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1.  The Effects of Short-term Overfeeding on Energy Expenditure and Nutrient Oxidation in Obesity Prone and Obesity Resistant Humans 
The roles that energy expenditure (EE) and nutrient oxidation play in a predisposition for weight gain in humans remains unclear.
We measured EE and respiratory exchange ratio (RER) in non-obese obesity prone (OP; n=22) and obesity resistant (OR; n=30) men and women following a eucaloric diet and after 3 days of overfeeding (1.4x basal energy).
Twenty four hour EE, adjusted for fat free mass and sex, measured while consuming a eucaloric diet was not different between OP and OR subjects (2367 ± 80 vs. 2285 ± 98 kcals; p=0.53). Following overfeeding, EE increased in both OP and OR (OP: 2506 ± 63.7, p<0.01; OR: 2386 ± 99 kcals, p<0.05). Overfeeding resulted in an increase in 24h RER (OP: 0.857 ± 0.01 to 0.893 ± 0.01, p=0.01; OR: 0.852 ± 0.01 to 0.886 ± 0.01, p=0.005), with no difference between groups in either the eucaloric or overfeeding conditions (p>0.05). Nighttime RER (~10pm-6:30am) did not change with overfeeding in OR (0.823 ± 0.02 vs. 0.837 ± 0.01, p=0.29), but increased significantly in OP subjects (0.798 ± 0.15 to 0.839 ± 0.15, p<0.05), suggesting that fat oxidation during the night was down-regulated to a greater extent in OP subjects following a brief period of overfeeding, as compared to OR subjects who appeared to maintain their usual rate of fat oxidation. Protein oxidation increased significantly in both OP (p<0.001) and OR (p<0.01) with overfeeding, with no differences between OP and OR.
These results support the idea that overfeeding a mixed diet results in increases in EE and RER, but these increases in EE and RER are likely not responsible for obesity resistance. Adaptive responses to overfeeding that occur during the night may play a role in opposing weight gain.
PMCID: PMC3770765  PMID: 23229737
obesity prone; obesity resistant; overfeeding; indirect calorimetry; energy expenditure; fat oxidation; carbohydrate oxidation; protein oxidation
2.  The Effects of Overfeeding on Spontaneous Physical Activity in Obesity Prone and Obesity Resistant Humans 
Obesity (Silver Spring, Md.)  2012;20(11):2186-2193.
Despite living in an environment that promotes weight gain in many individuals, some individuals maintain a thin phenotype while self-reporting expending little or no effort to control their weight. When compared with obesity prone (OP) individuals, we wondered if obesity resistant (OR) individuals would have higher levels of spontaneous physical activity (SPA) or respond to short-term overfeeding by increasing their level of SPA in a manner that could potentially limit future weight gain. SPA was measured in 55 subjects (23 OP and 32 OR) using a novel physical activity monitoring system (PAMS) that measured body position and movement while subjects were awake for 6 days, either in a controlled eucaloric condition or during 3 days of overfeeding (1.4× basal energy) and for the subsequent 3 days (ad libitum recovery period). Pedometers were also used before and during use of the PAMS to provide an independent measure of SPA. SPA was quantified by the PAMS as fraction of recording time spent lying, sitting, or in an upright posture. Accelerometry, measured while subjects were in an upright posture, was used to categorize time spent in different levels of movement (standing, walking slowly, quickly, etc.). There were no differences in SPA between groups when examined across all study periods (P > 0.05). However, 3 days following overfeeding, OP subjects significantly decreased the amount of time they spent walking (−2.0% of time, P = 0.03), whereas OR subjects maintained their walking (+0.2%, P > 0.05). The principle findings of this study are that increased levels of SPA either during eucaloric feeding or following short term overfeeding likely do not significantly contribute to obesity resistance although a decrease in SPA following overfeeding may contribute to future weight gain in individuals prone to obesity.
PMCID: PMC3782097  PMID: 22522883
3.  Continuous Glucose Profiles in Obese and Normal-Weight Pregnant Women on a Controlled Diet 
Diabetes Care  2011;34(10):2198-2204.
We sought to define 24-h glycemia in normal-weight and obese pregnant women using continuous glucose monitoring (CGM) while they consumed a habitual and controlled diet both early and late in pregnancy.
Glycemia was prospectively measured in early (15.7 ± 2.0 weeks’ gestation) and late (27.7 ± 1.7 weeks’ gestation) pregnancy in normal-weight (n = 22) and obese (n = 16) pregnant women on an ad libitum and controlled diet. Fasting glucose, triglycerides (early pregnancy only), nonesterified fatty acids (FFAs), and insulin also were measured.
The 24-h glucose area under the curve was higher in obese women than in normal-weight women both early and late in pregnancy despite controlled diets. Nearly all fasting and postprandial glycemic parameters were higher in the obese women later in pregnancy, as were fasting insulin, triglycerides, and FFAs. Infants born to obese mothers had greater adiposity. Maternal BMI (r = 0.54, P = 0.01), late average daytime glucose (r = 0.48, P < 0.05), and late fasting insulin (r = 0.49, P < 0.05) correlated with infant percentage body fat. However, early fasting triglycerides (r = 0.67, P < 0.001) and late fasting FFAs (r = 0.54, P < 0.01) were even stronger correlates.
This is the first study to demonstrate that obese women without diabetes have higher daytime and nocturnal glucose profiles than normal-weight women despite a controlled diet both early and late in gestation. Body fat in infants, not birth weight, was related to maternal BMI, glucose, insulin, and FFAs, but triglycerides were the strongest predictor. These metabolic findings may explain higher rates of infant macrosomia in obese women, which might be targeted in trials to prevent excess fetal growth.
PMCID: PMC3177740  PMID: 21775754
4.  Eating-related Behaviors and Appetite During Energy Imbalance in Obese-Prone and Obese-Resistant Individuals 
Appetite  2013;65:96-102.
While the majority of Americans are now overweight, some individuals maintain their weight with minimal effort. This study investigated behavioral differences between 58 individuals recruited as either obese-resistant (OR) or obese-prone (OP) based on self-identification, BMI, and personal/family weight history. Subjects were studied during Eucaloric (EU), Overfed (OF), and Underfed (UF) phases which included a run-in diet, 1 day intervention diet, and a study day. At baseline, subjects completed the Three Factor Eating Questionnaire (TFEQ) and Power of Food Scale (PFS). On the study day, ratings of appetite, food appeal and desire, and food cravings were performed in response to a breakfast shake. OF resulted in reduced hunger and food desire while UF resulted in increased hunger and food appeal and desire. While hunger did not differ between groups, OP had higher scores for TFEQ measures (hunger, restraint and disinhibition), higher “hedonic hunger” as measured by the PFS, and greater food cravings and ratings of food appeal and desire. These results suggest that subjective hunger and desire for food change significantly after only one day of over- or underfeeding. Additionally, we found several behavioral differences between groups that are likely to promote weight gain over time in the OP.
PMCID: PMC3622833  PMID: 23402714
overfeeding; underfeeding; obesity prone; obesity resistant; hunger; satiety
5.  Twenty-Four Hour Total and Dietary Fat Oxidation in Lean, Obese and Reduced-Obese Adults with and without a Bout of Exercise 
PLoS ONE  2014;9(4):e94181.
It has been hypothesized that obese and reduced-obese individuals have decreased oxidative capacity, which contributes to weight gain and regain. Recent data have challenged this concept.
To determine (1) whether total and dietary fat oxidation are decreased in obese and reduced-obese adults compared to lean but increase in response to an acute exercise bout and (2) whether regular physical activity attenuates these metabolic alterations.
We measured 24-hr total (whole-room calorimetry) and dietary fat (14C-oleate) oxidation in Sedentary Lean (BMI = 21.5±1.6; n = 10), Sedentary Obese (BMI = 33.6±2.5; n = 9), Sedentary Reduced-Obese (RED-SED; BMI = 26.9±3.7; n = 7) and in Physically Active Reduced-Obese (RED-EX; BMI = 27.3±2.8; n = 12) men and women with or without an acute exercise bout where energy expended during exercise was not replaced.
Although Red-SED and Red-EX had a similar level of fatness, aerobic capacity and metabolic profiles were better in Red-EX only compared to Obese subjects. No significant between-group differences were seen in 24-hr respiratory quotient (RQ, Lean: 0.831±0.044, Obese: 0.852±0.023, Red-SED: 0.864±0.037, Red-EX: 0.842±0.039), total and dietary fat oxidation. A single bout of exercise increased total (+27.8%, p<0.0001) and dietary (+6.6%, p = 0.048) fat oxidation across groups. Although exercise did not impact RQ during the day, it decreased RQ during sleep (p = 0.01) in all groups. Red-EX oxidized more fat overnight than Red-SED subjects under both resting (p = 0.036) and negative energy balance (p = 0.003) conditions, even after adjustment for fat-free mass.
Obese and reduced-obese individuals oxidize as much fat as lean both under eucaloric and negative energy balance conditions, which does not support the hypothesis of reduced oxidative capacity in these groups. Reduced-obese individuals who exercise regularly have markers of metabolic health similar to those seen in lean adults. Both the acute and chronic effects of exercise were primarily observed at night suggesting an important role of sleep in the regulation of lipid metabolism.
PMCID: PMC3979741  PMID: 24714529
6.  Trafficking of Dietary Fat and Resistance to Obesity 
Physiology & behavior  2008;94(5):681-688.
The task of maintaining energy balance involves not only making sure that the number of calories ingested equals the number of calories burned but also involves ensuring nutrient balance. This means that over time, the quantity of carbohydrate, fat and protein consumed equals the amount of each oxidized. While the body has the ability to convert protein to carbohydrate and carbohydrate to fat, over long periods of time the body establishes nutrient balance with a high degree of accuracy storing excess nutrients as fat. To make decisions about food intake, the brain must assimilate information about the quantity of nutrients ingested and their disposition through the body over time. This is a very complex time ordered process as different tissues may be in different states of energy balance at different intervals following food ingestion. The fundamental task for the brain is to assess the influx of nutrients relative to stored pools of those nutrients and the rate at which they are being oxidized. It has been suggested that this task is particularly difficult for dietary fat because the stored pool of lipid is quite large compared to either the stored pools of carbohydrate and protein or the quantity of fat ingested per day. It is clear that some organisms resist weight gain even in the face of highly palatable diets. In fact most individuals eat less on any given day than they could given their maximal capacity for consumption. A central question then is: what restrains food intake in the setting of widely available highly palatable food? In this paper we will discuss the evidence that the movement of dietary fat between tissues may play an important role in the fidelity of nutrient sensing and as a result, resistance or susceptibility to obesity. In particular, the relative metabolism of dietary fat favoring oxidation over storage may be associated with more robust signaling of positive energy balance and resistance to dietary induced obesity in both humans and rats.
PMCID: PMC2494849  PMID: 18514237
Dietary fat; appetite; obesity; thinness; humans; rat models
7.  Differences in the Neuronal Response to Food in Obesity-Resistant as Compared to Obesity-Prone Individuals 
Physiology & behavior  2013;0:122-128.
Despite living in an obesogenic environment, some individuals maintain a thin phenotype compared to the majority who are at risk for weight gain and obesity. Understanding how these different phenotypes regulate energy intake is critical. The objective of this study was to examine the differences in neuronal response to visual food cues in adults recruited as either obesity-resistant (OR) or obesity-prone (OP) based on self-identification, BMI, and personal/family weight history. 25 OR and 28 OP individuals were studied after 4 days of eucaloric energy intake. Functional magnetic resonance imaging (fMRI) was performed in the fasted and acute fed states (30 minutes after a test meal) while subjects viewed images of foods of high hedonic value and neutral non-food objects. Measures of appetite using visual analog scales were performed before and every 30 minutes after the test meal for 3 hours. In the fasted state, food as compared to nonfood images elicited significant response in the insula, somatosensory cortex, parietal cortex, and visual cortex in both OR and OP. The acute fed state resulted in significant attenuation of these and other brain areas in the OR but not OP individuals. Furthermore, OP as compared to OR individuals showed greater activation of medial and anterior prefrontal cortex (PFC) in response to the test meal. Adjusting for fat mass did not impact these results. Attenuation of insula/PFC response to food images in the fed state was associated with greater reductions in hunger. These findings suggest that individuals prone to weight gain and obesity have altered neuronal responses to food cues in brain regions known to be important in energy intake regulation. These altered responses may represent an important mechanism contributing to excess energy intake and risk for obesity.
PMCID: PMC3615115  PMID: 23313402
fMRI; neuroimaging; pre-obesity; overweight; insula; prefrontal cortex
8.  The effects of sex, metabolic syndrome and exercise on postprandial lipemia 
Exercise has been suggested to have cardio protective benefits due to a lowering of postprandial triglycerides (PPTG). We hypothesized that a morning exercise bout would significantly lower PPTG measured over a full day, in response to moderate fat meals (35% energy) in men more so than women, and in metabolic syndrome (MetS) relative to normal weight (NW) individuals.
Participants completed two randomized study days; one control and one exercise day (60 min of morning exercise, 60% VO2peak). Meals were consumed at breakfast, lunch and dinner with the energy expended during exercise replaced on the active day. The areas (AUC) and incremental areas (IAUC) under the curve were calculated for total triglycerides, total cholesterol and other metabolites.
Exercise did not significantly change the PPTG AUC & IAUC overall, nor within, or between, each sex or group (NW and MetS). Exercise induced a 30% decrease in total cholesterol IAUC (p = 0.003) in NW subjects. Overall, women had a lower IAUC for PPTG compared to men (p = 0.037), with the greatest difference between MetS women and MetS men, due to a sustained drop in TG after lunch in the women. This suggests that PP, rather than fasting, lipid analyses may be particularly important when evaluating sex differences in metabolic risk.
With energy replacement, moderate morning exercise did not result in a significant decrease in PPTG excursions. Exercise did elicit a significant decrease in PP cholesterol levels in NW subjects, suggesting a potential mechanism for the cardio protective effects of exercise.
PMCID: PMC3534828  PMID: 22974968
obesity; triglyceride; cardiovascular disease; sex-based differences; cholesterol
9.  Circulating adiponectin levels are lower in Latino versus non-Latino white patients at risk for cardiovascular disease, independent of adiposity measures 
Latinos in the United States have a higher prevalence of type 2 diabetes than non-Latino whites, even after controlling for adiposity. Decreased adiponectin is associated with insulin resistance and predicts T2DM, and therefore may mediate this ethnic difference. We compared total and high-molecular-weight (HMW) adiponectin in Latino versus white individuals, identified factors associated with adiponectin in each ethnic group, and measured the contribution of adiponectin to ethnic differences in insulin resistance.
We utilized cross-sectional data from subjects in the Latinos Using Cardio Health Actions to reduce Risk study. Participants were Latino (n = 119) and non-Latino white (n = 60) men and women with hypertension and at least one other risk factor for CVD (age 61 ± 10 yrs, 49% with T2DM), seen at an integrated community health and hospital system in Denver, Colorado. Total and HMW adiponectin was measured by RIA and ELISA respectively. Fasting glucose and insulin were used to calculate the homeostasis model insulin resistance index (HOMA-IR). Variables independently associated with adiponectin levels were identified by linear regression analyses. Adiponectin's contribution to ethnic differences in insulin resistance was assessed in multivariate linear regression models of Latino ethnicity, with logHOMA-IR as a dependent variable, adjusting for possible confounders including age, gender, adiposity, and renal function.
Mean adiponectin levels were lower in Latino than white patients (beta estimates: -4.5 (-6.4, -2.5), p < 0.001 and -1.6 (-2.7, -0.5), p < 0.005 for total and HMW adiponectin), independent of age, gender, BMI/waist circumference, thiazolidinedione use, diabetes status, and renal function. An expected negative association between adiponectin and waist circumference was seen among women and non-Latino white men, but no relationship between these two variables was observed among Latino men. Ethnic differences in logHOMA-IR were no longer observed after controlling for adiponectin levels.
Among patients with CVD risk, total and HMW adiponectin is lower in Latinos, independent of adiposity and other known regulators of adiponectin. Ethnic differences in adiponectin regulation may exist and future research in this area is warranted. Adiponectin levels accounted for the observed variability in insulin resistance, suggesting a contribution of decreased adiponectin to insulin resistance in Latino populations.
PMCID: PMC3141565  PMID: 21736747
10.  Sex-Based Differences in the Behavioral and Neuronal Responses to Food 
Physiology & behavior  2010;99(4):538-543.
Sex-based differences in food intake related behaviors have been observed previously. The objective of this study was to examine sex-based differences in the behavioral and neuronal responses to food. 22 women and 21 men were studied. After 6 days of controlled eucaloric feeding, ad libitum energy intake (EI) was measured for three days. Appetite ratings using visual analog scales were obtained before and after each meal. Functional magnetic resonance imaging was performed in the overnight fasted state on the last day of eucaloric feeding while subjects were presented visual stimuli of food and neutral nonfood objects. While hunger and prospective consumption were not different between sexes, women had higher post-meal satiety ratings and dietary restraint than men. Images of hedonic foods resulted in significantly greater activation of lateral and dorsolateral prefrontal cortex (DLPFC) and parietal cortex in women as compared to men. No brain regions were more activated in men as compared to women. Men increased their EI during the ad libitum diet phase. While measures of appetite or feeding behaviors did not correlate with either neuronal activation or subsequent EI, DLPFC activation in response to hedonic foods was negatively correlated with EI. In summary, greater prefrontal neuronal responses to food cues in women may suggest increased cognitive processing related to executive function, such as planning, guidance or evaluation of behavior. Finally, increased DLPFC activation, perhaps relating to inhibitory cognitive control in response to food cues may be a better predictor of food intake than behavioral measures.
PMCID: PMC2826550  PMID: 20096712
fMRI; neuroimaging; obesity; food intake; gender; appetite
11.  The Effects of Overfeeding on the Neuronal Response to Visual Food Cues in Thin and Reduced-Obese Individuals 
PLoS ONE  2009;4(7):e6310.
The regulation of energy intake is a complex process involving the integration of homeostatic signals and both internal and external sensory inputs. The objective of this study was to examine the effects of short-term overfeeding on the neuronal response to food-related visual stimuli in individuals prone and resistant to weight gain.
Methodology/Principal Findings
22 thin and 19 reduced-obese (RO) individuals were studied. Functional magnetic resonance imaging (fMRI) was performed in the fasted state after two days of eucaloric energy intake and after two days of 30% overfeeding in a counterbalanced design. fMRI was performed while subjects viewed images of foods of high hedonic value and neutral non-food objects. In the eucaloric state, food as compared to non-food images elicited significantly greater activation of insula and inferior visual cortex in thin as compared to RO individuals. Two days of overfeeding led to significant attenuation of not only insula and visual cortex responses but also of hypothalamus response in thin as compared to RO individuals.
These findings emphasize the important role of food-related visual cues in ingestive behavior and suggest that there are important phenotypic differences in the interactions between external visual sensory inputs, energy balance status, and brain regions involved in the regulation of energy intake. Furthermore, alterations in the neuronal response to food cues may relate to the propensity to gain weight.
PMCID: PMC2712682  PMID: 19636426
12.  Skeletal muscle munc18c and syntaxin 4 in human obesity 
Animal and cell culture data suggest a critical role for Munc18c and Syntaxin 4 proteins in insulin mediated glucose transport in skeletal muscle, but no studies have been published in humans.
We investigated the effect of a 12 vs. 48 hr fast on insulin action and skeletal muscle Munc18c and Syntaxin 4 protein in lean and obese subjects. Healthy lean (n = 14; age = 28.0 +/- 1.4 yr; BMI = 22.8 +/- 0.42 kg/m2) and obese subjects (n = 11; age = 34.6 +/- 2.3 yr; BMI = 36.1 +/- 1.5 kg/m2) were studied twice following a 12 and 48 hr fast. Skeletal muscle biopsies were obtained before a 3 hr 40 mU/m2/min hyperinsulinemic-euglycemic clamp with [6,6-2H2]glucose infusion.
Glucose rate of disappearance (Rd) during the clamp was lower in obese vs. lean subjects after the 12 hr fast (obese: 6.25 +/- 0.67 vs. lean: 9.42 +/- 1.1 mg/kgFFM/min, p = 0.007), and decreased significantly in both groups after the 48 hr fast (obese 3.49 +/- 0.31 vs. lean: 3.91 +/- 0.42 mg/kgFFM/min, p = 0.002). Munc18c content was not significantly different between lean and obese subjects after the 12 hour fast, and decreased after the 48 hr fast in both groups (p = 0.013). Syntaxin 4 content was not altered by obesity or fasting duration. There was a strong positive relationship between plasma glucose concentration and Munc18c content in lean and obese subjects during both 12 and 48 hr fasts (R2 = 0.447, p = 0.0015). Significant negative relationships were also found between Munc18c and FFA (p = 0.041), beta-hydroxybutyrate (p = 0.039), and skeletal muscle AKT content (p = 0.035) in lean and obese subjects.
These data indicate Munc18c and Syntaxin 4 are present in human skeletal muscle. Munc18c content was not significantly different between lean and obese subjects, and is therefore unlikely to explain obesity-induced insulin resistance. Munc18c content decreased after prolonged fasting in lean and obese subjects concurrently with reduced insulin action. These data suggest changes in Munc18c content in skeletal muscle are associated with short-term changes in insulin action in humans.
PMCID: PMC2515313  PMID: 18652694
13.  Resistant starch consumption promotes lipid oxidation 
Although the effects of resistant starch (RS) on postprandial glycemia and insulinemia have been extensively studied, little is known about the impact of RS on fat metabolism. This study examines the relationship between the RS content of a meal and postprandial/post-absorbative fat oxidation.
12 subjects consumed meals containing 0%, 2.7%, 5.4%, and 10.7% RS (as a percentage of total carbohydrate). Blood samples were taken and analyzed for glucose, insulin, triacylglycerol (TAG) and free fatty acid (FFA) concentrations. Respiratory quotient was measured hourly. The 0%, 5.4%, and 10.7% meals contained 50 μCi [1-14C]-triolein with breath samples collected hourly following the meal, and gluteal fat biopsies obtained at 0 and 24 h. RS, regardless of dose, had no effect on fasting or postprandial insulin, glucose, FFA or TAG concentration, nor on meal fat storage. However, data from indirect calorimetry and oxidation of [1-14C]-triolein to 14CO2 showed that addition of 5.4% RS to the diet significantly increased fat oxidation. In fact, postprandial oxidation of [1-14C]-triolein was 23% greater with the 5.4% RS meal than the 0% meal (p = 0.0062).
These data indicate that replacement of 5.4% of total dietary carbohydrate with RS significantly increased post-prandial lipid oxidation and therefore could decrease fat accumulation in the long-term.
PMCID: PMC526391  PMID: 15507129
resistant starch; fat oxidation; glucose; insulin; amylose

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