Kazanna C. Hames

Effects of diet and physical activity interventions on weight loss and cardiometabolic risk factors in severely obese adults: a randomized trial.

CONTEXT The prevalence of severe obesity is increasing markedly, as is prevalence of comorbid conditions such as hypertension and type 2 diabetes mellitus; however, apart from bariatric surgery and pharmacotherapy, few clinical trials have evaluated the treatment of severe obesity. OBJECTIVE To determine the efficacy of a weight loss and physical activity intervention on the adverse health risks of severe obesity. DESIGN, SETTING, AND PARTICIPANTS Single-blind randomized trial conducted from February 2007 through April 2010 at the University of Pittsburgh. Participants were 130 (37% African American) severely obese (class II or III) adult participants without diabetes recruited from the community. INTERVENTIONS One-year intensive lifestyle intervention consisting of diet and physical activity. One group (initial physical activity) was randomized to diet and physical activity for the entire 12 months; the other group (delayed physical activity) had the identical dietary intervention but with physical activity delayed for 6 months. MAIN OUTCOME MEASURES Changes in weight. Secondary outcomes were additional components comprising cardiometabolic risk, including waist circumference, abdominal adipose tissue, and hepatic fat content. RESULTS Of 130 participants randomized, 101 (78%) completed the 12-month follow-up assessments. Although both intervention groups lost a significant amount of weight at 6 months, the initial-activity group lost significantly more weight in the first 6 months compared with the delayed-activity group (10.9 kg [95% confidence interval {CI}, 9.1-12.7] vs 8.2 kg [95% CI, 6.4-9.9], P = .02 for group × time interaction). Weight loss at 12 months, however, was similar in the 2 groups (12.1 kg [95% CI, 10.0-14.2] vs 9.9 kg [95% CI, 8.0-11.7], P = .25 for group × time interaction). Waist circumference, visceral abdominal fat, hepatic fat content, blood pressure, and insulin resistance were all reduced in both groups. The addition of physical activity promoted greater reductions in waist circumference and hepatic fat content. CONCLUSION Among patients with severe obesity, a lifestyle intervention involving diet combined with initial or delayed initiation of physical activity resulted in clinically significant weight loss and favorable changes in cardiometabolic risk factors. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00712127.

Reduced skeletal muscle oxidative capacity and elevated ceramide but not diacylglycerol content in severe obesity

The link between a reduced capacity for skeletal muscle mitochondrial fatty acid oxidation (FAO) and lipotoxicity in human insulin resistance has been the subject of intense debate. The objective of this study was to investigate whether reduced FAO is associated with elevated acyl CoA, ceramide, and diacylglycerol (DAG) in severely obese insulin resistant subjects.

Clinical trial demonstrates exercise following bariatric surgery improves insulin sensitivity

BACKGROUND Roux-en-Y gastric bypass (RYGB) surgery causes profound weight loss and improves insulin sensitivity (S(I)) in obese patients. Regular exercise can also improve S(I) in obese individuals; however, it is unknown whether exercise and RYGB surgery-induced weight loss would additively improve S(I) and other cardiometabolic factors. METHODS We conducted a single-blind, prospective, randomized trial with 128 men and women who recently underwent RYGB surgery (within 1-3 months). Participants were randomized to either a 6-month semi-supervised moderate exercise protocol (EX, n = 66) or a health education control (CON; n = 62) intervention. Main outcomes measured included S(I) and glucose effectiveness (S(G)), which were determined from an intravenous glucose tolerance test and minimal modeling. Secondary outcomes measured were cardiorespiratory fitness (VO2 peak) and body composition. Data were analyzed using an intention-to-treat (ITT) and per-protocol (PP) approach to assess the efficacy of the exercise intervention (>120 min of exercise/week). RESULTS 119 (93%) participants completed the interventions, 95% for CON and 91% for EX. There was a significant decrease in body weight and fat mass for both groups (P < 0.001 for time effect). S(I) improved in both groups following the intervention (ITT: CON vs. EX; +1.64 vs. +2.24 min⁻¹/μU/ml, P = 0.18 for Δ, P < 0.001 for time effect). A PP analysis revealed that exercise produced an additive S(I) improvement (PP: CON vs. EX; +1.57 vs. +2.69 min⁻¹/μU/ml, P = 0.019) above that of surgery. Exercise also improved S(G) (ITT: CON vs. EX; +0.0023 vs. +0.0063 min⁻¹, P = 0.009) compared with the CON group. Exercise improved cardiorespiratory fitness (VO2 peak) compared with the CON group. CONCLUSION Moderate exercise following RYGB surgery provides additional improvements in S(I), S(G), and cardiorespiratory fitness compared with a sedentary lifestyle during similar weight loss. TRIAL REGISTRATION clinicaltrials.gov identifier: NCT00692367. FUNDING This study was funded by the NIH/National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK078192) and an NIH/National Center for Research Resources/Clinical and Translational Science Award (UL1 RR024153).

Effect of physical activity on weight loss, energy expenditure, and energy intake during diet induced weight loss.

Objective measurements of physical activity (PA), energy expenditure (EE) and energy intake can provide valuable information regarding appropriate strategies for successful sustained weight loss.

Free Fatty Acid Uptake in Humans With CD36 Deficiency

Animal models have demonstrated that CD36 facilitates cell membrane free fatty acid (FFA) transport, but its role in human metabolism is not well understood. We measured heart, liver, adipose (three depots), and muscle (truncal postural and thigh locomotive) FFA uptake using [11C]palmitate positron emission tomography (PET) scans in a family of five carrying the Pro90Ser CD36 mutation (2 homozygotes had no CD36) and matched control volunteers. PET scans were done under conditions of suppressed and slightly increased palmitate concentrations. During suppressed palmitate conditions, muscle and adipose palmitate uptake were markedly reduced in homozygotes but not heterozygotes for the Pro90Ser CD36 mutation, whereas when palmitate concentration was slightly increased, uptake in muscle and adipose did not differ between control subjects and homozygous family members. Hepatic FFA uptake was similar in all participants regardless of palmitate concentrations, whereas myocardial FFA uptake was diminished in the Pro90Ser homozygotes during both suppressed and increased palmitate conditions. We conclude that CD36 1) facilitates FFA transport into muscle and adipose tissue in humans when extracellular concentrations are reduced but not when they are modestly elevated, 2) is not rate limiting for hepatic FFA uptake, and 3) is needed for normal cardiac FFA uptake over a range of FFA concentrations from low to slightly elevated.

Effects of acute lipid overload on skeletal muscle insulin resistance, metabolic flexibility, and mitochondrial performance

We hypothesized that acute lipid-induced insulin resistance would be attenuated in high-oxidative muscle of lean trained (LT) endurance athletes due to their enhanced metabolic flexibility and mitochondrial capacity. Lean sedentary (LS), obese sedentary (OS), and LT participants completed two hyperinsulinemic euglycemic clamp studies with and without (glycerol control) the coinfusion of Intralipid. Metabolic flexibility was measured by indirect calorimetry as the oxidation of fatty acids and glucose during fasted and insulin-stimulated conditions, the latter with and without lipid oversupply. Muscle biopsies were obtained for mitochondrial and insulin-signaling studies. During hyperinsulinemia without lipid, glucose infusion rate (GIR) was lowest in OS due to lower rates of nonoxidative glucose disposal (NOGD), whereas state 4 respiration was increased in all groups. Lipid infusion reduced GIR similarly in all subjects and reduced state 4 respiration. However, in LT subjects, fat oxidation was higher with lipid oversupply, and although glucose oxidation was reduced, NOGD was better preserved compared with LS and OS subjects. Mitochondrial performance was positively associated with better NOGD and insulin sensitivity in both conditions. We conclude that enhanced mitochondrial performance with exercise is related to better metabolic flexibility and insulin sensitivity in response to lipid overload.

High energy expenditure masks low physical activity in obesity.

Objective:To investigate energy expenditure in lean and obese individuals, focusing particularly on physical activity and severely obese individuals.Design:Total daily energy expenditure (TDEE) was assessed using doubly labeled water, resting metabolic rate (RMR) by indirect calorimetry, activity energy expenditure (AEE) by difference and time spent in physical activity by multisensor activity monitors.Subjects:In all, 177 lean, Class I and severely obese individuals (age 31–56 years, body mass index 20–64 kg m−2) were analyzed.Results:All components of energy expenditure were elevated in obese individuals. For example, TDEE was 2404±95 kcal per day in lean and 3244±48 kcal per day in Class III obese individuals. After appropriate adjustment, RMR was similar in all groups. Analysis of AEE by body weight and obesity class indicated a lower AEE in obese individuals. Confirming lower physical activity, obese individuals spent less time engaged in moderate-to-vigorous physical activity (2.7±1.3, 1.8±0.6, 2.0±1.4 and 1.2±1.0 h per day in lean, Class I, Class II and Class III individuals) and more time in sedentary behaviors.Conclusions:There was no indication of metabolic efficiency in even the severely obese, as adjusted RMR was similar across all groups. The higher AEE observed in the obese is consistent with a higher cost of activities due to higher body weight. However, the magnitude of the higher AEE (20–25% higher in obese individuals) is lower than expected (weight approximately 100% higher in Class III individuals). Confirming a lower volume of physical activity in the obese, the total time spent in moderate-to-vigorous physical activity and average daily metabolic equivalent of task level were lower with increasing obesity. These findings demonstrate that high body weight in obese individuals leads to a high TDEE and AEE, which masks the fact that they are less physically active, which can be influenced by duration or intensity of activity, than in lean individuals.

African American women exhibit similar adherence to intervention but lose less weight due to lower energy requirements.

Background:African American (AA) women have been shown to lose less weight than Caucasian women in response to behavioral interventions. Our objective was to examine adherence to intervention and metabolic factors that may explain this difference.Design and subjects:We examined longitudinal changes in body weight and energy expenditure (EE), and objective assessment of physical activity (PA) and energy intake (EI) during 6 months of a weight-loss intervention program, including prescribed calorie restriction and increased PA in 66 Caucasian and 39 AA severely obese women. Comparisons were also made in 25 Caucasian and 25 AA women matched for initial body weight.Results:The AA women lost 3.6 kg less weight than Caucasian women. Total daily EE (TDEE) and resting metabolic rate (RMR) adjusted for fat free mass (FFM) were significantly lower in the AA women, whereas the decrease in RMR in response to weight loss was greater in Caucasian women. Adherence to the prescribed PA and change in PA in response to intervention were similar in AA and Caucasian women. Prescribed EI (1794±153 and 1806±153 kcal per day) and measured EI during intervention (2591±371 vs 2630±442 kcal per day) were nearly identical in matched AA and Caucasian women. However, the AA women lost significantly less body weight due to lower energy requirements (2924±279 vs 3116±340 kcal per day; P<0.04), resulting in a lower energy deficit (333±210 vs 485±264 kcal per day).Conclusion:Adherence to the behavioral intervention was similar in AA and Caucasian women. However, neglecting to account for the lower energy requirements in AA women when calculating the energy prescription resulted in a lower level of calorie restriction and, hence, less body weight loss. Therefore, to achieve similar weight loss in AA women, the prescribed caloric restriction cannot be based on weight alone, but must be lower than in Caucasians, to account for lower energy requirements.

Effects of Dietary n-3 Fatty Acids on Hepatic and Peripheral Insulin Sensitivity in Insulin-Resistant Humans

OBJECTIVE Dietary n-3 polyunsaturated fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), prevent insulin resistance and stimulate mitochondrial biogenesis in rodents, but the findings of translational studies in humans are thus far ambiguous. The aim of this study was to evaluate the influence of EPA and DHA on insulin sensitivity, insulin secretion, and muscle mitochondrial function in insulin-resistant, nondiabetic humans using a robust study design and gold-standard measurements. RESEARCH DESIGN AND METHODS Thirty-one insulin-resistant adults received 3.9 g/day EPA+DHA or placebo for 6 months in a randomized double-blind study. Hyperinsulinemic-euglycemic clamp with somatostatin was used to assess hepatic and peripheral insulin sensitivity. Postprandial glucose disposal and insulin secretion were measured after a meal. Measurements were performed at baseline and after 6 months of treatment. Abdominal fat distribution was evaluated by MRI. Muscle oxidative capacity was measured in isolated mitochondria using high-resolution respirometry and noninvasively by magnetic resonance spectroscopy. RESULTS Compared with placebo, EPA+DHA did not alter peripheral insulin sensitivity, postprandial glucose disposal, or insulin secretion. Hepatic insulin sensitivity, determined from the suppression of endogenous glucose production by insulin, exhibited a small but significant improvement with EPA+DHA compared with placebo. Muscle mitochondrial function was unchanged by EPA+DHA or placebo. CONCLUSIONS This study demonstrates that dietary EPA+DHA does not improve peripheral glucose disposal, insulin secretion, or skeletal muscle mitochondrial function in insulin-resistant nondiabetic humans. There was a modest improvement in hepatic insulin sensitivity with EPA+DHA, but this was not associated with any improvements in clinically meaningful outcomes.

Adipose tissue fatty acid storage factors: effects of depot, sex and fat cell size.

Background/objectives:Patterns of postabsorptive adipose tissue fatty acid storage correlate with sex-specific body fat distribution. Some proteins and enzymes participating in this pathway include CD36 (facilitated transport), acyl-CoA synthetase (ACS; the first step in fat metabolism) and diacylglycerol acetyltransferase (DGAT; the final step of triglyceride synthesis). Our aim was to better define CD36, ACS and DGAT in relation to sex, subcutaneous fat depots and adipocyte size.Subjects/methods:Data were collected from studies conducted at Mayo Clinic between 2004 and 2012. Abdominal and femoral subcutaneous fat biopsy samples must have been collected in the postabsorptive state from healthy males and premenopausal females. Body composition was measured with dual-energy X-ray absorptiometry and abdominal computerized tomography scans. Adipocyte size (microscopy), CD36 protein content (enzyme-linked immunosorbent assay) and ACS and DGAT enzyme activities were measured. Data are presented as medians and 25th, 75th quartiles.Results:Males (n=60) and females (n=78) did not differ by age (37; 28, 46 years), body mass index (28.4; 24.6, 32.1 kg m−2) or abdominal (0.60; 0.45, 0.83 μg lipid per cell) and femoral adipocyte size (0.76; 0.60, 0.94 μg lipid per cell). Femoral ACS and DGAT were greater in females than males when expressed per mg lipid (ACS: 73 vs 55 pmol/mg lipid/min; DGAT: 5.5 vs 4.0 pmol/mg lipid/min; P<0.0001 for both) and per 1000 adipocytes (ACS: 59 vs 39 pmol per min per 1000 adipocytes; DGAT: 4.3 vs 3.1 pmol per min per 1000 adipocytes; P⩽0.0003 for both). There were no differences in abdominal fat storage factors between sexes. ACS and DGAT decreased as a function of adipocyte size (P<0.0001 for both). The decrease in ACS was greater in males and abdominal subcutaneous fat. There were no sex differences in CD36 in either fat depot, nor did it vary across adipocyte size.Conclusions:Facilitated transport of fatty acids by CD36 under postabsorptive conditions would not be different in those with large vs small adipocytes in either depot of both sexes. However, intracellular trafficking of fatty acids to triglyceride storage by ACS and DGAT may be less efficient in larger adipocytes.