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Thesis (Ph.D.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / The mechanisms by which diets high in saturated fat (HFD) contribute to intestinal adaptation and obesity are unknown. The hypothesis that functional changes in distal portions of small intestine are induced by HFD was tested in C57B1/6 mice. Specifically, it was examined whether the putative fatty acid translocase CD36 was phosphorylated in mouse intestinal epithelial cells and whether dephosphorylation of CD36 increased long chain fatty acid (LCFA) absorption. Co-immunoprecipitation was used to investigate specific intestinal alkaline phosphatases that might interact with CD36. It was also examined whether chronic ingestion of an HFD would lead to upregulation of the CD36 and/or one or more intestinal alkaline phosphatases that may activate CD36. CD36 was found to be phosphorylated on the surface of mouse enterocytes, indicating that there may be a phosphatase-sensitive pool of phospho-CD36 (pCD36) in mouse small intestinal tissue. CD36 was dephosphorylated by alkaline phosphatase and this treatment increased long chain but not short chain fatty acid uptake. Long chain fatty acid uptake was blocked with a specific CD36 inhibitor. CD36 from mouse small intestines physically interacted specifically with global intestinal alkaline phosphatase (gIAP) but not duodenal alkaline phosphatase (dIAP). As expected, HFD increased body weight, adiposity, and plasma triglycerides compared to control mice. CD36 and gIAP but not dIAP protein levels were significantly increased in distal but not proximal regions of intestines of HFD mice. Finally, HFD increased the absorptive capacity of the distal small intestine for LCFA in a CD36-dependent manner. It is concluded that HFD specifically upregulates gIAP protein in epithelial cells of the distal regions of the small intestine of mice, and that one of its substrates is pCD36, which has been implicated in transcellular fat transport. This diet also increases the absorptive capacity of the distal small intestine for LCFAs. Taken together, these results suggest that HFD causes intestinal adaptation that results in an increased capacity to absorb dietary fat. This effect is mediated in part by increasing the expression and activity of the fatty acid transporter CD36 and its regulatory enzyme gIAP. / 2031-01-02

>Magister Scientiae - MSc / The incidence of type 2 diabetes (T2D) is persistently increasing globally. T2D is associated with pancreatic β cell dysfunction and insulin resistance in peripheral tissues such as the liver and skeletal muscle. Skeletal muscle is the major site for insulin stimulated glucose uptake. Maintenance on a gestational high fat diet may programme insulin resistance. Programming is induced by the exposure of organisms to either a stimulus or insult during foetal and/or early neonatal life and alters offspring physiology and metabolism. The aim of the present study was therefore to investigate the effects of maternal diets, varying in fat content, on neonatal hepatic and skeletal muscle gene (mRNA) and protein (immunoreactivity) expression of proximal insulin signalling factors: insulin receptor alpha (IRα), insulin receptor substrate 2 (IRS2) and phosphoinositide 3-kinase-p110 alpha (PI3K-p110α), and to assess the therapeutic potential of Aspalathus linearis extract after high fat programming. Pregnant rats were randomised into groups maintained on diets with varying fat proportions: 10% (control), 20% (20F), 30% (30F) and 40% (40F) fat as energy throughout gestation. Neonatal liver and skeletal muscle were collected to determine the proximal insulin signalling expression profiles of the target factors: IRα, IRS2 and PI3K-p110α. Quantitative polymerase chain reaction (qPCR) was applied to determine mRNA expression of these target insulin signalling factors. Immunostaining of the target proteins in the liver and skeletal muscle was performed followed by relative quantification with image analysis software. Further, Aspalathus linearis (Al) extract was orally administered to mothers during gestation in the 10% (Control-Al) and 40% (HFD-Al) diets at a dose of 150 mg/kg. Body weight, food intake and blood glucose concentrations were monitored throughout gestation in mothers. Maternal diets, varying in the percentage of fat content, showed no significant effect on neonatal hepatic IR and IRS2 mRNA expression. However, hepatic PI3K mRNA expression was elevated in 30F neonates compared to 20F neonates. Skeletal muscle IR and PI3K mRNA expression were reduced in the 30F and 40F neonates compared to 20F neonates. There was reduced hepatic IRα immunoreactivity in 40F neonates compared to control and 20F neonates. Further, skeletal muscle IRα immunoreactivity was significantly reduced in 30F and 40F neonates compared to control neonates. Therefore foetal high fat programming reduced IRα in both the liver and skeletal muscle which may impair proximal insulin signalling in these glucose recipient organs. Aspalathus linearis had no effect on maternal serum insulin and glucagon concentrations. In addition, maternal caloric intake, body weight and organ weights (liver, brain and pancreas) were not altered amongst the groups. Further, HFD-Al neonates were heavier than control neonates. In conclusion, Aspalathus linearis, at a dose of 150 mg/kg, had neither harmful nor ameliorative effects in pregnant mothers fed high fat diet during gestation. In addition, Aspalathus linearis treatment had no ameliorative effects on neonates from mothers fed high fat diet throughout gestation.

Binge Eating Disorder (BED) is a deadly, psychiatric condition which affects about 10 million people in the USA. It is characterized by discrete and recurrent binge eating episodes consisting of rapid consumption of excessive amounts of highly palatable, energy-dense food (e.g. rich in sugars and fats) within discrete periods of time. Our laboratory has been focusing on the understanding of the behavioral, metabolic, and neurobiological factors underlying BED, through the development of an animal model of binge-like eating. This model is based on a limited access schedule in which rats are exposed 1-hour/day to a high-sucrose diet (HSD) in operant conditioning self-administration boxes. However, the consummatory and metabolic outcomes of exposing rats to a high-fat diet (HFD) in the same procedure are unknown. The aim of this thesis was to test the consummatory and metabolic effects of 1-hour limited access to either a HSD or a HFD in an operant rat model of binge-like eating. For this purpose, female rats were subjects of the binge-like eating procedure by limiting access to a HSD, a HFD, or a standard Chow diet. Our results show that limiting access to either a HSD or a HFD promoted binge-like eating as compared to control Chow diet. HSD binge-like eating was based on a true increase in the amount of food consumed, that is, an increased eating rate. Such suggests increase in palatability and a decrease in the home-cage standard chow intake, likely due to a negative contrast effect. Conversely, binge-like eating of the high-fat diet resulted from passive energy consumption due to the high energy-density of the food. Also, HFD binge-like eating was accompanied by neither increased eating rate nor rejection of the home-cage chow. Moreover, while HSD rats consumed less energy than HFD rats, the former were more energy efficient and gained more body weight than the latter. These results provide information on how the quality of food can deeply influence the behavioral and metabolic outcomes of binge-like eating. / 2022-06-07T00:00:00Z

Indiana University-Purdue University Indianapolis (IUPUI) / Chronic consumption of a high-fat diet is a lifestyle factor that increases the risk for cognitive impairment (Granholm et al., 2008; Greenwood & Winocur, 2005; Mattson, 2004; Winocur & Greenwood, 2005). A high-fat diet appears to facilitate cognitive impairment through the promotion of insulin resistance (Greenwood & Winocur, 2005; Stranahan et al., 2008; Winocur & Greenwood, 2005). A gap in the literature is an established timeframe of the progression and underlying mechanism, which study in animals would better afford. Furthermore, A limited number of studies have investigated the relationship between a high-fat diet and behavioral dysregulation such as anxiety and depression. The 1st aim of the study was to determine if consumption of a high-fat diet leads to cognitive impairment and behavioral dysfunction at 3, 8, or 13 weeks of consumption. The 2nd aim was to determine if cholesterol levels and HBP activity are aberrantly increased in specific regions in mice that display feeding induced cognitive/behavioral dysfunction. Consumption of the experimental specialty diets produced a number of significant behavioral effects. These significant effects began to emerge after only 3 weeks of low-and high-fat feeding with increased anxiety-like behavior displayed higher in the high-fat diet group for the Elevated Plus Maze and Open Field Test. There was increased thigmotactic behavior and floating in the low-fat diet group in the Morris Water Maze (MWM) task, therefore making cognitive assessment uninterpretable. This pattern in the behavioral tasks were more robust in the 8 week group and alleviated in the 13 week group. There was only a significant difference in depression-like symptoms in the Forced Swim (FS) Task in the 3 week group. Cholesterol analysis is still under review in Dr. Elmendorf’s lab to correlate cholesterol levels and cognitive/behavioral impairment.

Metabolic flexibility plays a significant role in energy homeostasis by regulating fuel selection in correspondence to energy demand. Obese and type II diabetic populations have displayed a hindered ability to properly transition from fat oxidation while in a fasted state to carbohydrate oxidation once fed, leading to a buildup of mitochondrial metabolites such as acylcarnitines. Carnitine, essential for fatty acyl-CoA transport through the inner and outer mitochondrial membranes, can be an indicator of mitochondrial distress as elevated levels tend to spill over into plasma suggesting a disruption in oxidation. The current study was designed to examine the effect of short term, high fat feeding on plasma acylcarnitine species diversity and levels and if acylcarnitines are associated with metabolic flexibility. 13 healthy, non-obese, sedentary males, aged 18-40 years participated in this study. Following a 12-hour overnight fast a biopsy was taken from the quadricep before and 4 hours after a high fat meal. Blood draws were obtained pre-biopsy while fasted and every hour for 4 hours post high fat meal consumption. Acylcarnitines from plasma were converted to their butyl esters and analyzed by electrospray ionization tandem mass spectrometry (MS/MS). Changes were observed in acetylcarntine (P=0.0125), glucose oxidation (P=0.0295), C16:1/C16:0 desaturation index (P= 0.0397), and C18:1/C18:0 desaturation index (P=0.0012). We did not find that individual changes in flexibility correlated with circulating acylcarnitine measurements in a fasted state / Master of Science

Skeletal muscle is highly involved in macronutrient metabolism. To maintain proper energy metabolism and physiology, skeletal muscle must adapt to nutrient supply. Thus, diet macronutrient composition is an important modulator of skeletal muscle metabolism. Evidence from rodent and human models show high-fat diets contribute to impaired insulin signaling, as well as decreased fatty acid and glucose oxidation. Utilizing proteomic analysis of metabolic proteins in humans may lead to the mechanism behind skeletal muscle adaption to macronutrient composition, potentially providing the groundwork for characterizing the etiology of high-fat feeding induced metabolic disease. The objective of this study was to compare the substrate oxidation patterns and the levels of metabolic proteins in the fasted skeletal muscle of lean, healthy males that either increased fatty acid oxidation in response to the high-fat diet, termed responders, or males that decreased fatty acid oxidation, termed non-responders. We employed a controlled feeding study design, where the participants served as their own controls. Following a 2-week control diet (30% fat, 55% carbohydrate and 15% protein), participants came to the lab fasted overnight and a muscle biopsy was taken from their vastus lateralis muscle. Participants were then placed on a 5-day high-fat diet (50% fat [45% saturated fat], 35% carbohydrate, and 15% protein). Following this diet, participants again came to the lab fasted overnight and another muscle biopsy was taken from their vastus lateralis muscle. Both the control and the high-fat diets were isocaloric to habitual diets. Muscle from the biopsies were utilized for substrate metabolism measures and mass spectrometry. We did not observe any significant differences in glucose oxidation between responders and non-responders, prior to or following the high-fat diet. Our proteomic analysis identified 81 proteins and protein subunits involved in substrate metabolism but only 6 were differentially regulated by the high-fat diet. Independent of the high-fat diet, compared to non-responders, responders contained an overall higher content of protein subunits belonging to Complex I and ATP synthase. The findings from this study suggest that adaption to high-fat feeding is individual specific and proteomic changes alone cannot explain high-fat feeding induced metabolic changes. / Ph. D. / Skeletal muscle is highly involved in macronutrient metabolism, which consist of the breakdown and utilization of glucose and fatty acids, thus making the foods we ingest a major modulator of skeletal muscle metabolism. Over the last few decades, Americans have increased their ingestion of foods high in saturated fats, which has coincided with the increased prevalence of obesity and type 2 diabetes. Further, evidence suggests these metabolic diseases are associated with the skeletal muscle’s inability to switch between the utilization of glucose and fatty acid in response to nutrient supply. Analyzing metabolic protein content in humans may lead to the mechanism behind skeletal muscle adaption to macronutrient composition, potentially leading to the cause behind the development of high-fat feeding induced metabolic disease. The objective of our controlled feeding study was to compare the macronutrient metabolism and the content of metabolic proteins in the fasted skeletal muscle of healthy males that either increased fatty acid utilization in response to a high-fat diet, termed responders, or males that decreased fatty acid utilization, termed non-responders. Following a 2-week control diet (30% fat, 55% carbohydrate and 15% protein), participants came to the lab fasted overnight and a biopsy was taken from their thigh muscle called the vastus lateralis. Participants then began a 5-day high-fat diet (50% fat [45% saturated fat], 35% carbohydrate, and 15% protein). Following this diet, participants came to the lab fasted overnight and another biopsy was taken from their vastus lateralis muscle. Both the control and the high-fat diets were isocaloric to habitual diets. The muscle samples were used to analyze macronutrient metabolism and identify metabolic protein content. We did not observe differences in glucose utilization between responders and non-responders, prior to or following the high-fat diet. We identified 81 metabolic proteins and protein subunits but only 6 were differentially regulated by the high-fat diet. Independent of diet, responders contained higher levels of subunits from 2 proteins involved in cell energy production, Complex I and ATP synthase. Our findings suggest that adaption to high-fat feeding is individual specific and protein content changes alone cannot explain high-fat feeding induced metabolic changes.

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Recent evidence suggests that sustained consumption of a high-fat diet is associated with reduced CB1 receptor expression in some brain areas. Many of the neuromodulatory functions of endogenous cannabinoids are mediated by the CB1 receptor. The CB1 receptor also mediates the behavioral and physiological effects of delta-9-tetrahydrocannabinol (delta-9-THC), the primary psychoactive constituent of marijuana. While high-fat diets are associated with region-specific changes in CB1 receptor expression, it is not clear whether such changes are behaviorally relevant. To that end, separate groups of male and female rats were placed on either a high-fat diet or a standard diet. Cannabinoid function was determined in a triad of measures (e.g., hypothermia, gross locomotion, time on bar apparatus) at postnatal day 30 (PD30), PD44, PD68 and PD114. These age points respectively correspond to rodent models of early adolescence, late adolescence, early adulthood and full maturity in humans. Male rats were also tested at PD37 and PD61. Subsequently, the antinociceptive properties of delta-9-THC and the effect of delta-9-THC on food intake were also measured. After 38 days, female rats maintained on a high-fat diet were significantly less sensitive to the psychomotor effects of delta-9-THC than were the female rats maintained on the control diet. These diet-related differences persisted into full maturity. Female rats maintained on a high-fat diet were also less sensitive to changes in food intake caused by delta-9-THC than were female rats maintained on the control diet. In contrast, the hypothermic effects of delta-9-THC were not differentially affected by the type of diet consumed. Likewise, female rats maintained on a high-fat diet exhibited tail-flick latencies that were indistinguishable from those of female rats maintained on the control diet. With two minor exceptions, and in sharp contrast to female rats, sensitivity to the pharmacological effects of delta-9-THC was not differentially affected by the type of diet in male rats. In short, female rats maintained on a high-fat diet appeared to be cross-tolerant to the psychomotor and hyperphagic effects of delta-9-THC while male rats maintained on a high-fat diet exhibited responses to delta-9-THC that were virtually indistinguishable from control animals.

Syfte och frågeställningar Syftet med denna litteraturstudie är att undersöka om det finns stöd i nuvarande forskning för att en fettrik kost är mer effektiv som nutritionsstrategi vid uthållighetsprestationer jämfört med en kolhydratrik kost. Studiens frågeställningar är: Förbättras uthållighetsprestationen av en fettrik kost jämfört med en kolhydratrik kost? Hur påverkas kolhydrat- och fettmetabolismen av en högfett- och lågkolhydratkost? Metod Litteratursökningen genomfördes i databaserna Ebsco, Pubmed och Cinahl. Totalt inkluderades 16 artiklar, 11 artiklar från litteratursökningen i databaserna och 5 artiklar från valda referenslistor. Studierna kvalitetsgranskades med hjälp av SBU:s granskningsmall för randomiserade kontrollerade studier. Resultat I 3 av 16 studier förbättrades uthållighetprestationen vid intag av högfett- och lågkolhydratkost, i 4 av 16 studier försämrades prestationen och i resterande 9 studier sågs ingen signifikant skillnad i prestationen mellan kostinterventionerna. Majoriteten av studierna fick en förhöjd fettoxidation som resultat av en högfett- och lågkolhydratkost men ingen signifikant skillnad gällande blodglukos-, blodinsulin- eller blodlaktatvärde mellan kostinterventionerna. Slutsats Trots en förhöjd fettoxidation och välfyllda glykogenlager finns inte tillräcklig evidens för att påvisa en generell prestationshöjning vid uthållighetsprestationer av en högfettkost jämfört med en högkolhydratkost. Detta troligtvis på grund av nedsatt förmåga hos musklerna att använda glykogen. Resultaten från de studier som ingick i denna systematiska litteraturstudie visar konsekvent en försämrad prestation efter intag av högfett- och lågkolhydratkost vid arbetsintensiteter över 80% av VO2max. Vid arbetsintensiteter omkring 60-70% av VO2max kan prestationen eventuellt förbättras efter intag av högfettkost bestående av 60-70% fett och mindre än 15% kolhydrater. / Aim The purpose of this study is to investigate whether there is scientific evidence that a high fat diet is more effective as a nutrition strategy for endurance performance than a high carbohydrate diet is. The objectives of the study are: Does endurance performance improve by a high fat diet compared by a high carbohydrate diet? How is the metabolism of fat and carbohydrate affected by a high fat and low carbohydrate diet? Method The literature search was conducted in the databases Ebsco, Pubmed and Cinahl. A total of 16 studies was included, 11 studies from the literature search and 5 studies from selected reference lists. The studies quality was audited by SBU: s questionnaire for randomized controlled studies. Results Endurance performance was enhanced after ingesting a high fat- and low carbohydrate diet in 3 of 16 studies and was decreased in 4 of 16 studies. In the remaining 9 studies there was no significant difference in performance between the two trials. A high fat- and low carbohydrate diet resulted in an increased fat oxidation in the majority of the studies but there was no significant difference in bloodglucose-, blodinsulin- or blodlactatelevels between the two trials. Conclusions Despite increased fat oxidation and well-filled glycogen levels there is not sufficient evidence to prove that endurance performance will be enhanced by a high fat diet compared to a high carbohydrate diet. This is probably because of a lower ability of the muscles to use glycogen. The results from this systematic review consequently shows a decreased performance after a high fat- and low carbohydrate diet at work intensities over 80% of VO2max. At intensities around 60-70% of VO2max, the performance can possibly be enhanced after a high fat diet consisting 60-70% of fat and 15% or lower of carbohydrate.