Surgery for Obesity and Related Diseases 10 (2014) 138–143
Integrated health article
Diet-induced thermogenesis and respiratory quotient after Roux-en-Y gastric bypass surgery: A prospective study Silvia Leite Faria, M.Sc., Ph.D.a,c,*, Orlando Pereira Faria, M.D.a, Mariane de Almeida Cardeal, L.D.N.a, Marina Kiyomi Ito, Ph.D.c, Cynthia Buffington, M.D., Ph.D.b b
a Gastrocirurgia de Brasilia, Brasilia, Brazil Florida Celebration Health Hospital, Celebration, Florida c University of Brasília, Brasilia, Brazil Received March 7, 2013; accepted September 27, 2013
Abstract
Background: Studies in humans and other animals have shown that Roux-en-Y gastric bypass (RYGB) leads to increased energy expenditure (EE). We analyzed several components of EE, such as the respiratory quotient (RQ), resting metabolic rate (RMR), and diet-induced thermogenesis (DIT) among patients before and after RYGB. Methods: In this prospective clinical study, RMR, DIT, and RQ were measured by indirect calorimetry (IC) in the same patients before and 12 months after RYGB (the preoperative and postoperative time points, respectively). Postprandial RQ and DIT were measured after patients consumed a standard 270 kcal meal (62% carbohydrates, 12% proteins, and 26% lipids). Results: The population studied consisted of 13 patients (mean age 40.8 ⫾ 6.7 years, 85% female). At the postoperative (postop) time point, patients showed higher weight-adjusted RMR compared with the preoperative (preop) time point (P o .01). The absolute and weight-adjusted metabolic rates 20 minutes after the meal were increased postoperatively (P o .0001) but not preoperatively (P ¼ 0.2962) (DIT); this increase in RQ was significantly higher in the postop than in the preop time point. Conclusion: The observed patients showed increased EE, DIT, and RQ after RYGB surgery. These data may serve as important physiologic factors contributing to the loss and maintenance of weight after RYGB. (Surg Obes Relat Dis 2014;10:138–143.) r 2014 American Society for Metabolic and Bariatric Surgery. All rights reserved.
Keywords:
Diet-induced Thermogenesis; Respiratory Quotient; Energy expenditure; RYGB; Bariatric surgery; Morbid obesity
Decreased food intake and/or increased energy expenditure (EE) are the primary methods recommended for combating obesity [1]. However, weight loss through diet modification, physical activity, and medication may lead to increased appetite and decreased EE [2]. There is growing evidence of the role of EE in weight control and obesity. Recent studies have questioned the classical model in which bariatric surgery works by simple mechanical restriction or *
Correspondence: Silvia Leite Faria, M.Sc., Gastrocirurgia de Brasilia, Human Nutrition, SEPS 710/910 Sul Centro Clinico via Brasil Sala 334 and 337, Brasilia, Distrito Federal 70390108, Brazil. E-mail: [email protected]
nutrient malabsorption. The emerging model of Roux-en-Y gastric bypass (RYGB) argues that the loss of excess weight [3] and the improvement of obesity-related co-morbidities [4,5] may be the result of changes in the hormone metabolism [6] and energy balance after surgery [3,4,7]. Previous studies by the authors in humans [7,8] and by others in animals [5,9] have reported that the various components of EE, such as diet-induced thermogenesis (DIT), respiratory quotient (RQ), and resting metabolic rate (RMR) may influence the long-term loss/maintenance of weight after RYGB. DIT is the energy spent by an organism on the digestion and absorption of nutrients. It is defined through an increase of the
1550-7289/14/$ – see front matter r 2014 American Society for Metabolic and Bariatric Surgery. All rights reserved. http://dx.doi.org/10.1016/j.soard.2013.09.020
DIT and RQ RYGB—A Prospective Study / Surgery for Obesity and Related Diseases 10 (2014) 138–143
RMR after food consumption. In healthy individuals, DIT shows considerable interindividual variation and may represent 10%–15% of the total energy expenditure (TEE) [10]. DIT may affect the development or maintenance of obesity [11]. A low DIT has been linked to weight gain [12] and obesity [13], even after accounting for several potential confounding factors. While DIT can quantitatively assist TEE, RQ qualitatively affects this same variable, because it provides a basis for estimating the utilization of energy substrates by an organism; as the RQ approaches 1.0, the organism is more likely to use carbohydrate oxidation, and the closer it gets to .7, the greater the tendency for fat oxidation [14]. Studies in mice [9] and humans [4] have shown that the RQ undergoes important changes after RYGB. In particular, the increased production of glucagon-like peptide 1 (GLP 1), which aids in carbohydrate metabolism after RYGB, can increase the RQ value [5]. A cross-sectional study of RQ and DIT among patients before and after RYGB showed higher DIT and postprandial RQ results after surgery [8]. This result has since been confirmed by other studies in animals [4,5]. Changes in RQ and DIT can contribute to EE and possibly play an important role in the results obtained after RYGB. The objective of this prospective study was to analyze these variables among the same patient population before and after RYGB (the preop and postop time points, respectively).
Methodology Patients This prospective study was approved by the Ethics Committee of the Faculty of Health of the University of Brasília (Brasília, DF, Brazil, number 169 965) and registered as a clinical trial (NCT01759667). All participants signed an informed consent form. The participants were patients of a private bariatric surgery center in Brasília, Brazil. These patients had participated in previous research performed at the same clinic measuring EE in the fasting and postprandial states by indirect calorimetry (IC) among a population with clinically severe obesity [8]. One year later, after undergoing RYGB, these patients were invited again to perform the same tests. In the preop time point, the inclusion criteria were as follows: body mass index (BMI) Z40 kg/m2 (or BMI Z35 kg/m2 with associated co-morbidities) and age 418 years. Exclusion criteria were the following: age 465 years, severe heart or respiratory problems, breastfeeding, apparent infection, or fever. For the postop time point, the inclusion criteria were as follows: inclusion in the preop time point, RYGB surgery performed by the head surgeon of the same clinic, time since RYGB surgery Z12 months, and good physical health. Exclusion criteria for this group were the following: pregnancy, breastfeeding, apparent infection or fever, and age 465 years.
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The sample size was calculated based on the satisfactory statistical power above the recommended level of .80, a significance level of 5%, and effects size between 1.55 and 3.37. Thus, comparisons of the variables of weight, BMI, kcal/kg, and adjusted DIT present a satisfactory power for n ¼ 13. The weights and heights of the patients were measured to calculate BMI and EE, which were adjusted per kilogram of weight (kcal/kg). Weight-adjusted EE and DIT values were used because there was a considerable difference in the absolute terms. The percentage of excess weight loss (%EWL) was calculated as previously described [15]. The percentages of body fat (%BF) and lean mass (%LM) were assessed with multifrequency bioelectrical impedance analysis (Inbody, Biospace, Seoul, Korea).
Measurement of EE components Before the measurement of the RMR and RQ, the patients were instructed to abstain from food for 12 hours and to avoid alcohol, coffee, physical exercise, and cigarette use on the day before the examination. Patients in a supine position were examined by the Quark RMR IC system (Cosmed, Milan, Italy), which analyzes expired air with paramagnetic O2 and infra-red CO2 analyzers. Ventilation was measured with a special RMR turbine. The RQ was calculated as the volume ratio of oxygen consumed (VO2) to carbon dioxide produced (VCO2/VO2). This equipment has been validated in comparison with the gold standard Deltatrac. For the determination of DIT, patients were offered a standard mixed meal of 200 mL of coconut water and a chicken salad sandwich on whole wheat bread. According to the packaging information, this meal contained 270 kcal (62% carbohydrates, 12% proteins, and 26% lipids). The same commercial brands were used throughout the entire data collection period. IC was performed at 20 minutes (in the preop and postop time points) after eating to determine the metabolic rate (MR) and the postprandial RQ. DIT was calculated using the following equation: DIT ¼ postprandial MR RMR. Data and statistical analyses The primary outcomes of interest were weight, BMI, %BF, %LM, %EWL, RMR, DIT, and RQ. Pearson’s linear correlation coefficients were used to test the correlations among %EWL, %BF, and %LM, with DIT and weightadjusted DIT. To compare the mean %BF and %LM values between the time points (preop versus postop), the Student’s t test was used if both groups showed normal distributions; otherwise, the nonparametric Mann-Whitney test was used. To compare the mean values of various measurements between the time points, the nonparametric Wilcoxon test was used. To compare the mean absolute and weight-adjusted RMR values between the time points with the absolute and
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Table 1 Descriptive analysis and co-morbidities prevalence of the study population (n ¼ 13)
For the purpose of this analysis, a significance level of 5% was set. Data were analyzed by the SAS application 9.2.
Variable
Preoperative
Postoperative
P value
Analysis of biochemical exams
Gender
Male: 15% Female: 85% 39.5 ⫾ 7.0 110.0 ⫾ 14.32 40.6 ⫾ 3.0
—
— 50.8 ⫾ 2.9 46.6 ⫾ 14.9
Male: 15% Female: 85% 40.8 ⫾ 6.7 77.3 ⫾ 10.4 28.4 ⫾ 3.0 12.2 ⫾ 2.8 66.1 ⫾ 17.0 34.9 ⫾ 7.0 64.2 ⫾ 7.0
o.001 o.001 o.001 — — o.0001 o.0001
85 60 50 40 40 30 23 20
0 0 0 0 0 0 8 0
— — — — — — — —
Age (years) Weight (kg) BMI (kg/m2) Time since surgery (months) %EWL %BF %LM Co-morbidities Prevalence (%) Insulin resistance Dyspnea Arthritis Steatosis Dyslipidemia Sleep Apnea Back Pain High blood pressure
%BF ¼ percentage of body fat; BMI ¼ body mass index; %EWL ¼ excess weight loss percentage; %LM ¼ percentage of lean mass.
weight-adjusted DIT values taken 20 minutes after consuming the standard meal, the paired Student’s t test was used. Longitudinal measurements between and within time points were tested by analysis of variance with mixedeffect models for repeated measures. This analysis had as its main focus the changes after the standard meal consumption compared with results before the meal. A residual analysis was conducted for each measurement to verify if the residuals of the model showed signs of a Gaussian distribution with constant variance. If the residuals did not present this distribution, then a Neperian logarithmic transformation was used.
The results of biochemical exams gathered at the preop and postop phases related to glucose metabolism, namely glycated hemoglobin, the HOMA-IR index, fasting glycemia and baseline insulin levels were collected from the medical reports and analyzed. A statistical analysis of comparison of means was applied using data of glycated hemoglobin, the HOMA-IR index, fasting glycemia, and baseline insulin levels. A simple linear regression model was used to uncover the degree of variation of HOMA-IR during the preop phase, in relation to the postop phase, that could explain the DIT. Results The population studied consisted of 13 patients (mean age 40.8 ⫾ 6.7 years, 85% female). Table 1 compares the body composition and prevalence of co-morbidities among patients before and after RYGB surgery. At the preop time point, patients presented the following prevalence levels: 85% of insulin resistance, 60% of dyspnea, 50% of arthritis, 40% of steatosis, 40% of dyslipidemia, 30% of sleep apnea, 23% of back pain, and 20% of high blood pressure. At the postop time point, in 92% of the patients, all co-morbidities improved. However, 8% of patients still had back pain. At the preop time point, all patients consumed 100% of the standard meal. At the postop time point, 1 patient (8.0%) consumed half of the sandwich, 10 patients (75%) consumed 90% of the sandwich (removed all of the bread crust), and 2 patients (15%) consumed the entire sandwich. 6 patients (45%) consumed half of the drink, 1 patient (7%) consumed 20% of the drink (2 small sips, about 40 mL),
Table 2 Respiratory quotient, resting metabolic rate, and diet-induced Thermogenesis fasting values and values at 20 minutes after the standard meal Variable RQ Fasting Postprandial Δ RQ (postprandial-fasting) P value† Fasting RMR RMR (kcal) Weight-adjusted-RMR (kcal/kg) Postprandial RMR RMR (kcal) Weight-adjusted-RMR (kcal/kg) ΔDIT (fasting to postprandial) DIT (kcal) Weight-adjusted-DIT (kcal/kg)
Preoperative group
Postoperative group
.80 ⫾ .04 .81 ⫾ .04 .01 ⫾ .01 .2962
.78 ⫾ .07 .85 ⫾ .08 .07 ⫾ .01 o .0001
1952.3 ⫾ 82.3 17.75 ⫾ 2.70
1581.2 ⫾ 82.3 20.49 ⫾ 1.6
2067.3 ⫾ 295.11 18.77 ⫾ 2.94
1947.38 ⫾ 335.46 25.11 ⫾ 1.78
115.0 ⫾ 46.26 1.91 ⫾ 1.38†
366.15 ⫾ 46.26 4.62 ⫾ 1.88*
Difference between groups –.02 ⫾ .03 .04 ⫾ .04 .06 ⫾ .02 –371.0 ⫾ .0 2.74 ⫾ 1.1
P value* .390 .127 .018
o.01 o.01
–120 ⫾ 40.35 6.34 ⫾ 1.16
.273 o.01
251.15 ⫾ 65.42 2.71 ⫾ .5
o.001 o.001
* P values for the comparison between groups in the fasting and postprandial periods and changes from fasting to postprandial were calculated by mixedeffects ANOVA for repeated measurements. † P o .001 for the comparison of the postprandial value relative to the fasting value in the same group.
DIT and RQ RYGB—A Prospective Study / Surgery for Obesity and Related Diseases 10 (2014) 138–143
Fig. 1. Difference in metabolic rate between the two time points 20 minutes after intake of a standard meal. RMR ¼ resting metabolic rate.
and the remaining patients consumed all of the drink (200 mL). Based on the weighted average, the postop time point, consumed approximately 240 kcal, whereas the same patients in the preop time point, consumed 270 kcal. The absolute RMR was higher in the preop time point, whereas the fasting weight-adjusted RMR was higher in the postop time point (both P o .01) (Table 2). The increase in absolute and weight-adjusted MRs (Fig. 1) at 20 minutes after the meal were higher in the postop compared with the preop time point (P o .01 for both). Thus, the absolute and weight-adjusted DITs were increased by 4300% and 4200%, respectively, after surgery compared with the preop time point (Table 2). In the postop time point, there was an inverse correlation between %EWL and DIT (r ¼ –.59, P ¼ .0320), although no correlation was observed with weight-adjusted DIT (r ¼ –.48, P ¼ .0942). There were no correlations between %BF and %LM with DIT and weight-adjusted DIT (P ¼ .5316 and P ¼ .6094; P ¼ .5324, and P ¼ .6071, respectively). The mean fasting and postprandial RQ values did not differ from each other in either the preop or postop time point. The RQ increased 20 minutes after the meal in the postop time point (P o .0001), but the RQ in the preop time point did not present any differences (P ¼ .2962). The difference between the time points was significant, being about 7 times higher for the postoperative time point (Table 2 and Fig. 2). Regarding the biochemical parameters, it was noted that the glycated hemoglobin, the HOMA-IR index, fasting glycemia, and baseline insulin levels diminished significantly in the postop time period (P o .05 for all parameters, except for HOMA-IR) (Table 3). From the results of the linear regression model, it was noted that the HOMA-IR index variation may explain the DIT in terms of the following equation: DIT ¼ 466:8553:73 Δ ΗΟΜΑ-ΙRDIT ¼ 466; 8553; 73 ΔHomalR
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Fig. 2. Difference between the time points in relation to RQ increase after intake of a standard meal. RQ ¼ respiratory quotirespiratory quotient.
This equation, however, was not statistically significant (P ¼ .40). Discussion The mechanisms underlying the proven efficacy of RYGB have not been clearly elucidated. To examine the role of EE components in the mechanism of weight loss/maintenance after RYGB, we measured the RQ, RMR, and DIT among the same 13 patients before and Z12 months after RYGB. The weight-adjusted RMR was increased after surgery. In the postop time point, the weight-adjusted RMR and DIT results 20 minutes after consumption of a standard meal were markedly increased compared with the preop time point. The postop time point showed an increased postprandial RQ compared with the fasting RQ, whereas the preop time point did not show this result. This study confirms the results of our transversal study showing an increased DIT and EE after RYGB [8]. Our first study showed a 200% increase in DIT among 2 groups: the preoperative (obese population) and postRYGB population. This study is a prospective one that shows an increased DIT among RYGB patients that is higher than was found in the transversal study [8]. Anatomic changes in the gastrointestinal (GI) tract can cause unexpected alterations in the secretion of the gut hormones that influence several neurotransmitters related to the energy intake/expenditure balance [2]. Patients who lose 10% of their original weight through diet modification and medication show a much lower EE compared with “always Table 3 Biochemical parameters of glucose metabolism Biochemical parameter
Preop time point
Postop time point
P value
Glycated hemoglobin HOMA-IR Fasting glycemia Baseline insulin levels
5.55 ⫾ .27 3,40 ⫾ 1.83 97.89 ⫾ 9.61 13.41 ⫾ 6.70
5.03 ⫾ .29 .63 ⫾ .43 83.67 ⫾ 4.82 3.11 ⫾ 1.91
.031 .083 .012 .016
HOMA-IR ¼ homeostatic model assessment-insulin resistance; Postop ¼ postoperative; Preop ¼ preoperative.
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lean” individuals (i.e., individuals of the same weight who never went through a dramatic weight change). One possible explanation for this drop in EE is the subregulation of certain hormones that maintain an active metabolism (e.g., PYY, leptin, GLP-1) and the simultaneous overproduction of hormones that increase hunger (e.g., ghrelin) [16]. Through adaptive thermogenesis, the brain perceives the restriction of food intake as an imbalance [17]. Researchers have questioned whether individuals have their own “equilibrium point” related to body fat mass, above or below which variations will provoke compensatory changes in the EE. Weight loss after RYGB does not appear to follow the same pattern of EE change as is observed in individuals who lose weight through diet modification. We previously showed that RYGB was associated with an increase in RMR, which has been shown to have a positive correlation with weight loss [7,8]. Similarly, in the present study, the weight-adjusted RMR was higher among patients at the postop time point. Several studies in humans and mice have also confirmed this result [5,7–9]. Nevertheless, criticisms concerning the analytical methods used and/or the comparison of EE between populations with different characteristics remain (i.e., between preop and postop groups). Recently, Nestoridi et al. analyzed several methods for obtaining EE data obtained in mice [5]. Regardless of the analytical method used, RYGB was associated with an increase in TEE and its components. RYGB-treated mice showed a 75% higher heat output compared with sham-operated and control animals. The results suggest that RMR is the main component responsible for the increased TEE after RYGB. Several other animal studies have indicated that about half of the weight loss achieved after RYGB can be explained by the RMR [18,19]. Accordingly, researchers have suggested a direct link between increased EE and weight loss/maintenance after bariatric surgery [5,7,9,20]. As another component of the EE, DIT has been proposed to contribute to the increase in TEE observed after RYGB. Studies in humans [8] and other animals [5] have shown that DIT is significantly higher after RYGB, compared with the preop (obese) time point. In the present study, 20 minutes after food intake, the absolute and weight-adjusted DIT values were 4300% higher in the postop compared with the preop time point. Stylopoulos et al. observed a 30% higher increase in VO2 during and after episodes of food intake in RYGB-treated compared with sham-operated mice [5]. Regression analysis suggested that DIT increased with increasing food intake, with a higher correlation in the RYGB group compared with the sham-operated group. Every gram of food increased EE by 12.416 kcal after RYGB versus 7.659 kcal after sham operation [5]. Our findings are consistent with these previous results and with the hypothesis that RYGB is associated with an increase in DIT.
Nevertheless, the association between obesity and a lower DIT remains controversial [21,22]. Tentalouros et al. found that DIT did not differ between lean and obese individuals after the consumption of isocaloric diets [23]. Studies of previously obese individuals who had lost weight by nonsurgical methods suggested that reduced DIT in obesity may not be a primary pathogenic factor in human obesity, because it was reversed by weight reduction [24,25]. To gain insight into the impact of the DIT, we estimated the average proportion of the TEE that was comprised by DIT among our study participants. We considered the average value of RMR in the preop and postop time points (1952.3 and 1581.2 kcal per day, respectively) and calculated TEE by the formula TEE = TMR AF, with an activity factor (AF) of 1.2 for a sedentary population. We estimated average TEE values of 2342.8 and 1897.4 kcal per day at the preop and postop time points, respectively. Thus, the preop and postop DIT values corresponded to 5% and 19%, respectively, of the TEE (Table 2). The postoperative DIT is higher than the established value for healthy weight populations. We hypothesize that RYGB increases DIT to levels that are higher than those of “always lean” individuals. Some other factors can be related to the increased DIT among RYGB patients. The sympathetic nervous system (SNS) has been proposed as the efferent pathway responsible for the regulation of adaptive thermogenesis [17]. Food intake may stimulate the cerebral channels that activate the SNS, which in turn stimulate the metabolically active tissues (e.g., the muscles) to increase the EE, thus protecting the body from a state of obesity. Most cases of obesity are associated with low activity of the SNS [19]. The mechanism of RYGB seems to involve the activation of the SNS, which can contribute to the increased EE. Some authors have also indicated that changes in the flow of bile due to anatomic alterations of the GI tract after surgery may partly explain the metabolic results of RYGB [26]. The altered GI anatomy affects the delivery of bile acids to the ileum terminal and plasma. These changes could stimulate the intestinal L-cells, resulting in the increased secretion of GLP-1 and a consequent earlier increase in insulin secretion after RYGB [27]. We observed a significant increase in postprandial RQ among patients in the postop but not the preop time point. Similarly, Stylopoulos et al. observed a higher postprandial RQ in the RYGB-treated animals [5].They interpreted this result as stemming from the acquisition of greater metabolic flexibility after surgery, probably due to improved insulin sensitivity. Interestingly, improvements in insulin sensitivity have been reported to affect DIT [10]. In our study, we observed a significant improvement of the parameters related to glucose metabolism in the postop phase, including the HOMA-IR index, thus indicating a significant improvement of insulin resistance. In the analysis of the
DIT and RQ RYGB—A Prospective Study / Surgery for Obesity and Related Diseases 10 (2014) 138–143
linear regression model, it was seen that the HOMA-IR index variation may explain the DIT variation in such a way that a relation can be established. This relation, however, was not statistically significant in this study. Lower postprandial RQ values in obese individuals have also been attributed to increased fat oxidation [28,29], which is a compensatory mechanism by the obese body to restore the balance of body fat and to avoid additional weight gain [28]. The results of this and other studies suggest that GI tract rearrangement through RYGB may change the physiology of the energy balance and lead to a substantial EE increase. Some receptive mechanisms may detect these changes in the alimentary tract and relay a thermogenic signal to effector organs through the central nervous system [6]. Thus, RYGB appears to create an energy deficit in which increased EE is the primary conductor for the decrease in the amount of body fat [5]. Conclusion Increased EE may vitally contribute to the loss/maintenance of weight after RYGB. Based on our findings, we tentatively hypothesize that RYGB may establish a new “equilibrium point” for the organism after the imbalanced state of obesity. Further studies are needed to identify the primary mechanism underlying the EE increase after RYGB and to determine whether this EE increase continues over the long term. References [1] Feldmann HM, Golozoubova V, Cannon B, Nedergaard J. UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab 2009;9:203–9. [2] Rao RS. Bariatric surgery and the central nervous system. Obes Surg 2012;22:967–78. [3] Carey DG, Pliego GJ, Raymond RL, Skau KB. Body composition and metabolic changes following bariatric surgery: effects on fat mass, lean mass and basal metabolic rate. Obes Surg 2006;16:469–77. [4] Carrasco F, Papapietro K, Csendes A, et al. Changes in resting energy expenditure and body composition after weight loss following Rouxen-Y gastric bypass. Obes Surg 2007;17:608–16. [5] Nestoridi E, Kvas S, Kucharczyk J, Stylopoulos N. Resting energy expenditure and energetic cost of feeding are augmented after Rouxen-Y gastric bypass in obese mice. Endocrinology 2012;153: 2234–44. [6] Meguid MM, Glade MJ, Middleton FA. Weight regain after Roux-enY: a significant complication related to PYY. Nutrition 2008;24: 832–42. [7] Faria SL, Faria OP, Buffington C, de Almeida Cardeal M, Rodrigues de Gouvêa H. Energy expenditure before and after Roux-en-Y gastric bypass. Obes Surg 2012;22:1450–5. [8] Faria SL, Faria OP, Cardeal Mde A, de Gouvêa HR, Buffington C. Diet-induced thermogenesis and respiratory quotient after Roux-en-Y gastric bypass. Surg Obes Relat Dis 2012;8:797–802.
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Integrated health article
Diet-induced thermogenesis and respiratory quotient after Roux-en-Y gastric bypass surgery: A prospective study Silvia Leite Faria, M.Sc., Ph.D.a,c,*, Orlando Pereira Faria, M.D.a, Mariane de Almeida Cardeal, L.D.N.a, Marina Kiyomi Ito, Ph.D.c, Cynthia Buffington, M.D., Ph.D.b b
a Gastrocirurgia de Brasilia, Brasilia, Brazil Florida Celebration Health Hospital, Celebration, Florida c University of Brasília, Brasilia, Brazil Received March 7, 2013; accepted September 27, 2013
Abstract
Background: Studies in humans and other animals have shown that Roux-en-Y gastric bypass (RYGB) leads to increased energy expenditure (EE). We analyzed several components of EE, such as the respiratory quotient (RQ), resting metabolic rate (RMR), and diet-induced thermogenesis (DIT) among patients before and after RYGB. Methods: In this prospective clinical study, RMR, DIT, and RQ were measured by indirect calorimetry (IC) in the same patients before and 12 months after RYGB (the preoperative and postoperative time points, respectively). Postprandial RQ and DIT were measured after patients consumed a standard 270 kcal meal (62% carbohydrates, 12% proteins, and 26% lipids). Results: The population studied consisted of 13 patients (mean age 40.8 ⫾ 6.7 years, 85% female). At the postoperative (postop) time point, patients showed higher weight-adjusted RMR compared with the preoperative (preop) time point (P o .01). The absolute and weight-adjusted metabolic rates 20 minutes after the meal were increased postoperatively (P o .0001) but not preoperatively (P ¼ 0.2962) (DIT); this increase in RQ was significantly higher in the postop than in the preop time point. Conclusion: The observed patients showed increased EE, DIT, and RQ after RYGB surgery. These data may serve as important physiologic factors contributing to the loss and maintenance of weight after RYGB. (Surg Obes Relat Dis 2014;10:138–143.) r 2014 American Society for Metabolic and Bariatric Surgery. All rights reserved.
Keywords:
Diet-induced Thermogenesis; Respiratory Quotient; Energy expenditure; RYGB; Bariatric surgery; Morbid obesity
Decreased food intake and/or increased energy expenditure (EE) are the primary methods recommended for combating obesity [1]. However, weight loss through diet modification, physical activity, and medication may lead to increased appetite and decreased EE [2]. There is growing evidence of the role of EE in weight control and obesity. Recent studies have questioned the classical model in which bariatric surgery works by simple mechanical restriction or *
Correspondence: Silvia Leite Faria, M.Sc., Gastrocirurgia de Brasilia, Human Nutrition, SEPS 710/910 Sul Centro Clinico via Brasil Sala 334 and 337, Brasilia, Distrito Federal 70390108, Brazil. E-mail: [email protected]
nutrient malabsorption. The emerging model of Roux-en-Y gastric bypass (RYGB) argues that the loss of excess weight [3] and the improvement of obesity-related co-morbidities [4,5] may be the result of changes in the hormone metabolism [6] and energy balance after surgery [3,4,7]. Previous studies by the authors in humans [7,8] and by others in animals [5,9] have reported that the various components of EE, such as diet-induced thermogenesis (DIT), respiratory quotient (RQ), and resting metabolic rate (RMR) may influence the long-term loss/maintenance of weight after RYGB. DIT is the energy spent by an organism on the digestion and absorption of nutrients. It is defined through an increase of the
1550-7289/14/$ – see front matter r 2014 American Society for Metabolic and Bariatric Surgery. All rights reserved. http://dx.doi.org/10.1016/j.soard.2013.09.020
DIT and RQ RYGB—A Prospective Study / Surgery for Obesity and Related Diseases 10 (2014) 138–143
RMR after food consumption. In healthy individuals, DIT shows considerable interindividual variation and may represent 10%–15% of the total energy expenditure (TEE) [10]. DIT may affect the development or maintenance of obesity [11]. A low DIT has been linked to weight gain [12] and obesity [13], even after accounting for several potential confounding factors. While DIT can quantitatively assist TEE, RQ qualitatively affects this same variable, because it provides a basis for estimating the utilization of energy substrates by an organism; as the RQ approaches 1.0, the organism is more likely to use carbohydrate oxidation, and the closer it gets to .7, the greater the tendency for fat oxidation [14]. Studies in mice [9] and humans [4] have shown that the RQ undergoes important changes after RYGB. In particular, the increased production of glucagon-like peptide 1 (GLP 1), which aids in carbohydrate metabolism after RYGB, can increase the RQ value [5]. A cross-sectional study of RQ and DIT among patients before and after RYGB showed higher DIT and postprandial RQ results after surgery [8]. This result has since been confirmed by other studies in animals [4,5]. Changes in RQ and DIT can contribute to EE and possibly play an important role in the results obtained after RYGB. The objective of this prospective study was to analyze these variables among the same patient population before and after RYGB (the preop and postop time points, respectively).
Methodology Patients This prospective study was approved by the Ethics Committee of the Faculty of Health of the University of Brasília (Brasília, DF, Brazil, number 169 965) and registered as a clinical trial (NCT01759667). All participants signed an informed consent form. The participants were patients of a private bariatric surgery center in Brasília, Brazil. These patients had participated in previous research performed at the same clinic measuring EE in the fasting and postprandial states by indirect calorimetry (IC) among a population with clinically severe obesity [8]. One year later, after undergoing RYGB, these patients were invited again to perform the same tests. In the preop time point, the inclusion criteria were as follows: body mass index (BMI) Z40 kg/m2 (or BMI Z35 kg/m2 with associated co-morbidities) and age 418 years. Exclusion criteria were the following: age 465 years, severe heart or respiratory problems, breastfeeding, apparent infection, or fever. For the postop time point, the inclusion criteria were as follows: inclusion in the preop time point, RYGB surgery performed by the head surgeon of the same clinic, time since RYGB surgery Z12 months, and good physical health. Exclusion criteria for this group were the following: pregnancy, breastfeeding, apparent infection or fever, and age 465 years.
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The sample size was calculated based on the satisfactory statistical power above the recommended level of .80, a significance level of 5%, and effects size between 1.55 and 3.37. Thus, comparisons of the variables of weight, BMI, kcal/kg, and adjusted DIT present a satisfactory power for n ¼ 13. The weights and heights of the patients were measured to calculate BMI and EE, which were adjusted per kilogram of weight (kcal/kg). Weight-adjusted EE and DIT values were used because there was a considerable difference in the absolute terms. The percentage of excess weight loss (%EWL) was calculated as previously described [15]. The percentages of body fat (%BF) and lean mass (%LM) were assessed with multifrequency bioelectrical impedance analysis (Inbody, Biospace, Seoul, Korea).
Measurement of EE components Before the measurement of the RMR and RQ, the patients were instructed to abstain from food for 12 hours and to avoid alcohol, coffee, physical exercise, and cigarette use on the day before the examination. Patients in a supine position were examined by the Quark RMR IC system (Cosmed, Milan, Italy), which analyzes expired air with paramagnetic O2 and infra-red CO2 analyzers. Ventilation was measured with a special RMR turbine. The RQ was calculated as the volume ratio of oxygen consumed (VO2) to carbon dioxide produced (VCO2/VO2). This equipment has been validated in comparison with the gold standard Deltatrac. For the determination of DIT, patients were offered a standard mixed meal of 200 mL of coconut water and a chicken salad sandwich on whole wheat bread. According to the packaging information, this meal contained 270 kcal (62% carbohydrates, 12% proteins, and 26% lipids). The same commercial brands were used throughout the entire data collection period. IC was performed at 20 minutes (in the preop and postop time points) after eating to determine the metabolic rate (MR) and the postprandial RQ. DIT was calculated using the following equation: DIT ¼ postprandial MR RMR. Data and statistical analyses The primary outcomes of interest were weight, BMI, %BF, %LM, %EWL, RMR, DIT, and RQ. Pearson’s linear correlation coefficients were used to test the correlations among %EWL, %BF, and %LM, with DIT and weightadjusted DIT. To compare the mean %BF and %LM values between the time points (preop versus postop), the Student’s t test was used if both groups showed normal distributions; otherwise, the nonparametric Mann-Whitney test was used. To compare the mean values of various measurements between the time points, the nonparametric Wilcoxon test was used. To compare the mean absolute and weight-adjusted RMR values between the time points with the absolute and
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Table 1 Descriptive analysis and co-morbidities prevalence of the study population (n ¼ 13)
For the purpose of this analysis, a significance level of 5% was set. Data were analyzed by the SAS application 9.2.
Variable
Preoperative
Postoperative
P value
Analysis of biochemical exams
Gender
Male: 15% Female: 85% 39.5 ⫾ 7.0 110.0 ⫾ 14.32 40.6 ⫾ 3.0
—
— 50.8 ⫾ 2.9 46.6 ⫾ 14.9
Male: 15% Female: 85% 40.8 ⫾ 6.7 77.3 ⫾ 10.4 28.4 ⫾ 3.0 12.2 ⫾ 2.8 66.1 ⫾ 17.0 34.9 ⫾ 7.0 64.2 ⫾ 7.0
o.001 o.001 o.001 — — o.0001 o.0001
85 60 50 40 40 30 23 20
0 0 0 0 0 0 8 0
— — — — — — — —
Age (years) Weight (kg) BMI (kg/m2) Time since surgery (months) %EWL %BF %LM Co-morbidities Prevalence (%) Insulin resistance Dyspnea Arthritis Steatosis Dyslipidemia Sleep Apnea Back Pain High blood pressure
%BF ¼ percentage of body fat; BMI ¼ body mass index; %EWL ¼ excess weight loss percentage; %LM ¼ percentage of lean mass.
weight-adjusted DIT values taken 20 minutes after consuming the standard meal, the paired Student’s t test was used. Longitudinal measurements between and within time points were tested by analysis of variance with mixedeffect models for repeated measures. This analysis had as its main focus the changes after the standard meal consumption compared with results before the meal. A residual analysis was conducted for each measurement to verify if the residuals of the model showed signs of a Gaussian distribution with constant variance. If the residuals did not present this distribution, then a Neperian logarithmic transformation was used.
The results of biochemical exams gathered at the preop and postop phases related to glucose metabolism, namely glycated hemoglobin, the HOMA-IR index, fasting glycemia and baseline insulin levels were collected from the medical reports and analyzed. A statistical analysis of comparison of means was applied using data of glycated hemoglobin, the HOMA-IR index, fasting glycemia, and baseline insulin levels. A simple linear regression model was used to uncover the degree of variation of HOMA-IR during the preop phase, in relation to the postop phase, that could explain the DIT. Results The population studied consisted of 13 patients (mean age 40.8 ⫾ 6.7 years, 85% female). Table 1 compares the body composition and prevalence of co-morbidities among patients before and after RYGB surgery. At the preop time point, patients presented the following prevalence levels: 85% of insulin resistance, 60% of dyspnea, 50% of arthritis, 40% of steatosis, 40% of dyslipidemia, 30% of sleep apnea, 23% of back pain, and 20% of high blood pressure. At the postop time point, in 92% of the patients, all co-morbidities improved. However, 8% of patients still had back pain. At the preop time point, all patients consumed 100% of the standard meal. At the postop time point, 1 patient (8.0%) consumed half of the sandwich, 10 patients (75%) consumed 90% of the sandwich (removed all of the bread crust), and 2 patients (15%) consumed the entire sandwich. 6 patients (45%) consumed half of the drink, 1 patient (7%) consumed 20% of the drink (2 small sips, about 40 mL),
Table 2 Respiratory quotient, resting metabolic rate, and diet-induced Thermogenesis fasting values and values at 20 minutes after the standard meal Variable RQ Fasting Postprandial Δ RQ (postprandial-fasting) P value† Fasting RMR RMR (kcal) Weight-adjusted-RMR (kcal/kg) Postprandial RMR RMR (kcal) Weight-adjusted-RMR (kcal/kg) ΔDIT (fasting to postprandial) DIT (kcal) Weight-adjusted-DIT (kcal/kg)
Preoperative group
Postoperative group
.80 ⫾ .04 .81 ⫾ .04 .01 ⫾ .01 .2962
.78 ⫾ .07 .85 ⫾ .08 .07 ⫾ .01 o .0001
1952.3 ⫾ 82.3 17.75 ⫾ 2.70
1581.2 ⫾ 82.3 20.49 ⫾ 1.6
2067.3 ⫾ 295.11 18.77 ⫾ 2.94
1947.38 ⫾ 335.46 25.11 ⫾ 1.78
115.0 ⫾ 46.26 1.91 ⫾ 1.38†
366.15 ⫾ 46.26 4.62 ⫾ 1.88*
Difference between groups –.02 ⫾ .03 .04 ⫾ .04 .06 ⫾ .02 –371.0 ⫾ .0 2.74 ⫾ 1.1
P value* .390 .127 .018
o.01 o.01
–120 ⫾ 40.35 6.34 ⫾ 1.16
.273 o.01
251.15 ⫾ 65.42 2.71 ⫾ .5
o.001 o.001
* P values for the comparison between groups in the fasting and postprandial periods and changes from fasting to postprandial were calculated by mixedeffects ANOVA for repeated measurements. † P o .001 for the comparison of the postprandial value relative to the fasting value in the same group.
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Fig. 1. Difference in metabolic rate between the two time points 20 minutes after intake of a standard meal. RMR ¼ resting metabolic rate.
and the remaining patients consumed all of the drink (200 mL). Based on the weighted average, the postop time point, consumed approximately 240 kcal, whereas the same patients in the preop time point, consumed 270 kcal. The absolute RMR was higher in the preop time point, whereas the fasting weight-adjusted RMR was higher in the postop time point (both P o .01) (Table 2). The increase in absolute and weight-adjusted MRs (Fig. 1) at 20 minutes after the meal were higher in the postop compared with the preop time point (P o .01 for both). Thus, the absolute and weight-adjusted DITs were increased by 4300% and 4200%, respectively, after surgery compared with the preop time point (Table 2). In the postop time point, there was an inverse correlation between %EWL and DIT (r ¼ –.59, P ¼ .0320), although no correlation was observed with weight-adjusted DIT (r ¼ –.48, P ¼ .0942). There were no correlations between %BF and %LM with DIT and weight-adjusted DIT (P ¼ .5316 and P ¼ .6094; P ¼ .5324, and P ¼ .6071, respectively). The mean fasting and postprandial RQ values did not differ from each other in either the preop or postop time point. The RQ increased 20 minutes after the meal in the postop time point (P o .0001), but the RQ in the preop time point did not present any differences (P ¼ .2962). The difference between the time points was significant, being about 7 times higher for the postoperative time point (Table 2 and Fig. 2). Regarding the biochemical parameters, it was noted that the glycated hemoglobin, the HOMA-IR index, fasting glycemia, and baseline insulin levels diminished significantly in the postop time period (P o .05 for all parameters, except for HOMA-IR) (Table 3). From the results of the linear regression model, it was noted that the HOMA-IR index variation may explain the DIT in terms of the following equation: DIT ¼ 466:8553:73 Δ ΗΟΜΑ-ΙRDIT ¼ 466; 8553; 73 ΔHomalR
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Fig. 2. Difference between the time points in relation to RQ increase after intake of a standard meal. RQ ¼ respiratory quotirespiratory quotient.
This equation, however, was not statistically significant (P ¼ .40). Discussion The mechanisms underlying the proven efficacy of RYGB have not been clearly elucidated. To examine the role of EE components in the mechanism of weight loss/maintenance after RYGB, we measured the RQ, RMR, and DIT among the same 13 patients before and Z12 months after RYGB. The weight-adjusted RMR was increased after surgery. In the postop time point, the weight-adjusted RMR and DIT results 20 minutes after consumption of a standard meal were markedly increased compared with the preop time point. The postop time point showed an increased postprandial RQ compared with the fasting RQ, whereas the preop time point did not show this result. This study confirms the results of our transversal study showing an increased DIT and EE after RYGB [8]. Our first study showed a 200% increase in DIT among 2 groups: the preoperative (obese population) and postRYGB population. This study is a prospective one that shows an increased DIT among RYGB patients that is higher than was found in the transversal study [8]. Anatomic changes in the gastrointestinal (GI) tract can cause unexpected alterations in the secretion of the gut hormones that influence several neurotransmitters related to the energy intake/expenditure balance [2]. Patients who lose 10% of their original weight through diet modification and medication show a much lower EE compared with “always Table 3 Biochemical parameters of glucose metabolism Biochemical parameter
Preop time point
Postop time point
P value
Glycated hemoglobin HOMA-IR Fasting glycemia Baseline insulin levels
5.55 ⫾ .27 3,40 ⫾ 1.83 97.89 ⫾ 9.61 13.41 ⫾ 6.70
5.03 ⫾ .29 .63 ⫾ .43 83.67 ⫾ 4.82 3.11 ⫾ 1.91
.031 .083 .012 .016
HOMA-IR ¼ homeostatic model assessment-insulin resistance; Postop ¼ postoperative; Preop ¼ preoperative.
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lean” individuals (i.e., individuals of the same weight who never went through a dramatic weight change). One possible explanation for this drop in EE is the subregulation of certain hormones that maintain an active metabolism (e.g., PYY, leptin, GLP-1) and the simultaneous overproduction of hormones that increase hunger (e.g., ghrelin) [16]. Through adaptive thermogenesis, the brain perceives the restriction of food intake as an imbalance [17]. Researchers have questioned whether individuals have their own “equilibrium point” related to body fat mass, above or below which variations will provoke compensatory changes in the EE. Weight loss after RYGB does not appear to follow the same pattern of EE change as is observed in individuals who lose weight through diet modification. We previously showed that RYGB was associated with an increase in RMR, which has been shown to have a positive correlation with weight loss [7,8]. Similarly, in the present study, the weight-adjusted RMR was higher among patients at the postop time point. Several studies in humans and mice have also confirmed this result [5,7–9]. Nevertheless, criticisms concerning the analytical methods used and/or the comparison of EE between populations with different characteristics remain (i.e., between preop and postop groups). Recently, Nestoridi et al. analyzed several methods for obtaining EE data obtained in mice [5]. Regardless of the analytical method used, RYGB was associated with an increase in TEE and its components. RYGB-treated mice showed a 75% higher heat output compared with sham-operated and control animals. The results suggest that RMR is the main component responsible for the increased TEE after RYGB. Several other animal studies have indicated that about half of the weight loss achieved after RYGB can be explained by the RMR [18,19]. Accordingly, researchers have suggested a direct link between increased EE and weight loss/maintenance after bariatric surgery [5,7,9,20]. As another component of the EE, DIT has been proposed to contribute to the increase in TEE observed after RYGB. Studies in humans [8] and other animals [5] have shown that DIT is significantly higher after RYGB, compared with the preop (obese) time point. In the present study, 20 minutes after food intake, the absolute and weight-adjusted DIT values were 4300% higher in the postop compared with the preop time point. Stylopoulos et al. observed a 30% higher increase in VO2 during and after episodes of food intake in RYGB-treated compared with sham-operated mice [5]. Regression analysis suggested that DIT increased with increasing food intake, with a higher correlation in the RYGB group compared with the sham-operated group. Every gram of food increased EE by 12.416 kcal after RYGB versus 7.659 kcal after sham operation [5]. Our findings are consistent with these previous results and with the hypothesis that RYGB is associated with an increase in DIT.
Nevertheless, the association between obesity and a lower DIT remains controversial [21,22]. Tentalouros et al. found that DIT did not differ between lean and obese individuals after the consumption of isocaloric diets [23]. Studies of previously obese individuals who had lost weight by nonsurgical methods suggested that reduced DIT in obesity may not be a primary pathogenic factor in human obesity, because it was reversed by weight reduction [24,25]. To gain insight into the impact of the DIT, we estimated the average proportion of the TEE that was comprised by DIT among our study participants. We considered the average value of RMR in the preop and postop time points (1952.3 and 1581.2 kcal per day, respectively) and calculated TEE by the formula TEE = TMR AF, with an activity factor (AF) of 1.2 for a sedentary population. We estimated average TEE values of 2342.8 and 1897.4 kcal per day at the preop and postop time points, respectively. Thus, the preop and postop DIT values corresponded to 5% and 19%, respectively, of the TEE (Table 2). The postoperative DIT is higher than the established value for healthy weight populations. We hypothesize that RYGB increases DIT to levels that are higher than those of “always lean” individuals. Some other factors can be related to the increased DIT among RYGB patients. The sympathetic nervous system (SNS) has been proposed as the efferent pathway responsible for the regulation of adaptive thermogenesis [17]. Food intake may stimulate the cerebral channels that activate the SNS, which in turn stimulate the metabolically active tissues (e.g., the muscles) to increase the EE, thus protecting the body from a state of obesity. Most cases of obesity are associated with low activity of the SNS [19]. The mechanism of RYGB seems to involve the activation of the SNS, which can contribute to the increased EE. Some authors have also indicated that changes in the flow of bile due to anatomic alterations of the GI tract after surgery may partly explain the metabolic results of RYGB [26]. The altered GI anatomy affects the delivery of bile acids to the ileum terminal and plasma. These changes could stimulate the intestinal L-cells, resulting in the increased secretion of GLP-1 and a consequent earlier increase in insulin secretion after RYGB [27]. We observed a significant increase in postprandial RQ among patients in the postop but not the preop time point. Similarly, Stylopoulos et al. observed a higher postprandial RQ in the RYGB-treated animals [5].They interpreted this result as stemming from the acquisition of greater metabolic flexibility after surgery, probably due to improved insulin sensitivity. Interestingly, improvements in insulin sensitivity have been reported to affect DIT [10]. In our study, we observed a significant improvement of the parameters related to glucose metabolism in the postop phase, including the HOMA-IR index, thus indicating a significant improvement of insulin resistance. In the analysis of the
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linear regression model, it was seen that the HOMA-IR index variation may explain the DIT variation in such a way that a relation can be established. This relation, however, was not statistically significant in this study. Lower postprandial RQ values in obese individuals have also been attributed to increased fat oxidation [28,29], which is a compensatory mechanism by the obese body to restore the balance of body fat and to avoid additional weight gain [28]. The results of this and other studies suggest that GI tract rearrangement through RYGB may change the physiology of the energy balance and lead to a substantial EE increase. Some receptive mechanisms may detect these changes in the alimentary tract and relay a thermogenic signal to effector organs through the central nervous system [6]. Thus, RYGB appears to create an energy deficit in which increased EE is the primary conductor for the decrease in the amount of body fat [5]. Conclusion Increased EE may vitally contribute to the loss/maintenance of weight after RYGB. Based on our findings, we tentatively hypothesize that RYGB may establish a new “equilibrium point” for the organism after the imbalanced state of obesity. Further studies are needed to identify the primary mechanism underlying the EE increase after RYGB and to determine whether this EE increase continues over the long term. References [1] Feldmann HM, Golozoubova V, Cannon B, Nedergaard J. UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab 2009;9:203–9. [2] Rao RS. Bariatric surgery and the central nervous system. Obes Surg 2012;22:967–78. [3] Carey DG, Pliego GJ, Raymond RL, Skau KB. Body composition and metabolic changes following bariatric surgery: effects on fat mass, lean mass and basal metabolic rate. Obes Surg 2006;16:469–77. [4] Carrasco F, Papapietro K, Csendes A, et al. Changes in resting energy expenditure and body composition after weight loss following Rouxen-Y gastric bypass. Obes Surg 2007;17:608–16. [5] Nestoridi E, Kvas S, Kucharczyk J, Stylopoulos N. Resting energy expenditure and energetic cost of feeding are augmented after Rouxen-Y gastric bypass in obese mice. Endocrinology 2012;153: 2234–44. [6] Meguid MM, Glade MJ, Middleton FA. Weight regain after Roux-enY: a significant complication related to PYY. Nutrition 2008;24: 832–42. [7] Faria SL, Faria OP, Buffington C, de Almeida Cardeal M, Rodrigues de Gouvêa H. Energy expenditure before and after Roux-en-Y gastric bypass. Obes Surg 2012;22:1450–5. [8] Faria SL, Faria OP, Cardeal Mde A, de Gouvêa HR, Buffington C. Diet-induced thermogenesis and respiratory quotient after Roux-en-Y gastric bypass. Surg Obes Relat Dis 2012;8:797–802.
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