Weight loss through dietary energy restriction (ER) is an effective method to promote fat mass loss. However, a negative consequence of ER is the loss of lean body mass (LBM), particularly skeletal muscle, which is induced by an imbalance between rates of muscle protein synthesis (MPS) and muscle protein breakdown (MPB). Increased protein intake and resistance exercise (RE) during ER promote the retention of LBM. Currently, the relative contribution of MPS and MPB to diet-induced LBM loss, and the effect of protein intake and RE on these variables is not well characterized. In Study 1 we compared the acute (hour-to-hour) MPS response to the ingestion of whey and soy protein, before and after 14 days of ER (-750kcal/d). The results of Study 1 indicated that whey protein was superior to soy protein in stimulating MPS before and after ER. In Studies 2 and 3 we examined the effect of 10 days of a marked 40% energy restriction on acute postabsorptive MPS and MPB and integrated (day-to-day) MPS. Using unilateral RE, we examined the effects of protein (1.2g protein/kg/g or 2.4g protein/kg/d) at rest and in combination with resistance exercise. The results of Study 2 showed that there were no changes in acute MPB or markers of proteolysis with ER. The results of Study 3 indicated that acute and integrated MPS were reduced following ER at both protein levels (1.2g protein/kg/g or 2.4g protein/kg/d), but RE was able to prevent this decline. Taken together, these studies demonstrate that reductions in MPS are the likely reason for LBM loss during short-term dietary energy restriction, and strategies such as RE and high quality protein intake can help to prevent the decline in MPS. These findings provide information for the design of weight loss programs that wish to preserve skeletal muscle. / Thesis / Doctor of Philosophy (PhD) / Dietary energy restriction is commonly used to promote weight/fat loss; however, a potential negative consequence of dietary energy restriction is the loss of skeletal muscle mass. This thesis examines the impact of dietary energy restriction on the two processes that regulate skeletal muscle mass: muscle protein synthesis and muscle protein breakdown. Additionally, this thesis investigates the role of protein intake and resistance exercise as strategies to prevent diet-induced changes in muscle protein synthesis and breakdown. The studies within this thesis demonstrate that during energy restriction rates of muscle protein synthesis are reduced whilst muscle protein breakdown is unchanged. Importantly, consuming high quality protein such as whey protein and performing resistance exercise prevent the diet-induced decline in rates of muscle protein synthesis. These findings provide new and insightful information for the design of weight loss programs that aim to preserve skeletal muscle whilst also promoting the loss of body fat.

Mechanical unloading and food restriction (FR) are leading causes of bone loss, which increase the risk of fracture later in life. Leptin, a 16kDa cytokine like hormone principally produced by white adipocytes, may be involved in bone metabolism with physiological or mechanical changes causing bone loss. The hypotheses of the first study were aimed at determining if serum leptin is reduced by unloading or FR. The serum leptin level reduced by unloading or by global FR, is associated with the decline in bone formation rate. It was conjectured that decreased serum leptin may be due to reduced adipocyte number/size and/or sympathetic nervous system (SNS) activation of betaadrenoreceptors with unloading or FR, inhibiting the release of leptin from adipocytes. In the second experiment, we tested whether leptin or beta-adrenoreceptor blockade attenuates bone loss during unloading and whether such an effect due to beta blockade is associated with changes in serum leptin level. Beta-blockade mitigated unloading induced reduction in serum leptin and also beta blockade was as effective as leptin administration in mitigating a reduction in cancellous bone mineral density with unloading through both stimulation of bone formation and suppression of resorption. It was previously demonstrated that energy restriction (ER) is a major contributor to the bone loss during global FR. In the third study, we tested whether beta- blockade attenuates bone loss during ER and whether such an effect is associated with changes in serum leptin level and leptin localization in bone tissues. Beta blockade attenuated the ER induced reduction in serum leptin level, cancellous bone mineral density and bone formation rate, and also abolished the ER induced increase in bone resorption. Reduction in leptin expression in bone marrow adipocytes observed with ER was attenuated by beta-blockade. Reduction in the number of cells (bone lining cells, osteocytes and chondrocytes in cartilage) which are stained positive for leptin was also attenuated by beta-blockade. Collectively, these data identify circulating leptin effects on preventing bone loss during mechanical unloading or energy restriction. Also beta blockade is associated with mitigating reduction in serum leptin and subsequently with mitigating reduction in bone mass with unloading or ER.

Introduction Weight loss practices are commonly used by athletes who perceive lower levels of body fat and higher fat-free mass (FFM) as advantageous for physical performance. High protein diets have been associated with greater fat loss and greater retention of lean mass during periods of energy restriction (ER) in individuals with obesity. However, less is known about the effects of high protein diets in trained individuals during ER. It has been proposed that leaner individuals are more at risk of losing FFM during ER than individuals with overweight. The current ACSM recommendation for protein intake in active individuals is 1.2-1.7g/kg. However, it is unclear whether higher intakes are necessary to maximize FFM retention and maximize physical performance in athletes undergoing periods of ER. Objective Our primary objective was to determine whether high protein intakes could maximize FFM retention in trained individuals during periods of ER. We also aimed to determine whether higher protein intakes are superior at maintaining physical performance. Lastly, we aimed to determine whether high protein intakes could mitigate adaptive thermogenesis (AT) in response to ER. Methods Twelve college aged athletes (6 women and 6 men) from various sports were analyzed in this study. They underwent a 6-week 25% reduction in energy intake along side a 3-day full body resistance training program. Participants were randomly assigned to a low (~1.2g/kg), moderate (~1.6g/kg) or high (~2.2g/kg) protein group. Baseline and post-intervention measures were obtained via Dual X-ray absorptiometry (DXA), isotopic water dilution, indirect calorimetry, dietary records and strength based physical testing. Results Our results indicate a main effect of the intervention on fat mass reductions (19.66 ± 9.05 kg vs 18.02 ± 8.07 kg) (p = 0.016) despite non-significant reductions in body weight (p = 0.059). No significant changes in FFM were observed (p = 0.307). Significant increases in chest press 5RM strength (43.18 ± 14.95 kg vs 48.86 ± 17.46 kg) and chin-up maximal repetition (4.75 ± 5.64 vs 6.08 ± 6.56) were observed across all groups from baseline to post-intervention (p < 0.05). No significant increases in strength were noted on lower body movements. Resting energy expenditure (REE) was significantly reduced after the 6-week intervention (1743.52 ± 295.74 kcal vs 1655.18 ± 263.23 kcal) (p = 0.006). What is more, post-intervention measured and predicted REE were also significantly different (1655.18 ± 263.23 kcal vs 1747.92 ± 263.20) (p = 0.012). No significant effects of protein were noted on any of the outcomes. Conclusion Our preliminary results indicate that the ACSM recommendation of 1.2-1.7g/kg is sufficient for most athletes even during periods of ER to maintain FFM and physical performance. We also found the possibility of early AT in that population independently of protein intake. In fact, REE was reduced by ~100 kcal/day more than predicted despite minimal weight loss and relative preservation of FFM.

Two thirds of American adults are overweight and almost half of those qualify as obese. Obesity independently increases risk for cardiovascular disease (CVD), type II diabetes (T2D), and hypertension; thus, strategies to reduce risk in this population are desperately needed. Oxidative stress and inflammation are two perpetuators of these chronic diseases that are often elevated in obesity. Interventions that target reductions in oxidative stress and inflammation may help to reduce co-morbidities associated with obesity. Weight loss is shown to reduce oxidative stress and inflammation. However, the composition of and food choices within the weight loss diet may influence the response of these factors to weight loss, and has not been adequately assessed. We first tested whether there were differential effects of a conventional low-fat, high carbohydrate weight loss diet (LF) and the Atkins diet (a popular low carbohydrate, high fat diet (HF)) on oxidative stress and inflammation. We demonstrated that HF raised C-reactive protein (CRP) levels relative to LF in overweight and obese women over four weeks. This finding raises questions as to the long term safety of the HF eating plan in terms of CVD risk. We next examined the role of oxidative stress in the HF diet-induced increase in inflammation by evaluating the effects of an antioxidant supplement versus a placebo in conjunction with HF in overweight and obese men and women. Although our full hypothesis was not supported, as oxidative stress did not increase with HF, the trend for a differential effect on CRP when antioxidants were consumed is provocative. It suggests that future research on the connection between oxidative stress, the macronutrient content of the diet, and inflammation in obesity is warranted. Regarding the effects of specific fats, epidemiological research shows that diets high in saturated fat (SFA) are associated with higher CVD risk while diets higher in omega 3 fats (n-3FA) with lower CVD risk. However, the acute effects of these fats on indices of inflammation and oxidative stress are less understood, particularly in the overweight/obese population. As the majority of the time is spent in the postprandial state, the acute responses to high fat meals are gaining attention for their contribution to endothelial dysfunction and CVD. We showed that acute meals high in SFA increased a marker of endothelial activation (ICAM-1) which could contribute to the atherogenic associations with SFA. Conversely, including n-3FA in a high fat meal acutely enhanced NF-κB activation in circulating mononuclear cells; however, there were no increases in any inflammatory proteins measured over the 6 h postprandial period. It is apparent that dietary macronutrients can influence factors associated with chronic disease in overweight and obese individuals. The evidence presented here may help to refine dietary recommendations for this population. / Ph. D.

This study examined the effects of carbohydrate supplementation on resistance exercise performance, cortisol levels, and creatine kinase levels in trained males undergoing energy restriction. Sixteen experimental subjects were randomly assigned to a carbohydrate (C, n=8) or placebo group (P, n=8). The remaining six subjects served as controls (N). Performance tests were done before (Trials 1 and 2) and after (Trial 3) energy restriction. Experimental subjects consumed a low calorie formula diet for three days (18 kcal-1 kg-1 d-1). They had blood drawn before and after T2 and T3. For T3, they consumed either a carbohydrate (1g kg-1) or a placebo beverage 30 minutes before exercise. There was a significant increase in resting cortisol levels following energy restriction. CK levels were significantly elevated after exercise, suggestion muscle damage. Carbohydrate supplementation had no effect on blood glucose, cortisol, creatine kinase, or RPE. The number of repetitions performed during the final set of bench press showed significant interaction between groups and time. P and N increased the number of repetitions performed from T2 to T3 (15.0 + 1.4 to 17.3 + 0.8 for P, 15.0 + 2.7 to 16.7 + 2.3 for N). C decreased the number of repetitions performed 17.6 + 0.7 to 17.3 + 1.0). The number of repetitions performed during the final set of leg extensions showed no interaction between groups and time (p=0.801). This study did not support a benefit of consuming carbohydrate prior to resistance exercise for dieting athletes but illustrates that energy restriction increases a catabolic hormone. / Master of Science

It is known that during fluid restriction, obligatory water losses continue and hypohydration develops and that restricted energy intake leads to a concomitant restriction of all other dietary components, as well as hypohydration, but the specific effects of periods of fluid and/ or energy restriction on fluid balance, electrolyte balance and exercise performance have not been systematically described in the scientific literature. There were two main aims of this thesis. Firstly, to describe the effects of periods of severe fluid and/ or energy restriction on fluid and electrolyte balance; secondly, to determine the effect of electrolyte supplementation during and after energy restriction on fluid and electrolyte balance as well as energy exercise performance. The severe restriction of fluid and/ or energy intake over a 24 h period all resulted in body mass loss (BML) and hypohydration, but whilst serum osmolality increases during fluid restriction (hypertonic hypohydration), serum osmolality does not change during energy restriction (isotonic hypohydration), despite similar reductions in plasma volume (Chapter 3). These differences in the tonicity of the hypohydration developed are most likely explainable by differences in electrolyte balance, with fluid restriction resulting in no change in electrolyte balance over 24 h (Chapter 3) and energy restriction (with or without fluid restriction) producing significant reductions in electrolyte balance by 24 h (Chapter 3; Chapter 4; Chapter 5; Chapter 6; Chapter 7). Twenty four hour combined fluid and energy restriction results in large negative balances of both sodium and potassium, and whilst the addition of sodium chloride to a rehydration solution ingested after fluid and energy restriction increases drink retention, the addition of potassium chloride to a rehydration solution does not (Chapter 4). Supplementation of sodium chloride and potassium chloride during periods of severe energy restriction reduces the BML observed during energy restriction and maintains plasma volume at pre-energy restriction levels (Chapter 5; Chapter 6; Chapter 7). iv These responses to electrolyte supplementation during energy restriction appear to be related to better maintenance of serum osmolality and electrolyte concentrations and a consequential reduction in urine output (Chapter 5; Chapter 6; Chapter 7). Additionally, 48 h energy restriction resulted in a reduction in exercise capacity in a hot environment and an increase in heart rate and core temperature during exercise, compared to a control trial providing adequate energy intake. Whilst electrolyte supplementation during the same 48 h period of energy restriction prevented these increases in heart rate and core temperature and exercise capacity was not different from the control trial Chapter 8). In conclusion, 24-48 h energy restriction results in large losses of sodium, potassium and chloride in urine and a large reduction in body mass and plasma volume and supplementation of these electrolytes during energy restriction reduces urine output, attenuates the reduction in body mass and maintains plasma volume and exercise capacity.

Moderate energy restriction in young, exercising women attenuates the positive effects of exercise on bone density. Studies have shown that in the absence of adequate levels of circulating estrogen, there may not be enough functional estrogen receptor-a (ER-a) to respond adequately to loading. The experiment described in this document is significant because this model has not been explored under conditions of energy restriction (EnR) which are known to reduce circulating estrogen levels; it has been tested only in ovariectomized animals. The central hypothesis of this research is that reductions in estrogen due to EnR limit the ability of bone to respond to mechanical loading (LOAD) through a down-regulation of ER-a. Study one determined which nutrient’s (calcium or energy) restriction (-40 percent) had the greatest negative effects on the skeletal integrity of exercising female rats and whether exercise (EX) could mitigate these deleterious changes. EnR caused detrimental effects in many of the structural properties of bone; however EX attenuated losses in cancellous bone. Study two ascertained whether EX maintained cancellous bone mass in female rats subjected to graded EnR (-20 or -40 percent) and whether changes in endocrine factors were related. EX preserved cancellous bone volume and osteoblast activity under both levels of EnR, in addition to total body lean mass and bone mineral content. A similar maintenance of serum insulin-like growth factor and estradiol occurred in the EX EnR(40 percent) group suggesting that these changes may be related to the protective effects of EX. Study three determined the effects of 40 percent EnR on bone formation rate to LOAD in young adult female rats and tracked alterations in ovarian function (estradiol). Although higher than non-loaded animals, the response of bone to LOAD in EnR animals was dampened in comparison to energy-replete animals. The experiments described in this document are significant because these are the first experiments to explore the relationship between EnR and estrogen levels on cancellous bone response to LOAD. This is particularly important for physically active, energy restricted women because cancellous bone in these women will not experience the same effects of loading which can increase their risk for developing osteoporosis.

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Bakgrund: Övervikt och fetma ökar exponentiellt i alla samhällsklasser i alla delar av världen idag. Det kan orsaka lidande och förtida död för de drabbade. Risken att drabbas av våra vanligaste vällevnadssjukdomar som hjärt- och kärlsjukdom, typ 2 diabetes och neurodegenerativa sjukdomar som Alzheimers sjukdom ökar vid övervikt och fetma. Det i särklass mest effektiva sättet att gå ned i vikt är genom att minska sitt kaloriintag. För att behålla en viktnedgång behövs beteendeförändringar, stöttning och en långsiktig plan. Syfte: Syftet med studien är att undersöka om intermittent kalorirestriktion (CR) är mer effektivt än kontinuerlig CR när det gäller viktreduktion och bibehållande av ny vikt. Metod: En litteraturstudie genomfördes där fyra olika parallellstudiers resultat sammanställs. Parallellstudierna jämför effektiviteten av intermittent och kontinuerlig CR på viktreduktion och bibehållande av ny vikt. Resultat: I tre av de fyra studier som undersökts kan inga skillnader i effektivitet uppvisas mellan intermittent och kontinuerlig CR när det gäller viktreduktion och bibehållande av ny vikt över tid. En av studierna fann att intermittent CR, i form av ”week on, week off” två veckor i taget är mer effektiv när det gäller viktreduktion efter 16 veckors interventionsfas samt 6 månader senare. Slutsats: Som alla metastudier jag läst och de flesta studier på ämnet kan ingen skillnad i effektivitet mellan intermittent och kontinuerlig CR uppvisas gällande viktreduktion. Inte heller verkar den ena vara överlägsen den andra när det gäller bibehållande av ny vikt. Fler studier över längre tidsspann med fler deltagare krävs för att kunna dra slutsatser om vilken typ av CR som är mest effektiv på lång sikt. / Background: Overweight and obesity are increasing exponentially in all social classes in all parts of the world today. It can cause suffering and premature death to those affected. The risk of suffering from our most common well-being diseases such as cardiovascular disease, type 2 diabetes and neurodegenerative diseases such as Alzheimer's disease increases with overweight and obesity. By far the most effective way to lose weight is by reducing your calorie intake. To maintain a weight loss, behavioural changes, support and a long-term plan are needed. Purpose: The purpose of the study was to investigate whether intermittent calorie restriction (CR) is more effective than continuous CR in terms of weight reduction and maintenance of new weight. Method: A literature study was conducted where the results of four parallel studies were put together. The parallel studies compare the effectiveness of intermittent or continuous CR on weight reduction and maintenance of new weight. Result: In three of the four studies examined, no differences in effectiveness can be demonstrated between intermittent and continuous CR in terms of weight reduction and maintenance of new weight over time. One of the studies found that intermittent CR, in the form of "week on, week off" two weeks at a time, is more effective in weight reduction after 16 weeks of intervention and 6 months later. Conclusion: Like all meta-studies and most studies on the subject, no difference in effectiveness between intermittent and continuous CR can be demonstrated in terms of weight reduction. Nor does one seem superior to the other when it comes to maintaining new weight. More studies over longer time spans with more participants are required to be able to draw conclusions about the type of CR that is most effective in the long term.