Background Obesity is increasing worldwide and is a major contributor to morbidity and mortality. Notably, abdominal (central) obesity carries a high risk of obesity-related diseases, while peripheral fat accumulation can act in a protective manner. A redistribution of fat from peripheral to central depots is seen after the menopause and is associated with an increasing prevalence of diabetes and cardiovascular disease. A key mediator may be ectopic fat accumulation in the liver. Our hypothesis was that a Palaeolithic-type diet (PD) consumed ad libitum improves body composition and metabolic risk markers, including liver fat and insulin sensitivity, in obese postmenopausal women. Methods In study I the study subjects (n=10) used a PD during 5 weeks. In study II and III (n=70) the effect of a Palaeolithic-type diet (PD) was compared to a diet according to the Nordic Nutrition Recommendations diet (NNR) during a 2-year randomized clinical trial (RCT). Food records and nitrogen excretion in urine validated food intake. Anthropometric measurements were performed in a standardized manner. Body composition was calculated using Dual Energy X-ray Absorptiometry (DXA). Total energy expenditure was calculated by accelerometry (Actiheart®) in combination with indirect calorimetry. Liver and muscle fat content was estimated by magnet resonance spectroscopy (1H-MRS). Insulin sensitivity was measured either with hyperinsulinemic euglycemic clamps (paper I) or oral glucose tolerance tests (OGTTs) (paper III). Results In study I a significant weight loss, linked to improved lipid and blood pressure levels, was associated with a 49% decrease in liver fat. Concomitantly, hepatic insulin sensitivity improved, while peripheral insulin sensitivity (and muscle fat) was unaltered. In study II/III both groups had a significant and sustained weight loss after 2 years. The PD was more effective than the NNR diet regarding loss of weight and fat mass after 6 months, but not after 24 months. Serum triglyceride levels were significantly lower at 24 months in the PD group. Liver fat decreased throughout the study in both groups. Hepatic insulin sensitivity improved during the first 6 months of the study, while peripheral insulin sensitivity did not change. Hepatic insulin sensitivity was associated with liver fat at baseline, but not during the diet intervention. Energy expenditure did not change in any of the study groups. Conclusion Ad libitum diets can have sustained beneficial effects on weight and body composition in obese postmenopausal women, a PD being more effective on short-term than a diet according to the NNR. This is associated with a reduction in liver fat that may reduce the risk of future diabetes and cardiovascular disease. Further studies are needed in order to explore the association between liver fat and metabolic dysfunction, including insulin sensitivity.

Background: Previous research suggests associations between energy balance, eating frequency, macronutrient content, and macronutrient distribution with body composition. In particular, energy balance and protein intake have been conventionally evaluated in 24-hr time blocks, consistent with dietary recommendations and general public understanding. However, there is a potential benefit to investigating energy balance and protein intake in smaller increments of time to account for dynamic changes that occur within-day.Objective: The purpose of this study was to evaluate protein intake/distribution relative to energy balance fluctuations during the day and body composition in collegiate female basketball players.Methods: Subjects provided information on dietary intake and expenditure. Body composition was assessed by multi-current bioelectrical impedance. Energy balance (EB) and related protein distribution variables were determined with a Computerized Time-Line Energy Analysis procedure. Data were analyzed for associations between energy balance, protein intake and distribution, and body composition. Data are displayed as either traditional 24-hr EB and total protein intake or dynamic protein variables in relation to real-time EB (ingestion within ± 400 kcal EB or > 0 kcal EB).Results: There was no relationship between net 24-hr energy balance and percentage body fat. A statistically significant positive relationship was observed between total protein intake and body fat mass (R = .597; p = .031). No relationship was observed between protein distribution variables (g in ± 400 kcal EB, g in > 0 kcal EB) and percentage body fat. Protein eating occurrences (>10g, ± 400 kcal EB) was inversely correlated with BMI (R = -.650; p = .016). Subjects with the greatest energy deficits presented with lower lean body mass (R= -.736; p = .004).Conclusion: These data suggest that within-day protein distribution relative to energy balance are associated with BMI, but not with percentage body fat. Those with the highest protein intake had the highest body fat mass, with no correlation between protein intake and total energy intake detected. In this group, no association between 24hr intake net values or within-day intake values were found to be related to body fat percentage. However, the greatest energy balance deficit during the day was strongly inversely associated with lean body mass, indicative of potentially deleterious effects of energy restriction.

Obesity is a medical condition in which excess body fat has been accumulated. It is most commonly caused by imbalance between energy intake and energy expenditure (lack of physical activity and lower metabolic rate, etc.). The control of energy metabolism involves multiple tissues and signalling pathways and there is a great need for further understanding of these different interactions. In this study, I use Caenorhabditis elegans to study these complex pathways at the level of a whole organism. The downstream target of mTOR, p70 S6 kinase (S6K), has been implicated in the phosphorylation of multiple substrates and the regulation of growth and metabolism. In this study the worm homolog of S6K, rsks-1, found to be important for fat metabolism. Previous work in our lab found that RSKS-1::GFP is expressed at high levels in a set of sensory neurons and upregulated in ASJ, ASE and BAG sensory neurons in starved worms or mutants with low insulin activity. In this study, I found that the upregulation of rsks-1 expression was affected by serotonin, but not by the other neurotransmitters. Combined with the result that rsks-1 is required for the expression of TGFβ and insulin in ASI, rsks-1 may control dietary sensing by affecting insulin and TGFβ signalling within nervous system. Quantification of fat accumulation by TLC/GC revealed that in comparison to wild type worms, rsks-1 mutants have more than two-fold higher levels of triglycerides. This was confirmed by FT-IR microspectroscopy analysis. rsks-1 mutants also contain disproportionately high levels of C16:1n9 and C18:1n9 lipids compared with wild type worms. Genetic analysis has shown that rsks-1 acts either downstream of, or in parallel to the insulin and TGFβ pathways to affect fat levels. My studies showed that rsks-1 affects fat metabolism by influencing mRNA levels of genes encoding proteins in the β-oxidation pathway. Combined with defects in dietary sensing, fatty acid absorption, fertility and mitochondria function, the loss of rsks-1 activity induced much more energy storage than wild type by making a profound metabolic shift. These results are consistent with the metabolomics data analysis. Tissue specific RNAi showed that rsks-1 was required in many different tissues to regulate fat metabolism. Taken together, it can be concluded that RSKS-1 activity is needed for co-ordination of metabolic states in C. elegans. In order to understand more about the physiology behind fat accumulation, I analysed a mutant, aex-5, that has significantly lowered lipid levels. I found that this defect is associated with a significant reduction in the rate at which dietary fatty acids are taken up from the intestinal lumen. The aex-5 gene, which encodes a Kex2/subtilisin-family, Ca2+-sensitive proprotein convertase, is required for a discrete step in an ultraradian rhythmic phenomenon called the defecation motor program (DMP). Combined with other results, we conclude that aex-5 and other defecation genes may affect fat uptake by promoting the correct distribution of acidity within the intestinal lumen. This dissertation also described how to use Fourier transform infrared (FT-IR) microspectroscopy to detect lipids, proteins and carbohydrates directly in single worm. In conclusion, in this thesis I have uncovered several components that play roles in dietary sensing, fatty acid synthesis, adiposity regulation and fatty acid absorption in C. elegans.

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Fat talk refers to the negative, evaluative conversations that women have with each other about their bodies (e.g., "I'm so fat!"). These comments are often driven by negative self-evaluations and engaging in fat talk leads to negative health-related outcomes for the individual. Grounded in confirmation theory, the current research sought to uncover the role of communication in moderating the relationship between fat talk and health-related outcomes (i.e., mental health, body image, and weight management) by focusing on perceptions of both dysfunctional and functional responses to fat talk. Participants were young adult female friendship dyads (N = 239 dyads) who completed a number of measures including fat talk, depression, bulimia, drive for thinness, body dissatisfaction, dieting, and exercise. Statistical analyses included multilevel modeling and actor partner interdependence modeling. Results revealed that fat talk was associated with most of the health-related outcomes, even after controlling for BMI and different responses from a friend. Engaging in excessive conversations about weight with a friend (i.e., co-rumination) was positively associated with bulimia, drive for thinness, and body dissatisfaction. Showing warmth and attentiveness during conversations about weight (i.e., acceptance) was associated with lower levels of depression and bulimia. Pushing a friend to change her thoughts and habits (i.e., challenge) was associated with lower levels of body dissatisfaction. None of the interaction terms yielded significant results, indicating that responses to fat talk (either positive or negative) did not moderate the relationship between fat talk and the health-related outcome variables. This research highlights the importance of understanding fat talk as a communication process that may be driven by and result in intra-individual outcomes.

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Research conducted for this dissertation had three goals; 1) determine if CLA can induce milk fat depression immediately postpartum, 2) determine if CLA can alter energy availability, 3) determine the mechanism behind the mammary gland's decreased sensitivity to CLA immediately postpartum. The first study provides strong evidence indicating CLA can decrease milk fat synthesis immediately postpartum, but the dose required is approximately 3x greater than in established lactation. This trial also provided evidence that CLA can alter energy status, as CLA decreased days to EBAL nadir by nearly 5 days. This is relevant as recovery of EBAL from its lowest point provides an important signal for initiating ovarian activity and days to nadir is highly correlated with days to first ovulation. Study two was designed to determine if CLA induced milk fat depression could improve energy status during heat stress. Rumen-inert CLA reduced milk fat synthesis, and was able to improve energy availability, but did not increase milk yield or yield of other milk components. Although production was unchanged in this study, the study did provide further evidence that rumen-inert CLA can alter energy availability. Study three utilized intravenous infusion of CLA in cows in mid and early lactation to determine the mechanism for the mammary gland's decreased sensitivity in early lactation. It is postulated that increased fatty acid oxidation and subsequent enhanced levels of circulating NEFA present during the transition period competitively prevent adequate CLA uptake by the mammary gland. In the current study, trans-10, cis-12 CLA concentration in milk was not different between early and established lactation, while milk fat yield was drastically reduced on d 4 and 5 of trans-10, cis-12 CLA infusion in mid lactation cows, but unaltered in early lactation. Further, NEFA levels were nearly 3 fold higher in early lactation than in mid lactation, providing further evidence that increased circulating NEFAs in early lactation are unlikely to be the source of the mammary gland's decreased sensitivity during this time. Do to the variation in gene expression observed in this trial, we were unable to make any definitive conclusions as to the sensitivity of the expression of genes involved in milk lipid synthesis to CLA in early vs. mid lactation.

To examine the effect of diet fat type on rates of cholesterol synthesis and esterification during feeding and fasting, nine healthy male subjects were fed solid-food diets of 40% fat as predominantly either olive oil (MONO), safflower-oil margarine (POLY), or butter (SAT). At the end of each two-week diet trial, subjects were given deuterium (D) oxide orally and de novo synthesis was measured from D incorporation into cholesterol and interpreted as rates of fractional synthesis (FSR) (pools/day) into the rapidly exchangeable free cholesterol (FC) pool. Absolute synthesis rates (ASR) were calculated as the product of FSR and the FC pool. Pool size for each subject was obtained from analysis of the specific activity decay curve of an intravenous injection of 4-14C-cholesterol over nine months. Synthesis was measured over two consecutive 12-h fed periods followed by two consecutive 12-h fasted periods. Serum samples were also assayed for lathosterol concentration, an index of cholesterol synthesis. Serum cholesterol and non-HDL cholesterol concentrations were highest on the SAT diet, lowest (P<0.001) on the POLY diet and intermediate on the MONO diet, triglyceride levels were greater (P<0.03) on the SAT diet than on the POLY diet, and HDL levels were lowest (P<0.05) on the SAT diet and highest on the MONO diet. Cholesterol D enrichment and FSR during each 12-h period were greater (P<0.014) on the POLY diet than on the SAT diet; MONO enrichment and FSR were not significantly different from those on the other two diets. Similar results were obtained for rates of cholesterol esterification (P<0.001). Deuterium enrichment data suggested, and lathosterol data confirmed, that free cholesterol synthesis was greater during the fed period than during the fasted period (P<0.01); however, this could not be confirmed for rates of cholesterol esterification. Results suggest that POLY fat feeding augments de novo cholesterol synthesis without adverse effects on total serum cholesterol concentrations, and that the deleterious effects of SAT fat on serum cholesterol are not brought about by augmented de novo synthesis. Finally, the combination of deuterium incorporation and mathematical modelling produces estimates of daily cholesterol synthesis which are compatible with those invoked by more laborious techniques.