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1.  Increased Levels of Plasma Acylcarnitines in Obesity and Type 2 Diabetes and Identification of a Marker of Glucolipotoxicity 
Obesity (Silver Spring, Md.)  2010;18(9):1695-1700.
Dysregulation of fatty acid oxidation (FAO) is recognized as important in the pathophysiology of obesity and insulin resistance (IR). However, demonstrating FAO defects in vivo in humans has entailed complex and invasive methodologies. Recently, the identification of genetic blocks in FAO has been vastly simplified by using tandem mass spectrometry (MS/MS) of dried bloodspots to specify acylcarnitine (AcylCN) alterations characteristic for each disorder. This technology has recently been applied to examine FAO alterations in human and animal models of obesity and type 2 diabetes mellitus (T2DM). This study focused on characterizing AcylCN profiles in human plasma from individuals with obesity and T2DM during fasting and insulin-stimulated conditions. Following an overnight fast, plasma was obtained from lean (n = 12), obese nondiabetic (n = 14), and T2DM (n = 10) participants and analyzed for AcylCN using MS/MS. Plasma samples were also obtained at the end of a 4-h insulin-stimulated euglycemic clamp. In obesity and T2DM, long-chain AcylCNs were similarly significantly increased in the fasted state; free-CN levels were also elevated. Additionally, T2DM subjects of comparable BMI had increased short- and medium-chain AcylCNs, both saturated and hydroxy, as well as increased C4-dicarboxylcarnitine (C4DC–CN) that correlated with an index of poor glycemic control (HbA1c; r = 0.74; P < 0.0001). Insulin infusion reduced all species of plasma AcylCN but this reduction was blunted in T2DM. Plasma long-chain AcylCN species are increased in obesity and T2DM, suggesting that more fatty acids can enter mitochondria. In T2DM, many shorter species accumulate, suggesting that they have a generalized complex oxidation defect.
PMCID: PMC3984458  PMID: 20111019
2.  Obesity Paradox in Amputation Risk Among Nonelderly Diabetic Men 
Obesity (Silver Spring, Md.)  2011;20(2):460-462.
The association between BMI and amputation risk is not currently well known. We used data for a cohort of diabetic patients treated in the US Department of Veterans Affairs Healthcare System in 2003. Men aged <65 years at the end of follow-up were examined for their amputation risk and amputation-free survival during the next 5 years (2004–2008). Compared to overweight individuals (BMI 25–29.9 kg/m2), the risks of amputation and treatment failure (amputation or death) were higher for patients with BMI <25 kg/m2 and were lower for those with BMI ≥30 kg/m2. Individuals with BMI ≥40 kg/m2 were only half as likely to experience any (hazard ratios (HR) = 0.49; 95% confidence interval (CI), 0.30–0.80) and major amputations (HR = 0.53; 95% CI, 0.39–0.73) during follow-up as overweight individuals. While the amputation risk continued to decrease for higher BMI, amputation-free survival showed a slight upturn at BMI >40 kg/m2. The association between obesity and amputation risk in our data shows a pattern consistent with “obesity paradox” observed in many health conditions. More research is needed to better understand pathophysiological mechanisms that may explain the paradoxical association between obesity and lower-extremity amputation (LEA) risk.
PMCID: PMC3978648  PMID: 21996669
3.  Validity of the Remote Food Photography Method (RFPM) for estimating energy and nutrient intake in near real-time 
Obesity (Silver Spring, Md.)  2011;20(4):891-899.
Two studies are reported; a pilot study to demonstrate feasibility followed by a larger validity study. Study 1’s objective was to test the effect of two ecological momentary assessment (EMA) approaches that varied in intensity on the validity/accuracy of estimating energy intake with the Remote Food Photography Method (RFPM) over six days in free-living conditions. When using the RFPM, Smartphones are used to capture images of food selection and plate waste and to send the images to a server for food intake estimation. Consistent with EMA, prompts are sent to the Smartphones reminding participants to capture food images. During Study 1, energy intake estimated with the RFPM and the gold standard, doubly labeled water (DLW), were compared. Participants were assigned to receive Standard EMA Prompts (n=24) or Customized Prompts (n=16) (the latter received more reminders delivered at personalized meal times). The RFPM differed significantly from DLW at estimating energy intake when Standard (mean±SD = −895±770 kcal/day, p<.0001), but not Customized Prompts (−270±748 kcal/day, p=.22) were used. Error (energy intake from the RFPM minus that from DLW) was significantly smaller with Customized vs. Standard Prompts. The objectives of Study 2 included testing the RFPM’s ability to accurately estimate energy intake in free-living adults (N=50) over six days, and energy and nutrient intake in laboratory-based meals. The RFPM did not differ significantly from DLW at estimating free-living energy intake (−152±694 kcal/day, p=0.16). During laboratory-based meals, estimating energy and macronutrient intake with the RFPM did not differ significantly compared to directly weighed intake.
PMCID: PMC3975169  PMID: 22134199
Food Intake; Energy Intake; Dietary Intake; Dietary Assessment; Eating Behaviors
4.  Abdominal fat is associated with a greater brain reward response to high-calorie food cues in Hispanic women 
Obesity (Silver Spring, Md.)  2013;21(10):2029-2036.
Exposure to high-calorie foods may promote overeating by stimulating brain reward pathways and appetite. Abdominal fat has particularly adverse metabolic consequences and may alter brain pathways that regulate feeding behavior. Functional magnetic resonance imaging (fMRI) was used to test the hypothesis that high-calorie food cues activate brain reward regions and increase appetite, and to examine relationships between abdominal fat and brain reward responsiveness in Hispanic women.
Design and Methods
fMRI was performed while thirteen volunteers viewed twelve blocks of pictures of food and non-food items. Participants rated hunger and food desire after each block of pictures. Brain activation to high-calorie foods was determined by calculating a contrast of high-calorie food minus non-food images. Pearson’s correlations were used to test the relationship between brain reward activation and waist circumference.
High-calorie food images activated brain reward regions (Z>2.3, p<0.05 corrected for multiple comparisons) and increased hunger (p=0.001), desire for sweet (p=0.012) and savory (p=0.009) foods. The striatal response to high-calorie foods positively correlated with waist circumference, independent of BMI (r=0.621, p=0.031).
Exposure to high-calorie food images activates brain reward pathways and increases appetitive drive in Hispanic females. Abdominal fat, independent of BMI, parallels striatal responsiveness to high-calorie food images.
PMCID: PMC3659193  PMID: 23408738
food images; fMRI; appetite; desire; obesity; reward; brain; hunger
5.  Abdominal Myosteatosis is Independently Associated to Hyperinsulinemia and Insulin Resistance among Older Men without Diabetes 
Obesity (Silver Spring, Md.)  2013;21(10):2118-2125.
Design and Methods
Skeletal muscle adipose tissue (AT) infiltration (myosteatosis) increases with aging and may contribute to the development of type 2 diabetes mellitus (T2DM). It remains unclear if myosteatosis is associated to glucose and insulin homeostasis independent of total and central adiposity. We evaluated the association between intermuscular AT (IMAT) in the abdominal skeletal muscles (total, paraspinal and psoas) and fasting serum glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) in 393 non-diabetic Caucasian men aged 65+. Abdominal IMAT, visceral (VAT) and subcutaneous (SAT) AT (cm3) were measured by quantitative computed tomography at the L4-L5 intervertebral space.
In age, study site, height and muscle volume adjusted regression analyses, total abdominal and psoas (but not paraspinal) IMAT were positively associated with glucose, insulin and HOMA-IR (all P < 0.003). The associations between total abdominal and psoas IMAT and insulin and HOMA-IR remained significant after further adjusting for lifestyle factors, as well as DXA total body fat, VAT or SAT in separate models (all P <0.009).
Our study indicates a previously unreported, independent association between abdominal myosteatosis and hyperinsulinemia and insulin resistance among older Caucasian men. These associations may be specific for particular abdominal muscle depots, illustrating the potential importance of separately studying specific muscle groups.
PMCID: PMC3661705  PMID: 23408772
Myosteatosis; intermuscular fat; skeletal muscle; fat distribution; insulin; insulin resistance
6.  Satiety, but not total PYY, is increased with continuous and intermittent exercise 
Obesity (Silver Spring, Md.)  2013;21(10):2014-2020.
This study determined the hormonal and subjective appetite responses to exercise (1-h continuous v. intermittent exercise throughout the day) in obese individuals.
Design and Methods
Eleven obese subjects (>30 kg/m2) underwent 3, 12-hour study days: control condition (sedentary behavior-SED), continuous exercise condition ((EX) 1-h exercise), and intermittent exercise condition ((INT) 12 hourly, 5-minute bouts). Blood samples (every 10 min) were measured for serum insulin and total peptide YY (PYY) concentrations, with ratings of appetite (visual analog scale-VAS: every 20 minutes). Both total area under the curve (AUC), 2-h AUC and AUC above baseline, and subjective appetite ratings were calculated.
No differences were observed in total PYY AUC between conditions, but hunger was reduced with INT (INTEX and SED>EX; P<0.05). A correlation existed between the change in total PYY and insulin levels (r=−0.81; P<0.05), and total PYY and satiety (r=0.80; P<0.05) with the EX condition, not the SED and INT conditions.
The total PYY response to meals is not altered over the course of a 12-h day with either intermittent or continuous exercise; however, intermittent exercise increased satiety and reduced hunger to a greater extent than continuous exercise in obese individuals.
PMCID: PMC3661741  PMID: 23418154
gut hormones; exercise; visual analog scale; obesity
7.  Intrahepatic lipid, not visceral or muscle fat, is correlated with insulin resistance in older, female Rhesus macaques 
Obesity (Silver Spring, Md.)  2013;21(10):2021-2028.
Little is known of the effect of body composition on glucose metabolism in the aging female non-human primate. We studied these variables in older female Rhesus macaques.
Design and Methods
Female Rhesus macaques (Macacamulatta, n = 19, age range 23–30 yrs) underwent magnetic resonance imaging and 1H spectroscopy to quantify total abdominal fat, visceral fat (VF), subcutaneous fat (SF) area, extramyocellular lipid (EMCL), intramyocellular lipid (IMCL) and intrahepatic lipid (IHL) content, and DEXA scan for whole body composition. A subgroup (n=12) underwent a fasting blood draw and intravenous glucose tolerance test.
SF correlated with homeostatic model assessment of insulin resistance (HOMAIR) and quantitative insulin sensitivity check index (QUICKI), but not after adjustment for fat mass. IHL demonstrated the strongest correlation with HOMAIR, QUICKI and calculated insulin sensitivity index (CSI), and remained significant after adjustment for fat mass. VF, IMCL, and EMCL did not correlate with any of our measures of insulin sensitivity.
Despite a greater amount of VF compared to SF, VF was not associated with markers of insulin resistance (IR) in the older female monkey. Instead, IHL is a marker for IR in the fasting and post-prandial state in these animals.
PMCID: PMC3661746  PMID: 23408675
Body Composition; Insulin Resistance; Magnetic Resonance; Fat Distribution; Obesity
8.  Physicians build less rapport with obese patients 
Obesity (Silver Spring, Md.)  2013;21(10):2146-2152.
Physicians’ negative attitudes towards patients with obesity are well documented. Whether or how these beliefs may affect patient-physician communication is unknown. We aimed to describe the relationship between patient BMI and physician communication behaviors (biomedical, psychosocial/lifestyle, and rapport building) during typical outpatient primary care visits.
Design and Methods
Using audio-recorded outpatient encounters from 39 urban PCPs and 208 of their patients, we examined the frequency of communication behaviors using the Roter Interaction Analysis System. The independent variable was measured patient BMI and dependent variables were communication behaviors by the PCP within the biomedical, psychosocial/lifestyle, and rapport building domains. We performed a cross-sectional analysis using multilevel Poisson regression models to evaluate the association between BMI and physician communication.
PCPs demonstrated less emotional rapport with overweight and obese patients (IRR 0.65, 95%CI 0.48–0.88, p=0.01; IRR 0.69, 95%CI 0.58–0.82, p<0.01, respectively) than for normal weight patients. We found no differences in PCPs’ biomedical or psychosocial/lifestyle communication by patient BMI.
Our findings raise the concern that low levels of emotional rapport in primary care visits with overweight and obese patients may weaken the patient-physician relationship, diminish patients’ adherence to recommendations, and decrease the effectiveness of behavior change counseling.
PMCID: PMC3694993  PMID: 23512862
Obesity; patient-provider; primary care; psychosocial research
9.  Dyslipidemia links obesity to early cerebral neurochemical alterations 
Obesity (Silver Spring, Md.)  2013;21(10):2007-2013.
To examine the role of hypertension, hyperglycemia and dyslipidemia in potentially accounting for obesity-related brain vulnerability in the form of altered cerebral neurochemistry.
Design and Methods
Sixty-four adults, ages 40 to 60 years, underwent a health screen and proton magnetic resonance spectroscopy (1H MRS) of occipitoparietal grey matter to measure N-acetyl aspartate (NAA), choline (Cho), myo-inositol (mI) and glutamate (Glu) relative to creatine (Cr). The causal steps approach and non-parametric bootstrapping were utilized to assess if fasting glucose, mean arterial pressure or peripheral lipid/lipoprotein levels mediate the relationship between body mass index (BMI) and cerebral neurochemistry.
Higher BMI was significantly related to higher mI/Cr, independent of age and sex. BMI was also significantly related to two of the proposed mediators, triglyceride and HDL-cholesterol, which were also independently related to increased mI/Cr. Finally, the relationship between BMI and mI/Cr, was significantly attenuated after inclusion of triglyceride and HDL-cholesterol into the model, one at a time, indicating statistical mediation.
Higher triglyceride and lower HDL levels statistically account for the association between BMI and myo-inositol, pointing towards a potentially critical role for dyslipidemia in the development of cerebral neurochemical alterations in obesity.
PMCID: PMC3695042  PMID: 23512296
obesity; magnetic resonance spectroscopy; myo-inositol; triglycerides; cholesterol
10.  Extending the History of Child Obesity in the United States: The Fels Longitudinal Study, Birth Years 1930 to 1993 
Obesity (Silver Spring, Md.)  2013;21(10):2153-2156.
Little is known about the prevalence of child obesity in the U.S. before the first national survey in 1963. There is disagreement about whether the obesity epidemic is entirely a recent phenomenon or a continuation of longstanding trends.
We analyze the BMIs of 1,116 children who participated in the Fels Longitudinal Study near Dayton, Ohio. Children were born between 1930 and 1993 and measured between 3 and 18 years of age.
Between the birth cohorts of 1930 and 1993, the prevalence of obesity rose from 0% to 14% among boys and from 2% to 12% among girls. The prevalence of overweight rose from 10% to 28% among boys and from 9% to 21% among girls. The mean BMI Z-score rose from +0.25 to +0.72 among boys and from −0.11 to +0.26 among girls. Among boys, all these increases began after birth year 1970. Among girls, obesity began to rise after birth year 1970, but overweight and BMI Z-scores were already rising as early as the 1930s and 1940s.
Most of the results suggest that the child obesity epidemic was recent and sudden. The recency of the epidemic offers some hope that it may be reversed.
PMCID: PMC3695078  PMID: 23512972
11.  Changes in fat and skeletal muscle with exercise training in obese adolescents: comparison of whole-body MRI and dual energy X-ray absorptiometry 
Obesity (Silver Spring, Md.)  2013;21(10):2063-2071.
We examined skeletal muscle (SM) and fat distribution using whole-body MRI in response to aerobic (AE) versus resistance exercise (RE) training in obese adolescents and whether DXA provides similar estimates of fat and SM change as MRI.
Design and Methods
Thirty-nine obese boys (12–18 yr) were randomly assigned to one of three 3-month interventions: AE (n=14), RE (n=14) or a control (n=11).
At baseline, MRI-measured total fat was significantly greater than DXA-measured total fat [Δ=3.1 kg (95% CI: −0.4 to 7.4 kg, P<0.05)], wherein underestimation by DXA was greatest in those with the highest total fat. Overall, the changes in total fat were not significantly different between MRI and DXA [Δ= −0.4 kg (95% CI: −3.5 to 2.6 kg, P>0.05)], but DXA tended to overestimate MRI fat losses in those with larger fat losses. MRI-measured SM and DXA-measured LBM (lean body mass) were significantly correlated, but as expected the absolute values were different at baseline [Δ= −28.4 kg (95% CI: −35.4 to −21.3 kg, P<0.05)]. Further, DXA overestimated MRI gains in SM in those with larger SM gains.
Although DXA and MRI-measured total and regional measures tended to be correlated at baseline and changes with exercise, there were substantial differences in the absolute values derived using DXA versus MRI. Further, there were systemic biases in the estimation between the methods wherein DXA tended to overestimate fat losses and SM gains compared to MRI. Thus, the changes in body composition observed are influenced by the method employed.
PMCID: PMC3726562  PMID: 23512818
skeletal muscle; lean body mass; fat; adolescents; DXA; exercise training
12.  Relationship between Sexual Function and Quality of Life in Obese Persons Seeking Weight Reduction 
Obesity (Silver Spring, Md.)  2013;21(10):1966-1974.
This study investigated sexual functioning in persons with obesity and seeking weight loss, and the associations of sexual functioning with relevant demographic and clinical variables as well as quality of life.
Design and Methods
Participants were enrolled in a two-year randomized clinical trial. Participants were obese and had at least two components of metabolic syndrome. Male and female sexual functioning was assessed by the International Index of Erectile Function (IIEF) and the Female Sexual Function Index (FSFI) respectively.
The rate of female sexual dysfunction was 29%. The rate of erectile dysfunction (ED) was 45%. Of the characteristics considered, FSD was associated with age (p=0.002). ED was significantly associated with age and physical functioning (both p <0.01).
A large minority of patients with obesity reported sexual dysfunction. The occurrence of sexual dysfunction was associated with age, but, surprisingly, not weight-related comorbidities. This may be the result of the nature of the study sample or the methods used to administer the questionnaires that assessed sexual functioning.
PMCID: PMC3735672  PMID: 23512339
13.  Racial/ethnic Differences in Clinical and Biochemical Type 2 Diabetes Mellitus Risk Factors in Children 
Obesity (Silver Spring, Md.)  2013;21(10):2081-2090.
To examine whether peri-adolescent children demonstrate the significant racial/ethnic differences in body fatness relative to BMI and in the prevalence and relationship of body composition to risk factors for type 2 diabetes (T2DM) as in adults.
Design and Methods
We examined family history of obesity and T2DM, anthropometry, insulin sensitivity and secretory capacity, lipids, and cytokines (IL-6, CRP, TNF-α, and adiponectin) in a cohort of 994 middle school students (47% male, 53%, female; 12% African American, 14% East Asian, 13% South Asian, 9% Caucasian, 44% Hispanic, and 8% other).
Fractional body fat content was significantly greater at any BMI among South Asians. There were racial/ethnic specific differences in lipid profiles, insulin secretory capacity, insulin sensitivity, and inflammatory markers corrected for body fatness that are similar to those seen in adults. Family history of T2DM was associated with lower insulin secretory capacity while family history of obesity was more associated with insulin resistance.
Children show some of the same racial/ethnic differences in risk factors for adiposity-related co-morbidities as adults. BMI and waist circumference cutoffs to identify children at-risk for adiposity-related co-morbidities should be adjusted by racial/ethnic group as well as other variables such as birthweight and family history.
PMCID: PMC3766484  PMID: 23596082
Obesity; pediatrics; diabetes; inflammation; lipid
14.  QTL-based association analyses reveal novel genes influencing pleiotropy of Metabolic Syndrome (MetS) 
Obesity (Silver Spring, Md.)  2013;21(10):2099-2111.
Metabolic Syndrome (MetS) is a phenotype cluster predisposing to type 2 diabetes and cardiovascular diseases. In extended families of Northern European ancestry, we previously identified two significant QTLs 3q27 and 17p12 that were linked with multiple representative traits of MetS. To determine the genetic basis of these linkage signals, QTL-specific genomic and transcriptomic analyses were performed in 1,137 individuals from 85 extended families that contributed to the original linkage. We tested in SOLAR association of MetS phenotypes with QTL-specific haplotype-tagging SNPs as well as transcriptional profiles of peripheral blood mononuclear cells (PBMCs). SNPs significantly associated with phenotypes under the prior hypothesis of linkage mapped to seven genes at 3q27 and seven at 17p12. Prioritization based on biologic relevance, SNP association, and expression analyses identified two genes: insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) at 3q27 and tumor necrosis factor receptor 13B (TNFRSF13B) at 17p12. Prioritized genes could influence cell-cell adhesion and adipocyte differentiation, insulin/glucose responsiveness, cytokine effectiveness and plasma lipids and lipoprotein densities. In summary, our results combine genomic, transcriptomic, and bioinformatic data to identify novel candidate loci for MetS.
PMCID: PMC3769476  PMID: 23418049
15.  The Relationship of Waist Circumference and BMI to Visceral, Subcutaneous, and Total Body Fat: Sex and Race Differences 
Obesity (Silver Spring, Md.)  2010;19(2):402-408.
The purpose of this study was to examine sex and race differences in the relationship between anthropometric measurements and adiposity in white and African-American (AA) adults. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) areas were measured with computed tomography (CT). Fat mass (FM) was measured with dual-energy-X-ray absorptiometry (DXA). Correlation coefficients were used to assess the relationship of waist circumference (WC) and BMI to VAT, SAT, and FM within sex-by-race groups. General linear models were used to compare relationships between WC or BMI, and adiposity across sex and race, within age groups (18–39 and 40–64 years). The sample included 1,667 adults (men: 489 white; 120 AA; women: 666 white, 392 AA). WC and BMI correlations were highest for FM and SAT compared to VAT. Women had higher FM levels than men regardless of WC, but the sex difference in FM was attenuated in younger AA adults with a high BMI. For a given level of WC or BMI, women had higher levels of SAT than men; however, significant interactions indicated that the relationship was not consistent across all levels of BMI and WC. Sex and race differences in VAT varied significantly with WC and BMI. In general, white adults had higher levels of VAT than AA adults at higher levels of BMI and WC. Sex differences, and in some instances race differences, in the relationships between anthropometry and fat-specific depots demonstrate that these characteristics need to be considered when predicting adiposity from WC or BMI.
PMCID: PMC3960785  PMID: 20948514
16.  Environmental Endocrine Disruptors Promote Adipogenesis in the 3T3-L1 Cell Line through Glucocorticoid Receptor Activation 
Obesity (Silver Spring, Md.)  2009;18(7):1283-1288.
The burgeoning obesity and diabetes epidemics threaten health worldwide, yet the molecular mechanisms underlying these phenomena are incompletely understood. Recently, attention has focused on the potential contributions of environmental pollutants that act as endocrine disrupting chemicals (EDCs) in the pathogenesis of metabolic diseases. Because glucocorticoid signaling is central to adipocyte differentiation, the ability of EDCs to stimulate the glucocorticoid receptor (GR) and drive adipogenesis was assessed in the 3T3-L1 cell line. Various EDCs were screened for glucocorticoid-like activity using a luciferase reporter construct, and four (bisphenol A (BPA), dicyclohexyl phthalate (DCHP), endrin, and tolylfluanid (TF)) were shown to significantly stimulate GR without significant activation of the peroxisome proliferator-activated receptor-γ. 3T3-L1 preadipocytes were then treated with EDCs and a weak differentiation cocktail containing dehydrocorticosterone (DHC) in place of the synthetic dexamethasone. The capacity of these compounds to promote adipogenesis was assessed by quantitative oil red O staining and immunoblotting for adipocyte-specific proteins. The four EDCs increased lipid accumulation in the differentiating adipocytes and also upregulated the expression of adipocytic proteins. Interestingly, proadipogenic effects were observed at picomolar concentrations for several of the EDCs. Because there was no detectable adipogenesis when the preadipocytes were treated with compounds alone, the EDCs are likely promoting adipocyte differentiation by synergizing with agents present in the differentiation cocktail. Thus, EDCs are able to promote adipogenesis through the activation of the GR, further implicating these compounds in the rising rates of obesity and diabetes.
PMCID: PMC3957336  PMID: 19927138
17.  The Association of Restrained Eating With Weight Change Over Time in a Community-Based Sample of Twins 
Obesity (Silver Spring, Md.)  2010;18(6):1146-1152.
We investigated the association of restrained eating with BMI and weight gain while controlling for the influence of genes and shared environment. Participants were 1,587 twins enrolled in the University of Washington Twin Registry (UWTR). Restrained eating was assessed by the Herman and Polivy Restraint Scale. Height and weight were self-reported on two occasions. Analyses used generalized estimating equations or multiple linear regression techniques. Restraint Scale scores were positively associated with both BMI (adjusted β = 0.39 kg/m2; 95% confidence interval (CI) = 0.34–0.44; P < 0.001) and weight gain (adjusted β = 0.33 pounds; 95% CI = 0.17–0.49; P < 0.001). High Restraint Scale scorers had an adjusted mean BMI of 27.9 kg/m2 (95% CI = 27.4–28.4) as compared to intermediate (mean = 25.5 kg/m2; 95% CI = 25.2–25.8) and low scorers (mean = 23.0 kg/m2; 95% CI = 22.7–23.3). In within-pair analyses among 598 same-sex twin pairs, the adjusted association between Restraint Scale scores and BMI persisted even when genetic and shared environmental factors were controlled for (adjusted β = 0.18; 95% CI = 0.12–0.24; P < 0.001), as did the association with weight gain (adjusted β = 0.37; 95% CI = 0.13–0.61; P = 0.003). In stratified analyses, dizygotic (DZ) twins differed more in BMI for a given difference in the Restraint Scale score than monozygotic (MZ) twins, for whom genetics are 100% controlled (adjusted β = 0.32; 95% CI = 0.20–0.44 vs. adjusted β = 0.10; 95% CI = 0.04–0.16; P = 0.001 for test of interaction). These data demonstrate that observed relationships between BMI, weight gain, and restrained eating, as assessed by the Restraint Scale, have a strong environmental influence and are not solely due to shared genetic factors.
PMCID: PMC3954714  PMID: 20111024
18.  Ethnic Differences in the Effects of Hepatic Fat Deposition on Insulin Resistance in Non-Obese Middle School Girls 
Obesity (Silver Spring, Md.)  2013;22(1):243-248.
In non-obese youth, to investigate whether hepatic fat deposition and its metabolic consequences vary between ethnic groups.
Design Methods
Thirty-two non-obese girls (12 Hispanic White [H] and 20 non-Hispanic White [NHW] girls), aged 11–14 years old were recruited. Outcome measures were MRI measured hepatic proton density fat fraction (hepatic PDFF), BMI Z-score, waist circumference, fasting insulin, glucose, adiponectin, sex hormone binding globulin [SHBG], ALT, AST, and triglycerides, and HOMA-IR.
There were no significant differences in mean BMI Z-scores (p=0.546) or hepatic PDFF (p=0.275) between H and NHW girls; however, H girls showed significant correlations between hepatic PDFF and markers of IR (fasting insulin, HOMA-IR, adiponectin, SHBG, triglycerides; all p<0.05), while NHW girls showed no significant correlations. Matched by hepatic PDFF or BMI-Z score, H girls had more evidence of IR for a given hepatic PDFF (mean insulin, HOMA-IR, and SHBG; all p<0.05) or BMI-Z score (mean insulin and HOMA-IR; all p<0.01) than NHW girls.
In non-obese female youth, ethnicity-related differences in effects of hepatic fat on IR are evident, so that in H girls, a given amount of hepatic fat appears to result in a more predictable and greater degree of IR than in NHW girls.
PMCID: PMC3946962  PMID: 23804504
Ethnicity; Non-obese; Insulin Resistance; Hepatic Steatosis
19.  Effects of risperidone on energy balance in female C57BL/6J mice 
Obesity (Silver Spring, Md.)  2013;21(9):1850-1857.
To investigate the effect of risperidone on energy expenditure and weight gain in female C57BL/6J mice.
Design and Methods
Body weight and composition, food intake, energy expenditure, and activity were determined weekly. mRNA expression of uncoupling protein 1 in brown adipose tissue, orexin and brain-derived neurotrophic factor in the hypothalamus were quantified by Real-Time PCR.
Risperidone tended to induce a greater body weight gain (P=0.052) and significantly higher food intake (P=0.038) relative to the placebo-treated group. Risperidone-treated mice had a higher resting energy expenditure (P=0.001), and total energy expenditure (P=0.005) than the placebo group. There were no effects of treatment, time, and treatment by time on NREE between groups. Risperidone-treated mice showed a significantly lesser locomotor activity than placebo-treated mice over 3 weeks (P<0.001). Risperidone induced a higher UCP1 mRNA (P=0.003) and a lower orexin mRNA (P=0.001) than placebo.
Risperidone-induced weight gain is associated with hyperphagia and a reduction in locomotor activity in C57BL/6J mice. Additionally, higher total and resting energy expenditure were accompanied by higher levels of UCP1 mRNA in BAT. The increased total energy expenditure could not offset the total intake of energy through risperidone-induced hyperphagia, therefore resulting in weight gain in female C57BL/6J mice.
PMCID: PMC3657586  PMID: 23408466
risperidone; energy expenditure; locomotor activity; UCP1; orexin; BDNF
20.  The Relationship between Measures of Obesity and Incident Heart Failure: The Multi-Ethnic Study of Atherosclerosis 
Obesity (Silver Spring, Md.)  2013;21(9):1915-1922.
To evaluate the strength of association of body mass index (BMI) and waist circumference (WC) with incident heart failure (HF), exploring our associations by ethnicity and age.
Design and Methods
We included 6,809 participants, aged 45–84 years, without clinical cardiovascular disease (2000–2002), from the Multi-Ethnic Study of Atherosclerosis. Cox-Proportional hazards models were used to examine associations of BMI and WC with incident HF. The predictive abilities of BMI and WC were compared using receiver operating characteristic curves.
Over a median follow-up of 7.6 years, there were 176 cases. BMI and WC were associated with incident HF in men [1.33 (1.10–1.61) and 1.38 (1.18–1.62) respectively] and women [1.70 (1.33–2.17) and 1.64 (1.29–2.08) respectively]. These associations became non-significant after adjusting for obesity-related conditions (hypertension, dysglycemia, hypercholesterolemia, left ventricular hypertrophy, kidney disease and inflammation). The associations of BMI and WC did not vary significantly by ethnicity or age-group, but were inverse in Hispanic men. The area under the curve for BMI and WC was 0.749 and 0.750, respectively, in men and 0.782 and 0.777, respectively, in women.
The association between obesity and incident HF is largely mediated by obesity-related conditions. BMI and WC have similar predictive abilities for incident HF.
PMCID: PMC3664654  PMID: 23441088
Obesity; heart failure; body mass index and waist circumference
21.  IGF-I attenuates FFA-induced activation of JNK1 phosphorylation and TNFα expression in human subcutaneous preadipocytes 
Obesity (Silver Spring, Md.)  2013;21(9):1843-1849.
Free fatty acids (FFAs) are increased in visceral fat and contribute to insulin resistance through multiple mechanisms, including c-Jun N-terminal kinase (JNK) activation and expression of TNFα. Given that IGF-I-mediated proliferation is impaired in omental compared to subcutaneous (sc) preadipocytes, we investigated IGF-I anti-inflammatory action in preadipocytes from sc and omental adipose tissue.
Preadipocytes isolated from abdominal sc and omental fat of obese subjects were studied in primary culture. Cells were exposed to FFAs with or without IGF-I pretreatment followed by analysis of cytokine expression and JNK phosphorylation. Lentivirus infection was used to express a constitutively active AKT (myr-AKT) in omental preadipocytes.
FFAs increased expression of TNFα, IL-6 and MCP-1 in sc and omental preadipocytes. IGF-I pretreatment reduced FFA-induced JNK1 phosphorylation and TNFα expression in sc but not omental preadipocytes. Treatment with the JNK1/2 inhibitor SP600125 reduced FFAinduced expression of TNFα. FFAs and MALP-2, a specific TLR2/6 ligand, but not specific ligands for TLR4 and TLR1/2, increased JNK1 phosphorylation. IGF-I completely inhibited MALP-2-stimulated phosphorylation of JNK1. Expression of myr-AKT in omental preadipocytes inhibited FFA-stimulated JNK1 phosphorylation.
IGF-I attenuates FFA-induced JNK1 phosphorylation and TNFα expression through activation of AKT in human subcutaneous but not omental preadipocytes.
PMCID: PMC3690156  PMID: 23512893
subcutaneous; omental; preadipocyte; IGF-I; FFA; JNK; TNFα
22.  Body adiposity index and all-cause and cardiovascular disease mortality in men 
Obesity (Silver Spring, Md.)  2013;21(9):1870-1876.
To evaluate the association of body adiposity index (BAI) with all-cause and cardiovascular disease (CVD) mortality risk.
Design and Methods
The current analysis comprised 19 756 adult men who enrolled in the Aerobics Centre Longitudinal Study and completed a baseline examination during 1988-2002. All-cause and CVD mortality was registered till December 31, 2003.
During an average follow-up of 8.3 years (163 844 man-years), 353 deaths occurred (101 CVD deaths). Age- and examination year-adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) for all-cause mortality risk were higher for men with high values of BMI (HR = 1.63, 95% CI = 1.19–2.23), waist circumference (1.55, 1.22-1.96) and percentage of body fat (%BF) (1.36, 1.04-1.31), but not for men with high values of BAI (1.28, 0.98-1.66). The HRs for CVD mortality risks were higher for men with high values in all adiposity measures (HRs ranged from 1.73 to 2.06). Most of these associations, however, became nonsignificant after adjusting for multiple confounders including cardiorespiratory fitness.
BAI is not a better predictor of all-cause and CVD mortality risk than BMI, waist circumference or %BF.
PMCID: PMC3695010  PMID: 23512375
Adiposity; body mass index; mortality; adults
23.  Randomized Trial of a Family-based, Automated, Conversational Obesity Treatment Program for Underserved Populations 
Obesity (Silver Spring, Md.)  2013;21(9):E369-E378.
To evaluate the acceptability and feasibility of a scalable obesity treatment program integrated with pediatric primary care and delivered using interactive voice technology (IVR) to families from underserved populations.
Design and Methods
Fifty parent-child dyads (child 9–12 yrs, BMI >95th percentile) were recruited from a pediatric primary care clinic and randomized to either an IVR or a wait-list control (WLC) group. The majority were lower-income, African-American (72%) families. Dyads received IVR calls for 12 weeks. Call content was informed by two evidenced-based interventions. Anthropometric and behavioral variables were assessed at baseline and 3 mo follow-up.
Forty-three dyads completed the study. IVR parents ate 1 cup more fruit than WLC (p < .05). No other groups differences were found. Children classified as high users of the IVR decreased weight, BMI and BMI z-score compared to low users (p<.05). Mean number of calls for parents and children were 9.1 (5.2 SD) and 9.0 (5.7 SD), respectively. Of those who made calls, >75% agreed that the calls were useful, made for people like them, credible, and helped them eat healthy foods.
An obesity treatment program delivered via IVR may be an acceptable and feasible resource for families from underserved populations.
PMCID: PMC3695059  PMID: 23512915
24.  Weight-Related Teasing from Adolescence to Young Adulthood: Longitudinal and Secular Trends between 1999 and 2010 
Obesity (Silver Spring, Md.)  2013;21(9):E428-E434.
The purpose of this study is to examine longitudinal trends from 1999–2010 in weight-related teasing as adolescents transition to young adulthood and to examine secular trends in teasing among early and middle adolescents over the same time period. To examine longitudinal changes we used data from 2,287 participants in Project EAT-III, an ongoing cohort that followed two age cohorts of adolescents from 1999 to 2010. Over the study period the younger cohort transitioned from early adolescence to early young adulthood and the older cohort transitioned from middle adolescence to middle young adulthood. To examine how levels of teasing among early and middle adolescents changed from 1999–2010 (secular trends), we compared baseline data from EAT-I to cross-sectional data from a new cohort of early and middle adolescents that was established in 2010. In 1999, 29% of early adolescent and 23% of middle adolescent females reported being teased. Approximately 18% of males in both age groups reported being teased in 1999. Longitudinal trends suggest that weight-related teasing remained stable among all subgroups as they transitioned to young adulthood, except among early adolescent males where teasing increased to 27% in early young adulthood. Analyses of age-matched secular trends show that teasing decreased by 10.4% among early adolescent females and by 7.6% among middle adolescent males from 1999–2010. Results suggest that interventions that focus on reducing weight-based discrimination are needed throughout adolescence and young adulthood. The secular decrease in weight-related teasing is promising, but the high prevalence of teasing remains a public health concern.
PMCID: PMC3714368  PMID: 23585224
25.  Relation of food intake behaviors and obesity development in young common marmoset monkeys 
Obesity (Silver Spring, Md.)  2013;21(9):1891-1899.
Increasing prevalence of childhood obesity and associated risks of adult type disease have led to worldwide concern. It remains unclear how genetic predisposition, environmental exposure to obesogenic food, and developmental programming interact to lead to overweight and obese children. The development of a nonhuman primate model of obesity, and particularly juvenile obesity, is an important step to elucidating the factors associated with obesity and evaluating intervention strategies.
Design and Methods
Infant marmosets were followed from birth to 12 months of age. Feeding phenotypes were determined through the use of behavioral observation, solid food intake trials, and liquid feeding trials monitored via lickometer.
Marmosets found to be Obese at 12 months of age (more than 14%body fat) start consuming solid food sooner and initiate more time off of care givers. These individuals developed stable feeding phenotypes that included being more efficient consumers during liquid intake trials, drinking more grams of diet per contact with the licksit.
The weaning process appears to be particularly important in the development of feeding phenotypes and the development of juvenile obesity for the marmosets, and thus this is the time that should be focused upon for intervention testing in both nonhuman primates and children.
PMCID: PMC3722271  PMID: 23512878
weaning behavior; meal pattern; feeding phenotype; lickometer

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