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<p>A high-fat diet can adversely affect bone mechanical properties, but it is unknown how these changes affect bone adaptation. Bone adaptation occurs in response to strain-related mechanisms, and strain in the bone is affected by the size and mechanical properties of the bone.The purpose of this study was to compare the strain during loading in femurs from rats fed a high-fat (HF) or normal control (NC) diet. At 3 weeks of age, male and female Wistar rats were randomly assigned to receive a NC (NC–17% fat; N=8 per gender) or HF diet (HF–41% fat; N=8 per gender) until termination (39 weeks of age). Right femurs were loaded <em>ex vivo</em> in 3-point bending to physiologic levels and mechanical strain was measured. The mechanical properties of the left femurs were determined by 3-point bend tests to failure. The dietary effects were limited in both genders. Femoral cross-sectional area properties (bone area, moment of inertia), determined from µCT scans, were significantly greater in HF femurs vs. NC for males and females. Elastic modulus was calculated from strain and deformation data and no dietary effects were seen in either gender. At the applied loads, despite significantly larger cross-sectional area properties in the HF femurs, there was no significant difference in strain between HF and NC femurs for either gender. It appears that adaptive modeling occurs during growth in the HF bones to target a predetermined level of strain to preserve bone structural integrity.</p> / Master of Applied Science (MASc)

There is an association between the human microbiome and disease. Gut microbes metabolize dietary sources to release trimethylamine (TMA). TMA is absorbed and then oxidized by flavin monooxygenase 3 (FMO3) to form trimethylamine N-oxide (TMAO). Elevated TMAO is associated with increased risk of cardiovascular disease and type 2 diabetes; however, the causal nature is unclear. There is also limited evidence supporting the efficacy of strategies to reduce accumulation of TMAO. Therefore, the purpose of these studies is to determine the effects of increases in TMAO on cardiometabolic health. In study 1, healthy sedentary and endurance trained males consumed a high fat diet. Blood samples were obtained in a fasted state and every hour during a 4-hour high fat challenge. We hypothesized sedentary individuals would produce higher TMAO concentrations. In study 2, healthy sedentary individuals consumed an acute 1000 mg dose of choline (CHOL) and placebo (PLC). Fasted blood samples were collected, flow-mediated dilation (FMD) and oral glucose tolerance (OGT) were measured. In study 3, healthy sedentary individuals consumed 4-wks of CHOL and PLC. Fasted blood samples were collected, FMD and OGT were measured. We hypothesized acute and 4-wk choline supplementation would impair FMD and OGT. In study 1, neither fasting (1.49± 1.2 µM vs. 2.25 ± 1.4 µM, p>0.05) or postprandial TMAO changed significantly with the HFD in sedentary or endurance trained individuals even with the endurance group consuming more TMA dietary precursors. Study 2 found increased plasma TMAO concentrations after choline supplementation on day 1(PLC; 4.14 ± 2.6 μM vs. CHOL; 23.6 ± 33.8 μM, p=0.018) and day 2 (PLC; 5.13±4.9 μM vs. CHOL; 32.6±37.5 μM, p=0.082) however, there were no differences in OGT or FMD. Study 3 found no differences in FMD or OGT following 4-wks of choline consumption. In summary, there were no differences between sedentary and endurance trained individuals fasting or post-prandial TMAO. There was also no effect on acute or 4-wk supplementation of choline on FMD and OGT. More research is needed to understand effects of elevated TMAO on cardiometabolic health. / Doctor of Philosophy / For years, research has been performed to identify the health effects of eating large amounts of red meat on cardiovascular disease (CVD). Consuming red meat, fish, poultry and eggs increases a substance created during digestion and metabolism, called trimethylamine N-oxide (TMAO). Elevated TMAO has been associated with increased risk of CVD and type 2 diabetes but the direct causes are unknown. The purpose of these studies is to determine the effects of increases in TMAO on health in humans. Study 1 included healthy, sedentary and endurance trained males who consumed a high fat diet. Blood samples were collected to measure TMAO before and after a high fat meal. Study 2 included healthy, sedentary males and females who consumed 2 days of 1000 mg of choline, which is commonly found in red meat fish and eggs, and a placebo (carbohydrate) after subjects completed a series of tests to evaluate health. Study three included healthy, sedentary males and females who consumed 4-weeks of 1000 mg of choline per day and a placebo (carbohydrate). Following supplementation subjects underwent a series of tests to assess health. Overall, there were no differences found between sedentary and endurance trained individuals. Acute and 4-week supplementation of choline did not affect measures of blood sugar or blood vessel function.

Yes / In many species, seasonal changes in day length (photoperiod) have profound effects on physiology and behavior. In humans, these include cognitive function and mood. Here we investigated the effect of photoperiod and high fat diets on cognitive deficits, as measured by novel object recognition, in the photoperiod-sensitive F344 rat, which exhibits marked natural changes in growth, body weight and food intake in response to photoperiod. 32 male juvenile F344 rats were housed in either long or short photoperiod and fed either a high fat or nutrient-matched chow diet. Rats were tested in the novel object recognition test before photoperiod and diet intervention and re-tested 28 days after intervention. In both tests during the acquisition trials there was no significant difference in exploration levels of the left and right objects in the groups. Before intervention, all groups showed a significant increase in exploration of the novel object compared to the familiar object. However, following the photoperiod and diet interventions the retention trial revealed that only rats in the long photoperiod-chow group explored the novel object significantly more than the familiar object, whereas all other groups showed no significant preference. These results suggest that changing rats to short photoperiod impairs their memory regardless of diet. The cognitive performance of rats on long photoperiod-chow remained intact, whereas the high fat diet in the long photoperiod group induced a memory impairment. These findings suggest that rats exposed to long photoperiod have different cognitive responses to rats exposed to short photoperiod and high fat diet.

Chronic diseases such as osteoporosis, type 2 diabetes, and cardiovascular disease are diseases of long duration, slow progression, and are by far the leading cause of death worldwide. A growing body of evidence links adverse exposures in early development with an increased risk of chronic diseases in adult life. The studies presented in this dissertation sought to exploit this phenomenon to determine the extent to which gestational and lactational exposure to a high fat diet predisposes the offspring to certain diseases in later life and if the eating habits of adult offspring would be able to mitigate or exacerbate these conditions.  In the study presented in Chapter III, dams fed an atherogenic high fat diet prior to conception and throughout gestation and lactation experienced excess hepatic lipid accumulation and poor birth outcome as characterized by smaller litter sizes and higher post-delivery mortality. In the offspring, gestational and lactational exposure to such a diet resulted in growth restriction and skeletal aberrations indicative of osteoporosis, despite being fed a standard rodent diet post-weaning. We propose that dietary-induced hyperlipidemia, along with pregnancy-associated factors, resulted in fatty liver and subsequently reduced litter sizes and increased early mortality, and that the skeletal aberrations seen in the mature offspring represent dietary-induced inhibition of osteogenesis in favor of adipogenesis. In the study presented in Chapter IV, early exposure to a high fat diet resulted in central obesity, elevated lipid levels, hyperglycemia, and additional markers used in the diagnosis of the metabolic syndrome. Altering the diets of the mature offspring demonstrated that the eating habits of adulthood have the potential to mitigate or exacerbate certain metabolic parameters established earlier in life. Mechanisms contributing to the observed metabolic aberrations could include developmental plasticity and mismatch, catch-up growth, and altered programming of the appetite regulatory network. Collectively, this research suggests that early exposure to a fat-rich diet can lead to metabolic and skeletal aberrations in the adult offspring and adds support to the developmental origins of health and disease hypothesis by finding that adverse nutritional exposures in early life can play a role in the chronic diseases of adulthood. / Ph. D.

Obesity is associated with reduced skeletal muscle insulin sensitivity, a major risk factor for development of type II diabetes. These metabolic diseases are commonly associated with an accumulation of mitochondrial dysfunction, which is speculated to contribute toward insulin resistance. High-fat diets reduce human skeletal muscle insulin sensitivity and mitochondrial function. Conversely, endurance training increases insulin sensitivity and enhances mitochondrial performance. Recent evidence in mice has found that central mechanisms of mitochondrial quality control, autophagy and mitophagy, may be suppressed in response to excess fat intake, but upregulated following endurance exercise training. These data may provide a mechanism for dietary and exercise-mediated regulation of mitochondrial quality and metabolic function. The current study investigated the impact of an acute high-fat diet on skeletal muscle autophagy and mitophagy in sedentary, healthy, non-obese college age males'. The expression of skeletal muscle autophagy and mitophagy protein markers were analyzed in response to a high-fat meal before and after a 5-day high-fat diet. Next, we examined the differences in skeletal muscle autophagy and mitophagy protein markers, and associations with skeletal muscle metabolic flexibility between endurance-trained male runners' and sedentary, healthy, non-obese males' following an overnight fast and in response to a high-fat meal. Autophagy markers' indicated reduced autophagy activity in response to a high-fat meal and following a high-fat diet, which exacerbated the high-fat meal response. However, these data could not be confirmed due to methodological limitations. Mitophagy markers were not significantly affected by the high-fat meal or diet. There were no significant differences in the expression of autophagy protein markers between endurance-trained and sedentary groups', but mitophagy markers were significantly elevated in endurance-trained runners'. Metabolic flexibility was not significantly different between groups' following an overnight fast or in response to a high-fat meal, and was not associated with the expression of autophagy and mitophagy protein markers. In conclusion, autophagy may be suppressed by a 5-day high-fat diet, but further analysis is required for confirmation. Endurance-trained male runners show increased markers of mitophagy, which were not associated with improved metabolic flexibility while fasted or following a high-fat meal. / Ph. D.

Macronutrient metabolism plays an essential role in the overall health of an individual. Depending on a number of variables, for example, diet, fitness level, or metabolic disease state, protein, carbohydrate and fat have varying capacities to be oxidized and balanced. Further, when analyzing the oxidation of carbohydrate and fat in the skeletal muscle specifically, carbohydrate balance happens quite rapidly, while fat balance does not. The ability of skeletal muscle to adapt and respond to various nutrient states is critical to maintaining healthy metabolic function. Habitual high fat intake has been associated with reduced oxidative capacity, insulin resistance, increased gut permeability, inflammation, and other risk factors often preceding metabolic disease states. The disruption of gut function leads to gut permeability and increases endotoxins released into circulation. Endotoxins have been shown to play an important role in obesity-related whole body and tissue specific metabolic perturbations. Each of these disrupted metabolic processes is known to associate with obesity, metabolic syndrome and diabetes. To date, limited research has investigated the role of high fat diet on skeletal muscle substrate oxidation and its relationship to gut permeability and endotoxins. The purpose of this study was to determine the effects of an acute, five-day, isocaloric high fat diet (HFD) on skeletal muscle substrate metabolism in healthy non-obese humans. An additional purpose was to determine the effects of a HFD on gut permeability and blood endotoxins on healthy, non-obese, sedentary humans. Thirteen college age males were fed a control diet for two weeks, followed by five days of an isocaloric HFD. To assess the effects of a HFD on skeletal muscle metabolic adaptability and postprandial endotoxin levels, subjects underwent a high fat meal challenge before and after a HFD. Muscle biopsies were obtained; blood was collected; insulin sensitivity was assessed via intravenous glucose tolerance test; and intestinal permeability was assessed via the four-sugar probe test before and after the HFD. Postprandial glucose oxidation and fatty acid oxidation in skeletal muscle increased before the HFD intervention but was decreased after. Skeletal muscle in vitro assay of metabolic flexibility was significantly blunted following the HFD. Insulin sensitivity and intestinal permeability were not affected by HFD, but fasting endotoxin was significantly higher following the HFD. These findings demonstrate that in young, healthy males, following five days of an isocaloric high fat diet, skeletal muscle metabolic adaptation is robust. Additionally, increased fasting endotoxin independent of gut permeability changes are potentially a contributor to the inflammatory state that disrupts substrate oxidation. These findings suggest that even short-term changes in dietary fat consumption have profound effects on skeletal muscle substrate metabolism and fasting endotoxin levels, independent of positive energy balance and whole-body insulin sensitivity. / Ph. D. / Macronutrients, namely carbohydrates, fats and protein, and the way they are utilized play an important role in the overall health of an individual. Many variables come into play when considering the oxidization (or utilization) of each macronutrient, including, but not limited to diet, fitness level, and metabolic disease state. Skeletal muscle and its role in these processes is of special interest as it is the largest insulin sensitive organ in the body. Its ability to adapt and respond to various nutrient states is critical to maintaining healthy metabolic function. Habitual high fat intake has been associated with insulin resistance, increased gut permeability (increasing endotoxins, which are toxins released into circulation from the intestines), reduced oxidative capacity (ability to utilize macronutrients for energy), and inflammation, all of which are risk factors that precede metabolic disease states. To date, limited research has investigated the role of high fat diet on skeletal muscle oxidation of macronutrients and its relationship to what is going on in the gut, or intestines. The purpose of the study was to determine the effects of a short term high fat diet (five days) on skeletal muscle in healthy, non-obese humans, and to determine the effects of this diet on gut permeability and endotoxins. Thirteen college-age males were fed a control diet for two weeks followed by five days of a high fat diet. Each diet had the same caloric content. Subjects underwent a high fat meal challenge before and after the diet to assess the effects of the diet on skeletal muscle adaptability and post meal endotoxin levels. Before and after the high fat diet, muscle biopsies were obtained, blood was collected, insulin sensitivity was assessed and gut permeability was measured. We found that skeletal muscle metabolic adaptation is robust. Additionally, increased fasting endotoxin changes are a possible contributor to the inflammatory state that disrupts macronutrient oxidation. Therefore, even short-term changes in dietary fat consumption have profound effects on skeletal muscle metabolism and fasting endotoxin levels, independent of positive energy balance and whole-body insulin sensitivity.

Yes / In this study the effects of photoperiod and diet, and their interaction, were examined for their effects on growth and body composition in juvenile F344 rats over a 4-week period. On long (16L:8D), relative to short (8L:16D), photoperiod food intake and growth rate were increased, but percentage adiposity remained constant (ca 3-4%). On a high fat diet (HFD), containing 22.8% fat (45% energy as fat), food intake was reduced, but energy intake increased on both photoperiods. This led to a small increase in adiposity (up to 10%) without overt change in body weight. These changes were also reflected in plasma leptin and lipid levels. Importantly while both lean and adipose tissue were strongly regulated by photoperiod on a chow diet, this regulation was lost for adipose, but not lean tissue, on HFD. This implies that a primary effect of photoperiod is the regulation of growth and lean mass accretion. Consistent with this both hypothalamic GHRH gene expression and serum IGF-1 levels were photoperiod dependent. As for other animals and humans, there was evidence of central hyposomatotropism in response to obesity, as GHRH gene expression was suppressed by the HFD. Gene expression of hypothalamic AgRP and CRH, but not NPY nor POMC, accorded with the energy balance status on long and short photoperiod. However, there was a general dissociation between plasma leptin levels and expression of these hypothalamic energy balance genes. Similarly there was no interaction between the HFD and photoperiod at the level of the genes involved in thyroid hormone metabolism (Dio2, Dio3, TSHβ or NMU), which are important mediators of the photoperiodic response. These data suggest that photoperiod and HFD influence body weight and body composition through independent mechanisms but in each case the role of the hypothalamic energy balance genes is not predictable based on their known function. / Scottish Government (Rural and Environment Science and Analytical Services Division, http://www.scotland.gov.uk/), AWR LR LMT PJM and the BBSRC, (http://www.bbsrc.ac.uk/home/home.aspx, grant BB/K001043/1), AWR GH PJM

Yes / Evidence suggests vitamin D3 (VD) supplementation can reduce accumulation of adipose tissue and inflammation and promote myogenesis in obese individuals, and thus could mitigate obesity-induced reductions in skeletal muscle (SkM) contractility. However, this is yet to be directly investigated. This study, using the work-loop technique, examined effects of VD (cholecalciferol) supplementation on isolated SkM contractility. Female mice (n = 37) consumed standard low-fat diet (SLD) or high-fat diet (HFD), with or without VD (20,000 IU/kg-1 ) for 12 weeks. Soleus and EDL (n = 8-10 per muscle per group) were isolated and absolute and normalized (to muscle size and body mass) isometric force and power output (PO) were measured, and fatigue resistance determined. Absolute and normalized isometric force and PO of soleus were unaffected by diet (P > 0.087). However, PO normalized to body mass was reduced in HFD groups (P  0.588). HFD reduced EDL isometric stress (P = 0.048) and absolute and normalized PO (P  0.493). Cumulative work during fatiguing contractions was lower in HFD groups (P  0.060). This study uniquely demonstrated that high-dose VD had limited effects on SkM contractility and did not offset demonstrated adverse effects of HFD. However, small and moderate effect sizes suggest improvement in EDL muscle performance and animal morphology in HFD VD groups. Given effect sizes observed, coupled with proposed inverted U-shaped dose-effect curve, future investigations are needed to determine dose/duration specific responses to VD, which may culminate in improved function of HFD SkM. NEW FINDINGS: What is the central question of this study? Can vitamin D supplementation alleviate detrimental effects of high-fat diet (HFD) consumption on contractile performance of isolated skeletal muscles? What is the main finding and its importance? The present study is the first to examine the synergistic effects of HFD consumption and vitamin D supplementation on the contractile performance of isolated skeletal muscle. These findings suggest high dose vitamin D has limited effects on force, power or fatigue resistance of isolated mouse soleus and extensor digitorum longus.