Targeting Autophagy in Obesity‐Associated Heart Disease

Over the past three decades, the increasing rates of obesity have led to an alarming obesity epidemic worldwide. Obesity is associated with an increased risk of cardiovascular diseases; thus, it is essential to define the molecular mechanisms by which obesity affects heart function. Individuals with obesity and overweight have shown changes in cardiac structure and function, leading to cardiomyopathy, hypertrophy, atrial fibrillation, and arrhythmia. Autophagy is a highly conserved recycling mechanism that delivers proteins and damaged organelles to lysosomes for degradation. In the hearts of patients and mouse models with obesity, this process is impaired. Furthermore, it has been shown that autophagy flux restoration in obesity models improves cardiac function. Therefore, autophagy may play an important role in mitigating the adverse effects of obesity on the heart. Throughout this review, we will discuss the benefits of autophagy on the heart in obesity and how regulating autophagy might be a therapeutic tool to reduce the risk of obesity‐associated cardiovascular diseases.     

Cut‐off Point of BMI and Obesity‐Related Comorbidities and Mortality in Middle‐Aged Koreans

Objective: The need for a lower BMI to classify overweight in Asian populations has been controversial. Using both disease and mortality outcomes, we investigated whether lower BMI cut‐off points are appropriate for identifying increased health risk in Koreans. Research Methods and Procedures: We conducted a cohort study among 773, 915 men and women from 30 to 59 years old with 8‐ to 10‐year follow‐up periods. Primary outcomes were change of obesity prevalence, obesity‐related disease incidence, and all‐cause mortality. Results: Prevalence of overweight (BMI of 25.0‐29.9) has steadily increased (1.3% annually), whereas obesity (BMI ≥ 30) showed a lower prevalence and only a slight increase (0.1%‐0.2% annually). Our study revealed that dose‐response relationships exist between obesity and related disease incidences (hypertension, type 2 diabetes, and hypercholesterolemia) beginning at lower BMI levels than previously reported. Compared with those in the healthy weight range, Koreans with a BMI ≥ 25 were not at greater risk of hypertension, type 2 diabetes, or hypercholesterolemia than has been reported for whites in similar studies. Obesity‐related all‐cause mortality also did not seem so different from that of whites. Discussion: Our findings did not support the use of a lower BMI cut‐off point for defining overweight in Koreans compared with whites for the purpose of identifying different risks. However, populations with BMI ≥ 25 are rapidly increasing and have substantial risks of diseases. To preempt the rapid increases in obesity and related health problems that are occurring in Western countries, Korea should consider using a BMI of 25 as an action point for obesity prevention and control interventions.     

Leisure‐Time Physical Activity and Reduced Plasma Levels of Obesity‐Related Inflammatory Markers

Objective: This study investigated the relationship between physical activity and the obesity‐related inflammatory markers C‐reactive protein, interleukin‐6, and soluble tumor necrosis factor receptors (sTNF‐Rs) 1 and 2. Furthermore, we examined the relationship between physical activity and insulin sensitivity (insulin, C‐peptide, and hemoglobin A_1c levels) and whether inflammatory markers mediate this association. Research Methods and Procedures: Biomarkers were measured in 405 healthy men and 454 healthy women from two large ongoing prospective studies. Information about physical activity and other variables was assessed by questionnaires. Results: After adjustment for other predictors of inflammation, physical activity was inversely associated with plasma levels of sTNF‐R1, sTNF‐R2, interleukin‐6, and C‐reactive protein (p = 0.07, p = 0.004, p = 0.04, and p = 0.009). After further adjustment for BMI and leptin, as a surrogate for fat mass, most of these associations were no longer significant. Physical activity was also inversely related to insulin and C‐peptide levels (p = 0.008 and p < 0.001); however, in contrast to BMI and leptin, levels of inflammatory markers explained only very little of this inverse relationship. Discussion: These results suggest that frequent physical activity is associated with lower systemic inflammation and improved insulin sensitivity. These associations can partially be explained by a lower degree of obesity in physically active subjects. Although inflammatory markers may mediate obesity‐dependent effects of physical activity on inflammatory related diseases such as type 2 diabetes or coronary heart disease, our study suggests that they do not directly account for the beneficial effects of physical activity on insulin resistance.     

Diet‐Induced Changes in Stearoyl‐CoA Desaturase 1 Expression in Obesity‐Prone and ‐Resistant Mice

Objective: To investigate stearoyl‐coenzyme A desaturase (SCD) 1 expression in obesity‐prone C57BL/6 mice and in obesity‐resistant FVB mice to explore the relationship of SCD1 expression and susceptibility to diet‐induced obesity. Research Methods and Procedures: Nine‐week‐old C57BL/6 and FVB mice were fed either a high‐ or low‐fat diet for 8 weeks. Body weight and body composition were measured before and at weeks 4 and 8 of the study. Energy expenditure was measured at weeks 1 and 5 of the study. Hepatic SCD1 mRNA was measured at 72 hours and at the end of study. Plasma leptin and insulin concentrations were measured at the end of study. Results: When C57BL/6 mice were switched to a calorie‐dense high‐fat diet, animals gained significantly more body weight than those maintained on a low‐calorie density diet primarily due to increased fat mass accretion. Fat mass continued to accrue throughout 8 weeks of study. Increased calorie intake did not account for all weight gain. On the high‐fat diet, C57BL/6 mice decreased their energy expenditure when compared with mice fed a low‐fat diet. In response to 8 weeks of a high‐fat diet, SCD1 gene expression in liver increased >2‐fold. In contrast, feeding a high‐fat diet did not change body weight, energy expenditure, or SCD1 expression in FVB mice. Discussion: Our study showed that a high‐fat hypercaloric diet increased body adiposity first by producing hyperphagia and then by decreasing energy expenditure of mice susceptible to diet‐induced obesity. Consumption of a high‐fat diet in species predisposed to obesity selectively increased SCD1 gene expression in liver.     

Obesity‐susceptibility loci and the tails of the pediatric BMI distribution

Objective: To determine whether previously identified adult obesity susceptibility loci were associated uniformly with childhood BMI across the BMI distribution. Design and Methods: Children were recruited through the Children's Hospital of Philadelphia (n = 7,225). Associations between the following loci and BMI were assessed using quantile regression: FTO (rs3751812), MC4R (rs12970134), TMEM18 (rs2867125), BDNF (rs6265), TNNI3K (rs1514175), NRXN3 (rs10146997), SEC16B (rs10913469), and GNPDA2 (rs13130484). BMI z‐score (age and gender adjusted) was modeled as the dependent variable, and genotype risk score (sum of risk alleles carried at the 8 loci) was modeled as the independent variable. Results: Each additional increase in genotype risk score was associated with an increase in BMI z‐score at the 5th, 15th, 25th, 50th, 75th, 85th, and 95th BMI z‐score percentiles by 0.04 (±0.02, P = 0.08), 0.07 (±0.01, P = 9.58 × 10^?7), 0.07 (±0.01, P = 1.10 × 10^?8), 0.09 (±0.01, P = 3.13 × 10^?22), 0.11 (±0.01, P = 1.35 × 10^?25), 0.11 (±0.01, P = 1.98 × 10^?20), and 0.06 (±0.01, P = 2.44 × 10^?6), respectively. Each additional increase in genotype risk score was associated with an increase in mean BMI z‐score by 0.08 (±0.01, P = 4.27 × 10^?20). Conclusion: Obesity risk alleles were more strongly associated with increases in BMI z‐score at the upper tail compared to the lower tail of the distribution.     

High‐fat Diet‐induced Ultradian Leptin and Insulin Hypersecretion are Absent in Obesity‐resistant Rats*

Objective: Sprague‐Dawley rats fed a high‐fat diet (HFD) are either obesity prone (OP) or obesity resistant (OR). We tested the hypothesis that differences in the ultradian rhythmic patterns of insulin and ghrelin in OP vs. OR rats promote obesity in OP rats. Research Methods and Procedures: Rats were fed regular chow or an HFD, and ultradian fluctuations in leptin, insulin, and ghrelin were analyzed in blood samples collected at 5‐minute intervals from intrajugular cannulae of freely moving rats. Results: Regular chow feeding resulted in a slow weight gain accompanied by small increases in insulin and leptin and a decrease in ghrelin discharge, with only the pulse amplitude significantly altered. Similar changes were observed in OR rats, despite HFD consumption. In contrast, OP rats exhibited a high rate of weight gain and marked hyperinsulinemia, hyperleptinemia, and hypoghrelinemia; amplitude was altered, but frequency was stable. In a short‐term experiment, HFD elicited similar secretory patterns of smaller magnitude even in the absence of weight gain. Discussion: We showed that three hormonal signals of disparate origin involved in energy homeostasis were secreted in discrete episodes, and only the pulse amplitude component was vulnerable to age and HFD consumption. Increases in insulin and leptin and decreases in ghrelin pulse amplitude caused by HFD were exaggerated in OP rats relative to OR rats and preceded the weight increase. These findings show that a distinct genetic predisposition in the endocrine organs of OR rats confers protection against high‐fat intake‐induced ultradian hypersecretion of obesity‐promoting hormonal signals.     

COX‐2‐mediated Inflammation in Fat Is Crucial for Obesity‐linked Insulin Resistance and Fatty Liver

The aim was to examine the role of cyclooxygenase (COX)‐2‐mediated inflammation in the development of obese linked insulin resistance and fatty liver. The rats were fed separately regular diet (CONT), high‐fat diet (HFD) ad libitum, or energy restrictedly for 12 weeks. Rats fed HFD ad libitum were further divided into three subgroups co‐treated with vehicle (HFa), or a selective COX‐2 inhibitor celecoxib (HFa‐Cel) or mesulid (HFa‐Mes). Euglycemic hyperinsulinemic clamp (EHC) experiment was performed at the end of study. Another set of rats with similar grouping was further divided into those with a 4, 8, or 12‐week intervention period for hepatic sampling. Body weight was increased significantly and similarly in HFa, HFa‐Cel, and HFa‐Mes. Time‐dependent increases in plasma insulin, glucose, 8‐isoprostanes, leptin levels, homeostasis model assessment of insulin resistance (HOMA‐IR) and hepatic triglyceride contents shown in HFa were significantly reversed in HFa‐Cel and HFa‐Mes. During EHC period, the reduction in stimulation of whole body glucose uptake, suppression of hepatic glucose production and metabolic clearance rate of insulin shown in HFa were significantly reversed in HFa‐Cel and HFa‐Mes. The enhanced COX‐2 and tumor necrosis factor‐α (TNF‐α) but attenuated PPAR‐γ and C/EBP‐α mRNA expressions in epididymal fat shown in HFa were significantly reversed in HFa‐Cel and HFa‐Mes. The increases in average cell size of adipocytes and CD68 positive cells shown in HFa were also significantly reversed in HFa‐Cel and HFa‐Mes. Our findings suggest that COX‐2 activation in fat inflammation is important in the development of insulin resistance and fatty liver in high fat induced obese rats.     

Altered Kidney CYP2C and Cyclooxygenase‐2 Levels Are Associated with Obesity‐Related Albuminuria

Objective: To determine cytochrome P450 (CYP450) and cyclooxygenase (COX) expression and metabolite regulation and renal damage in the early stages of obesity‐related hypertension and diabetes. Research Methods and Procedures: Obese and lean Zucker rats at 10 to 12 weeks of age were studied. Blood pressure was measured in the conscious state using radiotelemetry. Blood glucose levels and body weight were measured periodically. Protein expression of CYP450 and COX enzymes in the kidney cortex, renal microvessels, and glomeruli was studied. The levels of CYP450 and COX metabolites in urine were measured, and urinary albumin excretion, an indicator of kidney damage, was measured. Results: Body weight and blood glucose averaged 432 ± 20 grams and 105 ± 5 mg/dl, respectively, in obese Zucker rats as compared with 320 ± 8 grams and 91 ± 5 mg/dl, respectively, in age‐matched 10‐ to 12‐week‐old lean Zucker rats. Renal microvascular CYP4A and COX‐2 protein levels were increased 2.3‐ and 17.0‐fold, respectively, in obese Zucker rats. The protein expression of CYP2C11 and CYP2C23 was decreased 2.0‐fold in renal microvessels isolated from obese Zucker rats when compared with lean Zucker rats. The urinary excretion rate of thromboxane B₂ was increased significantly in obese Zucker as compared with lean Zucker rats (22.0 ± 1.8 vs. 13.4 ± 1.0 ng/d). Urinary albumin excretion, an index of kidney damage, was increased in the obese Zucker rat at this early age. Discussion: These results suggest that increased CYP4A and COX‐2 protein levels and decreased CYP2C11 and CYP2C23 protein levels occur in association with microalbuminuria during the onset of obesity‐related hypertension and type 2 diabetes.     

No Decrease in Free IGF‐I with Increasing Insulin in Obesity‐Related Insulin Resistance

Objective: Different facts suggest that the insulin growth factor (IGF)/ insulin growth factor‐binding protein (IGFBP) system may be regulated by factors other than growth hormone. It has been proposed that, in healthy subjects, free IGF‐I plays a role in glucose metabolism. The role of free IGF‐I in glucose homeostasis in insulin resistance is poorly understood. This study was undertaken to evaluate the effects of acute changes in plasma glucose and insulin levels on free IGF‐I and IGFBP‐1 in obese and non‐obese subjects. Research Methods and Procedures: Nineteen lean and 24 obese subjects were investigated. A frequently sampled intravenous glucose tolerance test was performed. Free IGF‐I and IGFBP‐1 were determined at 0, 19, 22, 50, 100, and 180 minutes. Results: Basal free IGF‐I levels tended to be higher and IGFBP‐1 lower in obese than in lean subjects. IGFBP‐1 levels inversely correlated with basal insulin concentration. To determine the effects of insulin on the availability of free IGF‐I and IGFBP‐1, changes in their plasma concentrations were measured during a frequently sampled intravenous glucose tolerance test. After insulin administration, a significant suppression of free IGF‐I at 22% was observed in lean subjects. In contrast, plasma‐free IGF‐I levels remained essentially unchanged in the obese group. The differences between both groups were statistically significant at 100 minutes (p < 0.01) and 180 minutes (p < 0.05). Serum IGFBP‐1 was suppressed to a similar extent in both groups. Discussion: These data suggest that the concentrations of free IGF‐I and IGFBP‐1 are differentially regulated by obesity. Obesity‐related insulin resistance leads to unsuppressed free IGF‐I levels.     

Development and Initial Validation of an Obesity‐specific Quality‐of‐life Measure for Children: Sizing Me Up

The present study describes the development and initial validation of a new obesity‐specific, self‐report measure of health‐related quality of life (HRQOL) for children aged 5–13 years. Participants included 141 obese children (mean age = 9.2 years, 67% female, 55% black, mean zBMI = 2.52) and their primary caregivers. Children completed Sizing Me Up (obesity‐specific HRQOL) and the PedsQL (generic HRQOL). Item content for Sizing Me Up was based on the published child obesity and HRQOL literatures and expert opinion. Items use phrasing to orient children to respond to questions in context of his/her size (e.g., “were teased by other kids because of your size”). Caregivers completed Sizing Them Up, a parallel parent‐proxy, obesity‐specific HRQOL measure. Initial psychometric evaluation of Sizing Me Up was completed by conducting a factor analysis and determining internal consistency, test–retest reliability, and convergent and construct validity. Sizing Me Up is a 22‐item measure with five scales (i.e., Emotional Functioning, Physical Functioning, Social Avoidance, Positive Social Attributes, and Teasing/Marginalization) that account for 57% of the variance and a total HRQOL score. Internal consistency coefficients range from 0.68 to 0.85. Test–retest reliabilities range from 0.53 to 0.78. Good convergent validity was demonstrated with the PedsQL (rs = 0.35–0.65) and the parent‐proxy Sizing Them Up (rs = 0.22–0.44). Sizing Me Up represents the first obesity‐specific HRQOL measure developed specifically for younger school‐aged children (aged 5–13 years) with preliminary evidence of strong psychometric properties that likely has both clinical and research utility in a variety of settings.     

Obesity‐Related Knowledge,Attitudes, and Behaviors in Obese and Non‐obese Urban Philadelphia Female Adolescents

Objectives: To examine relationships between knowledge, attitudinal and behavioral factors, and obesity and to determine how these factors influence obesity status in west Philadelphia female adolescents. Research Methods and Procedures: A matched‐pairs study was conducted with 32 stature‐ and age‐matched pairs of obese (body mass index and triceps skinfold ≥95th percentile of National Health and Nutrition Examination Survey I) and non‐obese (body mass index and triceps skinfold between the 15th and 85th percentiles of National Health and Nutrition Examination Survey I) female African American adolescents (aged 11 to 15 years), selected from a school‐based study sample, based on obesity status and matching criteria. Adolescents were compared on the following measures: physical activity, inactivity, dietary intake, eating attitudes, health behavior knowledge, body image, self‐esteem, and maturation status. Differences between obese and non‐obese females were tested using paired t tests and Wilcoxon matched‐pairs signed‐rank tests. Results: Physical activity, inactivity, and perception of ideal body size emerged as the most important contributory factors to obesity status. There were no statistically significant matched‐pair differences in macronutrient and micronutrient intakes, self‐esteem, eating attitudes, health behavior knowledge, or maturation status of these adolescents. Obese adolescents had significantly lower levels of physical activity, higher inactivity, and a larger perception of ideal body size than non‐obese adolescents. Discussion: Knowledge and attitudinal factors (with the exception of perception of ideal body size) had far less association with obesity than activity‐related behavioral factors. These findings suggest that future intervention strategies should pay particular attention to physical activity, inactivity, and body image attitudes.     

β3 Adrenergic Receptor Polymorphism and Obesity‐Related Phenotypes in Hypertensive Patients

Objectives: Obesity is a complex trait that is affected by both environmental and genetic risk factors. The β₃ adrenergic receptor (ADRB3) is expressed in adipose tissue and plays a role in energy metabolism. A missense mutation on codon 64 of this gene (W64R) is associated with receptor malfunction. Previous studies examining the relation between this polymorphism and obesity produced inconsistent findings. The current study assessed the association between the W64R genotype and obesity‐related phenotypes, including body weight, BMI, and serum triglycerides, cholesterol, and glucose. Research Methods and Procedures: We determined the ADRB3 W64R genotypes and fasting serum lipid and glucose concentrations for 695 hypertensive adults (336 men, 359 women) from a rural county in Anhui Province, China. Multivariate linear regression models were fit to detect associations between the genetic polymorphism and obesity‐related phenotypes. Results: The ADRB3 W64R polymorphism was significantly associated with body weight and BMI in men but not in women. After controlling for potential confounding variables, men who were homozygous for the R64 allele were 11.8 kg heavier (p < 0.001) and had a BMI that was 3.7 kg/m² greater (p = 0.001) than men who were homozygous for the W64 allele. Serum concentrations of lipids and glucose were found not associated with the genetic polymorphism. Discussion: The ADRB3 R64 allele was associated with increased body weight and BMI in men but not in women. The genetic association was not modified by triglyceride, cholesterol, blood glucose, or blood pressure levels of the subjects.