The role of metabolic rate and substrate utilization in the maintenance of body weight, body composition and insulin sensitivity
Doctoral Thesis
2019
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Obesity treatment requires approaches that target the reduction of body weight and fat mass. The improvement of cardiorespiratory fitness (CRF), metabolic flexibility and insulin sensitivity also contribute towards reducing obesity-associated risk factors. While energy restriction alone results in significant weight loss, exercise-only interventions provide small amounts of weight loss and prevent weight gain, while also improving many of the other variables targeted in obesity treatment. Once achieved however, successful weight-loss maintenance is challenging, with many individuals subsequently experiencing weight regain. The main objectives of this thesis were to explore the role of metabolic rate and substrate utilization in influencing body weight, body composition and insulin sensitivity. This twopart thesis hypothesised that: 1) exercise training, without dietary intervention, will improve metabolic rate and substrate utilization in a sedentary obese population, and that this would be associated with improved body composition, insulin sensitivity and CRF; and 2) metabolic rate, substrate utilization and insulin sensitivity are altered through weight loss/regain, predisposing these individuals to weight regain and impairing successful weight-loss maintenance. In Part 1 of this thesis a 12 week exercise intervention in sedentary, obese (BMI 30-40kg.m-2 ) black South African (SA) women (aged 22, IQR 21-24 years) was completed. Previous studies have shown that black SA women present with very low CRF, a key indicator of increased risk for non-communicable disease (NCD), and have a high prevalence of obesity and insulin resistance (IR). They are thus at increased risk for developing type 2 diabetes (T2DM). Furthermore, physiologically black SA women have also been shown to have less visceral adipose tissue (VAT) and more peripheral gluteal fat mass (FM) compared to their white counterparts, but are paradoxically more IR. Despite this presentation, to date there has been no supervised exercise intervention studies undertaken in this very high risk population group. The first study of this thesis (chapter 2) aimed to assess the effects of the exercise intervention on changes in CRF, energy expenditure (EE) and substrate utilization, both at rest and during steady-state exercise compared to non-exercising controls. It also assessed baseline and changes in these measurements in relation to changes in body composition. Black SA women (BMI 30-40 kg.m-2 , 20-35 y) were recruited and randomized into control (CTL, n=15), or exercise (EXE, n=20) groups. The CTL was instructed to maintain usual activity while the EXE completed 12 weeks of combined resistance and aerobic exercise training (4d.wk-1 , 40-60min.d-1 @ >70% peak heart rate (HRpeak)). At pre-intervention, a treadmill-based CRF test, measuring peak volume of oxygen consumption (VO2peak), was carried out. Thereafter resting and steady state exercise (50% VO2peak) energy expenditure (EE) and respiratory exchange (RER) were measured along with body composition (dualenergy X-ray absorptiometry (DXA)). A frequently sampled intravenous glucose tolerance test (FSIGT) was also carried out to determine changes in insulin sensitivity. These tests were repeated at post-intervention testing with steady state testing being carried out both at the same relative intensity (50% post-testing VO2peak) and the same workload (treadmill speed and gradient) as used for pre-testing. Dietary intake (4d diary) and daily step-count (ActivPAL) data was collected at pre-testing, 4, 8 & 12 weeks. Results showed that all participants had very low baseline CRF, falling below the 20th percentile previously shown in African American women. In response to exercise training, CRF increased by ≈11% and rates of fat oxidation during steady-state exercise were improved, while in controls these remained unchanged. Compared to CTL, EXE also showed small but significant reductions, in weight, as well as BMI, waist (WC) and hip (HC) circumferences. In contrast weight, BMI and WC increased in non-exercising controls. Gynoid FM (absolute FM and as a proportion of total FM), rather than visceral adipose tissue (VAT), was reduced in exercise participants. Within the exercise group higher baseline fat oxidation rates during steady state exercise and lower resting carbohydrate oxidation rates explained 61.6% (p< 0.001) of the variability in changes in gynoid FM in response to 12 weeks of exercise training in this group. In conclusion, exercise training improved CRF and fat oxidation rates during submaximal exercise in sedentary, obese black SA women. Higher fat oxidation rates during steady state exercise and lower resting carbohydrate oxidation rates at baseline were associated with the mobilization of gynoid FM in response to exercise training, rather than VAT as is typically shown in exercise interventions. This novel finding potentially represents an ethnic/gender specific response to exercise training. Further studies are needed to confirm this. Similar exercise training programs, that are sustainable over the long term, would therefore be beneficial in achieving meaningful increases in CRF while also supporting weight management and body composition improvements in this high risk population group. Using data from the exercise intervention in obese black SA women, the second study of this thesis (chapter 3) investigated inter-individual variability in the CRF response (∆VO2peak) to exercise training. The study specifically aimed to compare changes in EE and substrate utilization at rest and during steady state exercise, body weight and composition and insulin sensitivity between high and low CRF responders to the 12 week intervention. Furthermore it aimed to explore associations between baseline metabolic rate, EE and substrate utilization and subsequent changes in CRF in response to exercise training, to determine if baseline variability in these measures contributed to inter-individual variability in the CRF outcome. Within the exercise group, high inter-individual variability in CRF response to exercise training was identified. Based on a median split in ∆VO2peak, high responders (HRS, n=10) increased CRF by 21.7 ±10.0% (p< 0.001) compared to no change in both low responders (LRS, n=10; +0.6 ±6.3%, p=0.748) and CTL (-3.2 ±10.8%, p=0.195). This occurred despite all groups having similar baseline VO2peak and the exercise group receiving the same exercise dose (number of exercise sessions attended and average intensity of the exercise sessions). At baseline, HRS derived ≈62% of energy expenditure from fat oxidation during steady-state exercise compared to just 41% in LRS, who relied to a greater extent on carbohydrate oxidation. Furthermore, HRS were ≈11 kg lighter than LRS. There was also a positive association between BMI and RER such that individuals with higher BMI showed lower fat utilization (i.e., higher RER). HRS reduced gynoid FM whereas in LRS this remained unchanged. This is in line with the findings of the previous chapter which showed that exercise-related reduction in gynoid FM was associated with greater baseline fat oxidation. LRS showed improvements in insulin sensitivity compared to CTL and HRS. Using regression analysis including the exercising participants, greater baseline carbohydrate oxidation rates both at rest and during steady state exercise predicted a poorer CRF to exercise training, explaining 37.5% of the variability in ∆VO2peak. To the best of my knowledge, this is the first study to show that baseline variability in substrate utilization among sedentary obese individuals contributes towards explaining the variability in the CRF response to exercise training. However, further studies are required to confirm these results. Together, these studies show that higher fat oxidation rates are necessary for FM mobilization, while correspondingly reduced reliance on carbohydrate oxidation both at rest and during exercise supports improvements in CRF in response to exercise training. These findings add to a growing body of research aimed at explaining inter-individual variability in exercise intervention outcomes and may contribute to individualizing the exercise prescription. Part 2 of this thesis used a cross-sectional approach and investigated firstly whether there was evidence for metabolic adaptation to weight loss/regain in response to long term weight maintenance, potentially predisposing individuals to future weight gain/regain. Secondly, I investigated whether insulin sensitivity is altered as a result of prior weight loss history, or whether successful weight loss restores insulin sensitivity to levels that are comparable to phenotypically similar controls with no weight loss history. Weight stable, BMI-matched South African women aged 20-45 years with or without a history of prior weight loss were screened and recruited. Four groups were defined as follows: Weight Reduced (RED, n=15) - lost at least 15% of body weight & maintained a reduced weight (BMI ≤ 27kg.m-2 ) for over 12 months (15% of body weight), but relapsed back to overweight or obese (BMI ≤ 27kg.m-2 ); and overweight or obese (BMI ≤ 27kg.m-2 ) stable-weight controls (OSW, n=11) - no history of significant weight loss. The first study in Part 2 (Chapter 4) compared metabolic rate and substrate utilization in RED and REL to their respective BMI-matched controls with no weight loss history, both at rest and in response to a high fat meal challenge. Metabolic rate and substrate utilization were measured both at rest, immediately after consumption of the high fat test-meal and every hour thereafter for three hours. Dietary intake (3 x 24h recalls) and physical activity (ACTi Graph GT3X accelerometer worn for 7 days) data was collected and body composition was measured (bioelectrical impedance, BIA). Questionnaires were also completed covering weight history, socio-economic status and eating behaviour. Results showed that there was no difference in either resting EE or substrate utilization between the RED and REL compared to the respective BMI-matched controls, after accounting for fat free mass (FFM). The TEF, postprandial EE (absolute and per kg FFM), post-prandial energy balance, RER, fat oxidation rate and post-prandial fat balance were similar between RED and REL compared to their respective controls, indicating that there was no evidence of metabolic adaption to weight loss. However, successful weight-loss maintainers did show behavioural strategies that may have counteracted weight-loss associated adaptive thermogenesis and supported weight-loss maintenance. These individuals had manipulated macronutrient intake (increasing protein and reducing carbohydrate intake), were more physically active, exhibiting less sedentary behaviour and increased moderate and vigorous activity, and had greater fat free soft tissue mass (FFSTM). While the presence of adaptive thermogenesis is not disputed in these results, the distinct physiological and behavioural differences together observed in the RED may have been instrumental in attenuating weight-loss associated declines in EE, shown to persist into weight-loss maintenance. Together with these lifestyle strategies, weight reduced individuals also reported greater dietary restraint in comparison to controls. This is surprising after such a significant period of weight-loss maintenance (median weight-loss maintenance: 30 months) and highlights the ongoing challenges to maintain reduced weight. These findings contribute to the relatively smaller body of research into the longer-term persistence of weight-loss associated adaptive responses in comparison to that covering the acute weight loss phase. It also highlights strategies that may be effective in counteracting metabolic adaption to weight loss. As such, these strategies may warrant inclusion as part of weight-loss maintenance programs as they potentially help to reduce the risk for weight regain as a result of weight-loss associated adaptive thermogenesis. The next study in Part 2 of the thesis (Chapter 5) aimed to examine the impact of successfully maintained weight loss and weight-loss relapse on insulin sensitivity compared to BMImatched controls without a weight loss history. Predictors of variability in insulin sensitivity were also explored. Following the measurement of resting metabolic rate and substrate utilization a 75g oral glucose tolerance test was used to determine fasting and 2hr plasma glucose and insulin. The Homeostatic Model Assessment (HOMA-IR) and insulin sensitivity index (ISI(0,120)) were used to assess insulin sensitivity. A novel finding of this study was that successfully maintained, weight-reduced individuals displayed enhanced measures of insulin sensitivity (lower HOMA-IR and higher ISI(0,120) measurements), compared to all other groups, including BMI-matched controls with no weight loss history. Previously studies have investigated changes in insulin sensitivity in response to weight loss and in weight-loss maintenance, but not necessarily in comparison to individuals without a weight loss history as defined by this study protocol. With weight regain however, insulin sensitivity measures for REL were not different compared to either LSW or OSW, showing that enhanced insulin sensitivity accompanying weight loss is likely reversed with weight regain. Prior weight history, fasting substrate utilization, measures of body weight and composition, protein intake per kilogram, physical activity and CRF were all associated with measures of insulin sensitivity. Using these variables in regression models, ≈60% of the variability in insulin sensitivity in both HOMA-IR and ISI(0,120). Weight loss and weight regain history followed by fasting RER were the most significant independent predictors of insulin sensitivity. In conclusion, a novel finding was that successfully weight-reduced individuals are more insulin sensitive than their BMI-matched controls with no weight loss history, independent of dietary intake and physical activity. This remains evident even after significant periods of maintaining the reduced weight. Weight loss maintenance programs are essential to retaining metabolic benefits acquired through weight loss. Remaining physically active by reducing sedentary behaviour and in particular including small amounts of vigorous physical activity significantly predicts improved insulin sensitivity. This thesis includes a number of novel findings. In Part 1, we showed that in response to exercise training gynoid FM, rather than VAT, was reduced in sedentary obese black SA women undergoing a 12 week exercise intervention, which may represent an important ethnic/gender specific response. We also showed that substrate utilization plays an important role in altering body composition and CRF in response to an exercise intervention. Greater fat oxidative capacity at the outset resulted in an enhanced ability to reduce gynoid FM in response to exercise training. Furthermore, a greater reliance on carbohydrate rather than fat oxidation during baseline testing predicted a poorer CRF response. Identification of individuals with a lower capacity for fat oxidation at the outset of an exercise intervention may therefore allow for a more targeted exercise prescription, which may in turn improve outcomes of exercise interventions. The lack of clinically significant weight loss suggests that future exercise interventions should prescribe exercise EE of sufficient magnitude to achieve weight loss and emphasize adherence to this prescription or include some dietary restriction. Education around the possible adaptive responses to increased EE and the imposed energy deficit, highlighting the strategies employed by weight reduced individuals from Part 2 of this thesis, may help to attenuate potential metabolic adaption to increased EE and further improve the weight loss outcomes of exercise-only interventions. It may also help to inform weight-loss maintenance programs to assist individuals to maintain the reduced weight following weight loss. The enhanced insulin sensitivity in weight reduced individuals as shown in Part 2, may potentially represent an ongoing and persistent adaptive response to weight loss that may in itself increase the risk for weight-loss relapse. Education around the physiological adaption to significant weight loss and emphasizing strategies that may counteract this metabolic adaptation may improve the efficacy of both weight-loss and weight-loss maintenance programs.
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Clamp, L.D. 2019. The role of metabolic rate and substrate utilization in the maintenance of body weight, body composition and insulin sensitivity. . ,Faculty of Health Sciences ,Department of Human Biology.