascular functions were evaluated. Prenatal hypoxia and HF diet were associated with an increased myocardial susceptibility to ischemia. Blood pressure, in vivo cardiac function, and ex vivo vascular function were not different among experimental groups; however, hypoxia-induced IUGR offspring had lower resting heart rates. Our results suggest that prenatal insults can enhance the susceptibility to a second hit such as myocardial ischemia, and that this phenomenon is exacerbated, in the early stages of life by nutritional stressors such as a HF diet. Supplementing HF diets with resveratrol improved cardiac tolerance to ischemia in offspring born IUGR but not in controls. Thus we conclude that the additive effect of prenatal (hypoxia-induced IUGR) and postnatal (HF diet) factors can lead to the earlier development of cardiovascular pathology in rats, and postnatal resveratrol supplementation prevented the deleterious cardiovascular effects of HF diet in offspring exposed to prenatal hypoxia.

Sildenafil citrate rescues fetal growth in the catechol-O-methyl transferase knockout mouse model.

Preeclampsia and fetal growth restriction are responsible for the majority of maternal and perinatal morbidity and mortality associated with complicated pregnancies. Although their etiologies are complex and multifactorial, both are associated with increased uterine artery resistance. Sildenafil citrate is able to rescue the dysfunction observed ex vivo in uterine arteries of women with preeclampsia. The ability of sildenafil citrate to increase uterine artery vasodilation, thereby decreasing uterine artery resistance and, hence, ameliorated preeclampsia and fetal growth restriction, was tested in a mouse model of preeclampsia, the catechol-O-methyl transferase knockout mouse (COMT(-/-)). COMT(-/-) and C57BL/6J mice were treated (0.2 mg/mL in drinking water, n=6-12) from gestational day 12.5 to 18.5. Measures of pup growth, including body weight, crown/rump length, and abdominal circumference, were reduced in COMT(-/-) mice; this was normalized after treatment with Sildenafil. COMT(-/-) mice also demonstrated abnormal umbilical Doppler waveforms, including reverse arterial blood flow velocity. This was normalized after treatment with Sildenafil. Abnormal uterine artery Doppler waveforms were not demonstrated in COMT(-/-) mice, although ex vivo responses of uterine arteries to phenylephrine were increased; moreover, treatment with Sildenafil did improve ex vivo sensitivity to an endothelium-dependent vasodilator. The data presented here demonstrate that Sildenafil can rescue pup growth and improve abnormal umbilical Doppler waveforms, providing support for a potential new therapeutic strategy targeting fetal growth restriction.

Continued postnatal administration of resveratrol prevents diet-induced metabolic syndrome in rat offspring born growth restricted.

OBJECTIVE: A prenatal hypoxic insult leading to intrauterine growth restriction (IUGR) increases the susceptibility to develop metabolic syndrome (MetS) later in life. Since resveratrol (Resv), the polyphenol produced by plants, exerts insulin-sensitizing effects, we tested whether Resv could prevent deleterious metabolic effects of being born IUGR. RESEARCH DESIGN AND METHODS: Pregnant rats were exposed to either a normoxic (control; 21% O(2)) or a hypoxic (IUGR; 11.5% O(2)) environment during the last third of gestation. After weaning, male offspring were randomly assigned to receive either a high-fat (HF; 45% fat) diet or an HF diet with Resv (4 g/kg diet) for 9 weeks when various parameters of the MetS were measured. RESULTS: Relative to normoxic controls, hypoxia-induced IUGR offspring developed a more severe MetS, including glucose intolerance and insulin resistance, increased intra-abdominal fat deposition and intra-abdominal adipocyte size, and increased plasma triacylglycerol (TG) and free fatty acids, as well as peripheral accumulation of TG, diacylglycerol, and ceramides. In only IUGR offspring, the administration of Resv reduced intra-abdominal fat deposition to levels comparable with controls, improved the plasma lipid profile, and reduced accumulation of TG and ceramides in the tissues. Moreover, Resv ameliorated insulin resistance and glucose intolerance as well as impaired Akt signaling in the liver and skeletal muscle of IUGR offspring and activated AMP-activated protein kinase, which likely contributed to improved metabolic parameters in Resv-treated IUGR rats. CONCLUSIONS: Our results suggest that early, postnatal administration of Resv can improve the metabolic profile of HF-fed offspring born from pregnancies complicated by IUGR.

The early origins of cardiovascular health and disease: who, when, and how.

Almost 30 years ago, a series of epidemiological studies popularized the early programming theory that had resulted from observed associations between low birthweight and increased cardiovascular morbidity and mortality later in life. Since then, several clinical and experimental models have been created to understand the principles and mechanisms of this fascinating phenomenon and describe its relevance to the pathophysiology of cardiovascular and many other chronic diseases. Despite the growing body of published evidence, the specific mechanisms mediating early programming effects are still elusive. Moreover, many controversial issues have arisen regarding the characteristics of the most commonly used clinical and experimental models, the existence of potential windows of susceptibility for different organs, and the presence of sex differences in its pathophysiology. Therefore, this review synthesizes some of the antecedents behind the early programming theory and discusses some of the controversial issues surrounding it. Early programming has been extensively linked to several chronic diseases; however, for the purposes of this review we have concentrated on the potential role of this entity in the pathophysiology of chronic cardiovascular diseases.