Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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Cold Induced Depot-Specific Browning in Ferret Aortic Perivascular Adipose Tissue
Reynés, Bàrbara ; Schothorst, Evert M. van; Keijer, Jaap ; Ceresi, Enzo ; Oliver, Paula ; Palou, Andreu - \ 2019
Frontiers in Physiology 10 (2019). - ISSN 1664-042X
adipose tissue - browning - cardiovascular disease - cold exposure - inflammation - thermogenesis

Brown adipose tissue is responsible for facultative thermogenesis to produce heat and increase energy expenditure in response to proper stimuli, e.g., cold. Acquisition of brown-like features (browning) in perivascular white adipose tissue (PVAT) may protect against obesity/cardiovascular disease. Most browning studies are performed in rodents, but translation to humans would benefit from a closer animal model. Therefore, we studied the browning response of ferret thoracic aortic PVAT (tPVAT) to cold. We performed global transcriptome analysis of tPVAT of 3-month-old ferrets acclimatized 1 week to 22 or 4°C, and compared the results with those of inguinal subcutaneous adipose tissue. Immunohistochemistry was used to visualize browning. Transcriptome data revealed a stronger cold exposure response of tPVAT, including increased expression of key brown/brite markers, compared to subcutaneous fat. This translated into a clear white-to-brown remodeling of tPVAT, with the appearance of multilocular highly UCP1-stained adipocytes. The pathway most affected by cold exposure in tPVAT was immune response, characterized by down-regulation of immune-related genes, with cardio protective implications. On the other hand, subcutaneous fat responded to cold by increasing energy metabolism based on increased expression of fatty acid oxidation and tricarboxylic acid cycle genes, concordant with lower inguinal adipose tissue weight in cold-exposed animals. Thus, ferret tPVAT responds to cold acclimation with a strong induction of browning and immunosuppression compared to subcutaneous fat. Our results present ferrets as an accessible translational animal model displaying functional responses relevant for obesity and cardiovascular disease prevention.

Replacing Part of Glucose with Galactose in the Postweaning Diet Protects Female But Not Male Mice from High-Fat Diet-Induced Adiposity in Later Life
Bouwman, Lianne M.S. ; Fernández-Calleja, José M.S. ; Stelt, Inge van der; Oosting, Annemarie ; Keijer, Jaap ; Schothorst, Evert M. van - \ 2019
The Journal of Nutrition 149 (2019)7. - ISSN 0022-3166 - p. 1140 - 1148.
adipose tissue - galactose - insulin signaling - lactose - postweaning - programming

BACKGROUND: Duration of breastfeeding is positively associated with decreased adiposity and increased metabolic health in later life, which might be related to galactose. OBJECTIVE: The aim of this study was to investigate if partial replacement of glucose with galactose in the postweaning diet had a metabolic programming effect. METHODS: Male and female mice (C57BL/6JRccHsd) received an isocaloric diet (16 energy% fat; 64 energy% carbohydrates; 20 energy% protein) with either glucose (32 energy%) (GLU) or glucose + galactose (GLU + GAL, 16 energy% each) for 3 wk postweaning. Afterwards, all mice were switched to the same 40 energy% high-fat diet (HFD) for 9 wk to evaluate potential programming effects in an obesogenic environment. Data were analyzed within sex. RESULTS: Female body weight (-14%) and fat mass (-47%) were significantly lower at the end of the HFD period (both P < 0.001) among those fed GLU + GAL than among those fed GLU; effects in males were in line with these findings but nonsignificant. Food intake was affected in GLU + GAL-fed females (+8% on postweaning diet, -9% on HFD) compared with GLU-fed females, but not for hypothalamic transcript levels at endpoint. Also, in GLU + GAL-fed females, serum insulin concentrations (-48%, P < 0.05) and the associated homeostasis model assessment of insulin resistance (HOMA-IR) were significantly lower ( P < 0.05) at endpoint, but there were no changes in pancreas morphology. In GLU + GAL-fed females, expression of insulin receptor substrate 2 (Irs2) (-27%, P < 0.01 ; -44%, P < 0.001) and the adipocyte size markers leptin (Lep) (-40%, P < 0.05; -63% , P < 0.05) and mesoderm-specific transcript homolog protein (Mest) (-80%, P < 0.05; -72%, P < 0.05) was lower in gonadal and subcutaneous white adipose tissue (WAT), respectively. Expression of insulin receptor substrate1 (Irs1) (-24%, P < 0.05) was only lower in subcutaneous WAT in GLU + GAL-fed females. CONCLUSIONS: Partial replacement of glucose with galactose, resulting in a 1:1 ratio mimicking lactose, in a 3-wk postweaning diet lowered body weight, adiposity, HOMA-IR, and expression of WAT insulin signaling in HFD-challenged female mice in later life. This suggests that prolonged galactose intake may improve metabolic and overall health in later life.

Using DNA methylation to predict cardiometabolic diseases | WURcast
Kupers, Leanne - \ 2019
Wageningen :
dna methylation - body mass index - adipose tissue - cardiovascular diseases - metabolic disorders - diabetes
Direct and Long-Term Metabolic Consequences of Lowly vs. Highly-Digestible Starch in the Early Post-Weaning Diet of Mice
Fernández-Calleja, José M.S. ; Bouwman, Lianne M.S. ; Swarts, Hans J.M. ; Oosting, Annemarie ; Keijer, Jaap ; Schothorst, Evert M. van - \ 2018
Nutrients 10 (2018)11. - ISSN 2072-6643
adipose tissue - amylopectin - amylose - C57BL mice - carbohydrates - glycemic index - indirect calorimetry - metabolic flexibility - nutrition - sexual dimorphism

Starches of low and high digestibility have different metabolic effects. Here, we examined whether this gives differential metabolic programming when fed in the immediate post-weaning period. Chow-fed mice were time-mated, and their nests were standardized and cross-fostered at postnatal days 1⁻2. After postnatal week (PW) 3, individually housed female and male offspring were switched to a lowly-digestible (LDD) or highly-digestible starch diet (HDD) for three weeks. All of the mice received the same high-fat diet (HFD) for nine weeks thereafter. Energy and substrate metabolism and carbohydrate fermentation were studied at the end of the HDD/LDD and HFD periods by extended indirect calorimetry. Glucose tolerance (PW 11) and metabolic flexibility (PW14) were analyzed. Directly in response to the LDD versus the HDD, females showed smaller adipocytes with less crown-like structures in gonadal white adipose tissue, while males had a lower fat mass and higher whole body fat oxidation levels. Both LDD-fed females and males showed an enlarged intestinal tract. Although most of the phenotypical differences disappeared in adulthood in both sexes, females exposed to LDD versus HDD in the early post-weaning period showed improved metabolic flexibility in adulthood. Cumulatively, these results suggest that the type of starch introduced after weaning could, at least in females, program later-life health.

Differences in transcriptional responses to acute and chronic dietary interventions with fatty acids
Matualatupauw, Juri C. - \ 2017
Wageningen University. Promotor(en): A.H. Kersten, co-promotor(en): L.A. Afman; J. Bouwman. - Wageningen : Wageningen University - ISBN 9789463432078 - 172
fatty acids - gene expression - genotyping - phenotypes - nutritional intervention - transcriptomics - fish oils - apolipoprotein e - adipose tissue - microarrays - polymerase chain reaction - vetzuren - genexpressie - genotyping - fenotypen - maatregel op voedingsgebied - transcriptomica - visoliën - apolipoproteïne e - vetweefsel - microarrays - polymerase-kettingreactie

Various types of dietary fatty acids have different effects on human health. The aim of this thesis was to increase our understanding of the molecular mechanisms underlying the effects of dietary fatty acids. To do this, we examined changes in whole genome gene expression profiles upon both acute as well as longer term dietary fatty acid interventions. Furthermore, from previous research, it is clear that large inter-individual differences in the response to dietary fatty acids exist. We used whole genome gene expression analyses to increase our understanding of the mechanisms underlying some of these inter-individual differences.

Many modifiable and non-modifiable factors can be the cause of these inter-individual differences. In chapter 2, we reviewed all studies that examined differences in the transcriptional response to dietary interventions based on the presence of one of these factors. These include gender, age, BMI, body composition, blood lipid levels and gut microbial composition. We conclude that transcriptome analyses are well-suited for studying the underlying mechanisms behind these differences in the response to diet. Nevertheless, the number of studies that use this approach remains limited.

Another factor that may modify the response to a dietary intervention is genetics, e.g. the apolipoprotein E4 (APOE4) variant. People who carry the APOE4 allele have an increased risk of cardiovascular disease. Fish-oil supplementation may help in the prevention of cardiovascular disease, though inter-individual differences in the response to n-3 polyunsaturated fatty acids on gene expression profiles have been observed. In chapter 3, we aimed to assess the impact of APOE4 on peripheral blood mononuclear cell (PBMC) whole genome gene expression at baseline and following a 6-month fish-oil intervention. We observed increased gene expression of IFN signaling and cholesterol biosynthesis pathways in APOE4 carriers, which might explain part of the association between APOE4 and CVD. Furthermore, fish-oil supplementation may be beneficial by decreasing interferon signalling-related gene expression in APOE4 carriers.

Another long-term dietary intervention with fatty acids was studied in chapter 4. We examined the effect of a 12-week high medium-chain saturated fatty acid diet on subcutaneous adipose tissue gene expression profiles. We observed increased expression of genes involved in oxidative energy metabolism and decreased inflammation-related gene expression due to the high medium-chain saturated fatty acid intake. Considering the role of the adipose tissue in sustaining the low-grade inflammation that is associated with obesity, these findings may be indicative of a more anti-inflammatory phenotype of the adipose tissue. We concluded that medium-chain saturated fatty acids may potentially have beneficial effects on adipose tissue functioning.

Besides studying the effects of long-term interventions with fatty acids on whole genome gene expression, we also examined the effects of acute high-fat challenges. In chapter 5, we determined the additional value of determining whole genome gene expression changes in response to a high-fat challenge compared to assessment at fasting only. In addition, we aimed to identify whether a 4 week high-fat high-calorie diet can induce a shift in gene expression profiles in healthy subjects towards a metabolic syndrome-like gene expression profile. We found that fasting whole blood whole genome gene expression profiles are highly responsive to a 4-week high-fat high-calorie diet, with changes in in the direction of a metabolic syndrome-like gene expression profile. High-fat challenge responses in healthy subjects show only minimal changes in gene expression upon the dietary intervention and a marginal shift in the direction of the metabolic syndrome. We concluded that fasting gene expression profiles are more responsive compared to high-fat challenge responses to a 4-week high-fat high-calorie diet.

Besides chapter 5, several other studies have also examined changes in whole genome gene expression in blood cells induced by high-fat challenges. In chapter 6, we combined microarray data from four high-fat challenge studies varying in study population, challenge composition and research laboratory. By performing this meta-analysis, we showed a general PBMC whole genome gene expression response to a high-fat challenge. We concluded that a meta-analysis provides added value for the discovery of consistently differentially expressed genes and pathways compared to selecting only those genes and pathways that are identified in all separate studies.

In conclusion, in this thesis we showed differences in the whole genome gene expression response to fish-oil supplementation in PBMCs of APOE4 carriers vs non-carriers. Furthermore, the effects on whole genome gene expression of the two long-term dietary interventions, i.e. the fish-oil supplementation in PBMCs of APOE4 carriers and the high medium-chain saturated fatty acid diet in adipose tissue, may be beneficial by downregulation of gene expression related to inflammation. We also showed that whole genome gene expression responses to high-fat challenges are affected by a 4-week high-fat high-calorie diet, though changes in fasting gene expression profiles are much more pronounced. Finally, we showed the value of meta-analysis of microarray data in high-fat challenge studies for identifying the general response to a high-fat challenge.

Young children and obesity : development and evaluation of familiy-oriented treatment
Hoek, E. van - \ 2015
Wageningen University. Promotor(en): Edith Feskens, co-promotor(en): A.J. Janse; Laura Bouwman. - Wageningen : Wageningen University - ISBN 9789462574540 - 182
obesitas - overgewicht - kinderen - peuters en kleuters - pediatrie - behandeling - kinderziekten - medische behandeling - lichaamssamenstelling - kwaliteit van het leven - vetweefsel - hart- en vaatziekten - kwantitatieve methoden - voeding en gezondheid - obesity - overweight - children - preschool children - paediatrics - treatment - childhood diseases - medical treatment - body composition - quality of life - adipose tissue - cardiovascular diseases - quantitative methods - nutrition and health

Thesis: Young Children and Obesity – Development and Evaluation of Family-oriented Treatment, Esther van Hoek


The prevalence of childhood obesity has increased rapidly during the last decades. Childhood obesity is a multisystem disease with serious consequences such as hypertension, dyslipidemia, chronic inflammation, endothelial dysfunction and hyperinsulinemia. In addition, obese children have a decreased health-related quality of life (HRQoL).

The age interval of 3 to 7 years is a critical growth period. Fast increase of weight in this period is associated with obesity later in life. Furthermore, starting treatment at younger age is associated with a larger reduction in overweight. At the start of this project in 2009, there was no evaluated treatment program available for young obese children (defined as 3 to 8 years).

The risk of cardiovascular diseases and type 2 diabetes (i.e. cardiometabolic risk) can be assessed by measuring conventional risk factors (for example blood pressure). Other markers, such as pro-inflammatory markers, are part of the cardiometabolic risk profile. Epicardial adipose tissue is a metabolically active cardiac fat depot. In obese adults, the epicardial adipose tissue thickness (EATT) is increased, this is correlated to atherosclerosis. It is unknown whether young overweight children have already increased EATT.

The aim of this thesis is to develop, implement and evaluate a treatment program for obese young children. Furthermore, it aims to assess whether EATT is increased in obese young children and is correlated with the cardiometabolic risk profile, and with treatment.


The treatment program for obese young children is developed based on a review of the clinical guidelines, a literature review (including a systematic review with meta-analysis and an extended literature review) and target group interviews. The findings were integrated with professional judgement. To evaluate the resulting program called AanTafel!, a pilot study was performed (n=7 children), including a process evaluation based on parental interviews and questionnaires with the therapists. The effectiveness of AanTafel! was evaluated with a pre-post-test design including 40 children with a median BMI z-score of 3.4 (standard deviation 1.0) in secondary care. The BMI-z-score was the main outcome measure. Secondary outcome measures were components of the metabolic syndrome, markers of cardiometabolic risk, and HRQoL. Outcome measures were assessed at baseline and at the end of treatment (1 year). The BMI z-score was also evaluated 3 years after baseline in the first 23 children who finished treatment. EATT was measured by echocardiography in 25 obese, 8 overweight, and 15 normal weight young children. In the obese and overweight children the EATT, as well as cardiometabolic risk factors, and the markers adiponectin and high sensitive CRP (hsCRP) were measured at baseline and after treatment.


Meta-analysis showed that multicomponent treatment programs of moderate or high intensity (> 26 hours) were the most effective and resulted in a decrease of BMI z-score of 0.5. During the development of the treatment program, the gaps in evidence in clinical guidelines for childhood obesity treatment were overcome by insights from an additional literature review, target group interviews and professional judgement. The resulting treatment program AanTafel! has the following key characteristics: multicomponent, multidisciplinary, family-based with focus on parents, age-specific, tailored to individual children and families, a duration of one year and a combination of individual and group sessions and a web-based learning module. The pilot study showed that to improve parental involvement, peer support, family tailoring, and highly participative elements (such as self-monitoring) are important. The treatment program AanTafel! resulted in a change of mean BMI z-score of -0.5 directly after finishing treatment. This clinical relevant result persisted 2 years after baseline. Furthermore, a significant increase in HDL cholesterol and a reduction in the number of components of metabolic syndrome were found. Regarding markers of cardiometabolic risk, an overall significant decrease was seen in IL18, e-selectin, and sICAM. The HRQoL showed a non-significant improvement in most domains, with a clinically relevant improvement in the physical summary score. EATT was higher in overweight and obese young children compared to their normal weight peers. EATT was inversely correlated with adiponectin, but correlations with other cardiometabolic risk factors were not statistically significant. EATT did not change during treatment (n=17).


During the development process of an obesity treatment program, it was important to add the views of the target group and therapists to the evidence from clinical guidelines and literature review. The resulting treatment program AanTafel! is effective with a clinically relevant decrease of BMI z-score, an improvement of cardiometabolic risk profile, and a clinically relevant increase in the physical summary score of HRQoL. EATT is increased in obese young children; this is inversely correlated with adiponectin.

Molecular and physiological assessment of metabolic health : adipose tissue, transcriptome analysis and challenge tests
Duivenvoorde, L.P.M. - \ 2015
Wageningen University. Promotor(en): Jaap Keijer, co-promotor(en): Evert van Schothorst. - Wageningen : Wageningen University - ISBN 9789462573017 - 186
muizen - metabolisme - gezondheid - vetweefsel - transcriptomen - stofwisselingsstoornissen - fysiologie - laboratoriumdieren - mice - metabolism - health - adipose tissue - transcriptomes - metabolic disorders - physiology - laboratory animals

Summary of main findings

Maintenance of metabolic health not only ensures that energy is made available in times of need and stored in times of excess, but also prevents resistance to nutritional cues, ectopic lipid accumulation and dysfunction of metabolic organs. The proportion of humans that is at risk for reduced metabolic health increases worldwide due to the current epidemic of obesity and the increase in both mean and maximum life span. Better understanding of the various factors that influence metabolic health may offer opportunities to fight this threat to human health. This thesis aims to assess metabolic health using transcriptome analysis and non-invasive challenge tests. Special focus is on the development and validation of InCa-based non-invasive challenge tests. In most chapters of this thesis white adipose tissue (WAT) formed the major organ of interest because of its key role in whole-body energy homeostasis. WAT function was, among others, studied with whole-genome gene expression analysis, which, compared to single parameter analysis, extends the scale and depth of understanding biological processes.

Metabolic health was also quantified as metabolic flexibility, with the use of non-invasive, indirect calorimetry (InCa) based challenge tests. One of the InCa based challenge tests described in this thesis, the oxygen restriction (OxR) challenge, is a novel approach to investigate metabolic flexibility in mice. In each study, OxR was applied acute ([O2] reduction within 30 minutes) and for a short period of 6 hours in fasted mice. The other two InCa-based challenge tests: fasting and re-feeding and fasting and glucose consumption are nutrient-based and were described previously, although in different formats and settings.

In chapter 2 we demonstrate that dietary restriction on a high-fat diet (HF-DR) improves metabolic health of mice compared with mice receiving the same diet on an ad libitum basis (HF-AL). Already after five weeks of restriction, the serum levels of cholesterol and leptin were significantly decreased in HF-DR mice, whereas their glucose tolerance and serum adiponectin levels were increased. The body weight and measured serum parameters remained stable in the following 7 weeks of restriction, implying metabolic adaptation. To understand the molecular events associated with this adaptation, we analysed gene expression in WAT with whole genome microarrays. HF-DR strongly influenced gene expression in WAT; in total, 8643 genes were differentially expressed between both groups of mice, with a major role for genes involved in lipid metabolism and mitochondrial functioning. DR also increases mitochondrial density in WAT. These results show that WAT, indeed, has an important role in the improvement of metabolic health of dietary restricted mice and suggest that the development of substrate efficiency plays an important role in the observed changes in health status. Finally, mitochondrial density might be used as a marker for WAT health status.

Chapter 3 shows how indirect calorimetry can be used to noninvasively assess metabolic and age-related flexibility in mice. In this study, we tested the sensitivity and response stability over time of three InCa-based treatments in old versus adult mice. For the first treatment, diurnal patterns of respiratory exchange ratio were followed for 24 hours under standard conditions. For the second and third treatment, which were both based on a challenge approach, mice were fasted and either received a glucose bolus to test switch-effectiveness from fat to glucose oxidation (Treatment 2), or were exposed to oxygen restriction (OxR, Treatment 3) in the InCa system, which was introduced as a novel approach to asses metabolic flexibility. Opposite to the mice that were dietary restricted (chapter 2), aging appeared to increase adiposity and decrease WAT mitochondrial density, which further suggests that WAT mitochondrial density might be used as a marker for WAT health. We observed that the test results of the first treatment were not stable between test periods, possibly because of behavioural differences within the group of old mice between both measurements. For the second treatment, no differences between groups were observed. With Treatment 3, however, stable significant differences could be detected: old mice did not maintain reduced oxygen consumption under OxR during both measurements, whereas adult mice did. Further biochemical and gene expression analyses showed that OxR affected glucose and lactate homeostasis in liver and WAT of adult mice, supporting the observed differences in oxygen consumption. This was the first study to show that InCa analysis of the response to OxR is a sensitive and reproducible treatment to noninvasively measure age-impaired metabolic health in mice. Evaluation of metabolic health under non-challenged conditions may be confounded by behavioural-induced variation between animals

The study described in chapter 4 followed up on the promising results that were obtained with the OxR challenge in chapter 3. In this study we tested whether OxR can also be used to reveal diet-induced health effects in an early stage. Early detection of diet-induced health effects might shorten animal experiments and reduce costs and age-related variation. Timely identification may increase options for reversal. Mice were exposed to a low-fat (LF) or high-fat (HF) diet for only 5 days, after which they were exposed to OxR or remained under normoxic conditions. The response to OxR was assessed by calorimetric measurements, followed by analysis of gene expression in liver and WAT. A novelty described in this chapter was the analysis of serum markers for protein glycation and oxidation, to detect differences in the response to OxR between LF and HF mice. Although HF feeding increased body weight, HF and LF mice did not differ in indirect calorimetric values under normoxic conditions and in a fasting state. Exposure to OxR however, increased oxygen consumption and lipid oxidation in HF mice versus LF mice. Furthermore, OxR induced gluconeogenesis and an antioxidant response in the liver of HF mice, whereas it induced de novo lipogenesis and an antioxidant response in eWAT of LF mice, indicating that HF and LF mice differed in their adaptation to OxR. OxR also increased serum markers of protein glycation and oxidation in HF mice, whereas these changes were absent in LF mice. From this study we concluded that OxR is a promising new method to test food products on potential beneficial effects for metabolic health.

The study described in chapter 5 aimed to assess differences in metabolic health of mice on iso-caloric diets differing in fatty acid composition using the OxR challenge. We also implemented a fasting and re-feeding challenge. One diet, the HFpu diet, predominantly contained poly-unsaturated fatty acids (PUFAs), which are considered to be healthier than saturated fatty acids (SFAs) that mainly made up the fat component of the second diet, the HFs diet. Since health effects of fatty acids also depend on the ratio of dietary omega-6 to omega-3 PUFAs (n6/n3 ratio), this ratio was kept similar between both diets. Mice received the isocaloric high-fat diets for six months, during and after which several biomarkers for health were measured. We found that HFpu and HFs diets only induce minor differences in static health markers: HFpu and HFs mice did not differ in body weight, total adiposity, adipose tissue health, serum adipokines, whole body energy balance, or circadian rhythm. HFpu and HFs mice also had a similar glucose tolerance, even though HFs mice had more triglycerides in liver and skeletal muscle and larger adipocytes in the eWAT depot. Interestingly, HFs mice were less flexible in their response to both fasting and re-feeding and OxR, which shows the relevance and sensitivity of InCa-based challenge tests. We concluded that InCa-based challenge tests are a valuable contribution to the analysis of metabolic health in mice. Challenge tests in the InCa system may, furthermore, reveal relevant consequences of small changes in metabolic health status, such as adipocyte hypertrophy or ectopic lipid storage.

Chapter 6 describes an in-depth study to the response to OxR both at whole body level using InCa and serum metabolomics (amino acids and (acyl)carnitines) and at WAT level using transcriptomics and the analysis of amino acid and (acyl)carnitine levels. Serum and tissue amino acids levels indicate the level of protein catabolism and certain amino acids are, typically, increased in obese individuals. Serum and tissue (acyl)carnitine levels indicate the rate and completeness of mitochondrial fatty acid oxidation; serum acylcarnitine levels are significantly increased in individuals that suffer from ambient oxygen restriction. The metabolic adaptation to OxR was studied in diet-induced moderately obese mice that received a high-fat diet (HFpu diet, as in chapter 5) for 6 weeks, which is expected to lead to WAT expansion and possibly to reduce oxygen availability in WAT. We found that OxR reduced mitochondrial oxidation at whole-body level, as shown by a reduction in whole-body oxygen consumption and an increase in serum long-chain acylcarnitine levels. WAT did not seem to contribute to this serum profile, since only short-chain acylcarnitines were increased in WAT and gene expression analysis indicated an increase in mitochondrial oxidation, based on coordinate down-regulation of Sirt4, Gpam and Chchd3/Minos3. In addition, OxR did not induce oxidative stress in WAT, but increased molecular pathways involved in cell growth and proliferation. OxR increased levels of tyrosine, lysine and ornithine in serum and of leucine/isoleucine in WAT. This study shows that OxR limits oxidative phosphorylation at whole-body level, but in WAT compensatory mechanisms seem to operate. The down-regulation of the mitochondria-related genes Sirt4, Gpam, and Chchd3 may be considered as a biomarker profile for WAT mitochondrial reprogramming in response to acute exposure to limited oxygen availability.

To conclude, the work presented in this thesis provides more insight in the analysis of metabolic health in mice with the use of transcriptome analysis and InCa-based challenge tests. We show that non-invasive tests using the InCa-system are more likely to reveal differences in metabolic flexibility than invasive challenge tests, such as the oral glucose tolerance test. Furthermore, we show that the challenge approach is more sensitive than analysis of metabolic health under non-challenged (free-feeding) conditions. Transcriptome analysis proved to be very valuable to provide in-depth molecular understanding of the mechanisms underlying reduced or improved metabolic health. Ideally, transciptomic or metabolomic approaches should be integrated with InCa-based challenge tests to further extent physiological understanding of diet-induced health effects.

Unravelling mechanisms of dietary flavonoid-mediated health effects: effects on lipid metabolism and genotoxicity
Hoek-van den Hil, E.F. - \ 2015
Wageningen University. Promotor(en): Ivonne Rietjens; Jaap Keijer, co-promotor(en): Peter Hollman. - Wageningen : Wageningen University - ISBN 9789462573031 - 157
flavanoïden - flavonoïden - vetzuren - quercetine - flavonolen - lichaamsgewicht - lipidenmetabolisme - hart- en vaatziekten - lever - vetweefsel - gezondheid - genotoxiciteit - voeding - muizen - flavanoids - flavonoids - fatty acids - quercetin - flavonols - body weight - lipid metabolism - cardiovascular diseases - liver - adipose tissue - health - genotoxicity - nutrition - mice


Consumption of foods containing flavonoids is associated with a reduced risk of cardiovascular diseases (CVD), possibly by lipid-lowering effects. On the other hand, for one of these flavonoids, quercetin, also genotoxicity was shown especially in in vitro bioassays. Therefore, the first aim of this thesis was to identify mechanisms underlying potential beneficial health effects of flavonoids. The focus was on hepatic lipid metabolism and circulating lipids and a molecular and physiological approach was used. Secondly, we aimed to study the potential in vivo genotoxic effects of quercetin by transcriptome analyses in liver and small intestine, since these represent the tissues of first contact exposed to relatively high levels upon oral intake of flavonoids.

Circulating lipids are important CVD-related risk markers, which are in general determined with commercially available enzyme-based assays. However, the usual enzyme in these assays, peroxidase, has previously been reported to be inhibited by flavonoids. Therefore, we have studied in chapter 2 whether these assays can adequately be used in flavonoid research. We observed that various flavonoid aglycones interfere with peroxidase used in triglycerides (TG) and free fatty acids (FFA) enzymatic assays, reporting incorrect lower TG and FFA levels than actually present. Furthermore, addition of metabolites such as isorhamnetin or quercetin-3-O-glucuronide, the major metabolite of quercetin in human and rat plasma, to murine serum also resulted in a significant reduction of the detected TG levels, while a trend was seen towards reduced FFA levels. It can be concluded that when applying these biochemical assays, vigilance is needed and alternative analytical methods assessing FFA or TG levels should preferably be applied for studying the biological effects of flavonoids on TG and FFA levels.

In chapter 3 mechanistic and physiological effects of quercetin on hepatic lipid metabolism were studied. C57BL/6JOlaHsd male adult mice received a mild high-fat (30 en%) diet without or with supplementation of 0.33% (w/w) quercetin for 12 weeks. Gas chromatography and 1H-NMR were used to quantitatively measure serum lipid profiles. Whole genome microarray analysis of liver tissue was used to identify potential mechanisms underlying altered circulating lipid levels by quercetin supplementation. Body weight, energy intake and hepatic lipid accumulation did not differ significantly between the quercetin and the control group. In serum of quercetin-fed mice, TG levels were decreased by 14% (p<0.001) and total poly unsaturated fatty acids (PUFA) levels were increased by 13% (p<0.01). Levels of palmitic acid, oleic acid, and linoleic acid were all decreased by 9-15% (p<0.05) in quercetin-fed mice. Both palmitic acid and oleic acid can be oxidized by omega-oxidation. Gene expression profiling showed indeed that quercetin increased hepatic lipid metabolism, especially omega-oxidation. At the gene level, this was reflected by the up-regulation of cytochrome P450 (Cyp) 4a10, Cyp4a14, Cyp4a31 and Acyl-CoA thioesterase 3 (Acot3). Two relevant regulators, cytochrome P450 oxidoreductase (Por, rate limiting for cytochrome P450 activities) and the transcription factor constitutive androstane receptor (Car; official symbol Nr1i3) were also up- regulated in the quercetin-fed mice. We concluded that quercetin intake increased hepatic lipid omega-oxidation and lowered corresponding circulating lipid levels, which may contribute to potential beneficial effects of quercetin on CVD.

Subsequently, in chapter 4 effects of quercetin supplementation were studied in mice given a high-fat (40 en%) background diet. The set-up of the experiment was the same as in chapter 3, with the exception of the background diet that was used, which was different in fat content and composition. This high-fat diet-induced body weight gain, and serum and hepatic lipid accumulation, which are all known risk factors for CVD. The aim of this study was to investigate the effects and underlying molecular mechanisms of the effects of the flavonoid quercetin on hepatic lipid metabolism in mice given this high-fat diet background. C57BL/6JOlaHsd male adult mice received the high-fat diet without or with supplementation of 0.33% (w/w) quercetin for 12 weeks. Body weight gain was 29% lower in quercetin fed mice versus control mice (p<0.01), while the energy intake was not significantly different. Quercetin supplementation lowered high-fat diet-induced hepatic lipid accumulation to 29% of the amount present in the control mice (p<0.01). 1H-NMR serum lipid profiling revealed that the supplementation also significantly lowered high-fat diet-induced increases in serum lipid levels. Global gene expression profiling of liver showed that cytochrome P450 2b (Cyp2b) genes, key target genes of the transcription factor Car, were down-regulated. However, the induction of omega-oxidation observed by quercetin supplementation to a mild high-fat (30en%) diet (chapter 3), was not observed this time with the high-fat (40en%) diet. Cumulatively, quercetin decreased high-fat diet-induced body weight gain, hepatic lipid accumulation and serum lipid levels. This was accompanied by regulation of cytochrome P450 2b genes in liver, which are considered to be under transcriptional control of CAR. The quercetin effects are likely dependent on the fat content and composition of the diet.

In chapter 5 we investigated whether flavonoids from other flavonoid subclasses can exert the same effects as we observed for quercetin. Effects of quercetin, hesperetin, epicatechin, apigenin and anthocyanins, in C57BL/6JOlaHsd male adult mice fed a high-fat diet for 12 weeks were compared, relative to a normal-fat diet. High-fat diet-induced body weight gain was significantly lowered by all flavonoids (17-29%), but most by quercetin. Quercetin significantly lowered high-fat diet-induced hepatic lipid accumulation (by 71%). High-fat diet-induced increases of mesenteric adipose tissue weight and serum leptin levels were significantly lowered by quercetin, hesperetin, and anthocyanins. Adipocyte cell size and adipose tissue inflammation were not affected.

The effects on body weight and adiposity could not be explained by individual significant differences in energy intake, energy expenditure, nor by differences in activity. Lipid metabolism was not changed as measured by indirect calorimetry or expression of known lipid metabolic genes in liver and white adipose tissue. Hepatic expression of Cyp2b9 was strongly down-regulated by all flavonoids. Overall, all five flavonoids lowered parameters of high-fat diet-induced adiposity, with quercetin being most effective.

Next to the beneficial health effects of flavonoids, the safety of flavonoids is under discussion, mainly because of potential genotoxic effects found for quercetin in vitro. Therefore, in chapter 6 the in vivo genotoxicity of this flavonoid was studied by transcriptome analyses in two tissues, small intestine and liver, where the highest exposure to quercetin is expected. This is especially of interest in view of high intake by widely available food supplements. Quercetin (0.33%) supplemented to a high-fat diet was administered to C57BL/6JOlaHsd male adult mice during 12 weeks. Serum alanine aminotransferase and aspartate aminotransferase levels revealed no indications for hepatotoxicity. General microarray pathway analysis of liver and small intestinal tissue samples showed no regulation of genotoxicity related pathways. In addition, analysis of DNA damage pathways in these tissues did also not point at genotoxicity. Furthermore, comparison with a published classifier set of transcripts for identifying genotoxic compounds did not reveal any similarities in the regulation of these classifier set by quercetin. Available microarray datasets of known genotoxic liver carcinogens, 2-acetylaminofluorene and aflatoxin B1 in mice were taken along as positive controls for comparison, and indeed showed genotoxic properties (regulation of genotoxic related genes) in the analyses. This transcriptomic analysis showed that supplementation with quercetin at ~350 mg/kg bw/day for 12 weeks did not induce genotoxicity in liver and small intestine.

In conclusion, we have shown in vivo efficacy of flavonoids reflected by effects on metabolic health parameters, including hepatic lipid metabolism. These effects on hepatic lipid metabolism seemed to be related or influenced by the transcription factor CAR. The dietary contexts appeared to modify the health effects. The five studied flavonoids in general showed the same effects, with quercetin being the most effective. No genotoxicity of quercetin was found by transcriptome analyses in liver and small intestine. Overall, we have obtained indications for beneficial health effects of flavonoids in mice, which makes it interesting to study if these effects can be extrapolated to humans to further explore their potential as functional compounds of dietary flavonoid intake.

Metabolic adaptation of white adipose tissue to nutritional and environmental challenges
Hoevenaars, F.P.M. - \ 2014
Wageningen University. Promotor(en): Jaap Keijer, co-promotor(en): Evert van Schothorst. - Wageningen : Wageningen University - ISBN 9789461739162 - 166
muizen - vetweefsel - metabolisme - adaptatiefysiologie - voeding - milieufactoren - obesitas - energieopname - zuurstoftekort - ontsteking - voedingsfysiologie - diermodellen - mice - adipose tissue - metabolism - adaptation physiology - nutrition - environmental factors - obesity - energy intake - oxygen deficiency - inflammation - nutrition physiology - animal models

Summary of main findings

When adipose tissue is present in excessive amounts, as in obesity, it predisposes to a number of pathologies. Obesity is a complex, multifactorial condition as it influences many endogenous genetic, endocrine, and inflammatory pathways. Excess dietary intake is one of the important factors which are responsible for the increasing prevalence of obesity. For the understanding of the reciprocity between

consumed diet and excessive amounts of adipose tissue, it is essential to investigate underlying functioning. In this thesis, I have addressed three important aspects that play a role in the development of diet induced obesity and its pathologies with a focus on adipose tissue metabolism.

Does a body weight set-point exist?

How is the diet-induced metabolic response affected by housing at


Does oxygen restriction induce inflammation in white adipose tissue?

The first aspect investigated was the existence of a body weight set point. A body weight set point is defined as a pre-determined or preferred level of body weight which is preserved by an internal feedback control mechanism. In chapter 2, a dietary intervention with none, one, or two diet alterations of purified diets was performed in C57BL/6J mice to investigate if a long lasting effect on body weight persistence was present. Diets contained equal protein content and source of ingredients but differed in the fat-to-sugar ratio. Therefore, energy content and amount of fat was different for either the low fat diet or the high fat. In the intervention the last consumed diet of the mice determined energy intake, energy expenditure, body weight, body fat stores, circulating hormones and metabolites. These data support the settling point theory as body weight and metabolic parameters ‘settle’ based on current energetic input and output and do not support the set point theory. Next to that it underlines the importance of diet choice in intervention studies focusing on aspects on the crossroads of nutrition and physiology.

In chapter 3adipose tissue physiology and molecular regulation was further investigated by exposure to more metabolic stress in the form of a weight loss challenge with different purified diets. Diet-induced obese C57BL/6J mice were fed a high fat diet restricted to 70% intake of previous ad libitum high fat diet

intake or they were changed to ad libitum low fat diet for 5 weeks. Beneficial effects were seen in both interventions regarding physiological parameters. However, molecular parameters in white adipose tissue differed between the two restriction interventions, with increased activation of mitochondrial carbohydrate and fat metabolism in high fat diet restricted mice. When extrapolated to the human

situation this may suggest that a reduction of portion size is the best method for weight loss.

It is standard practice to house mice at ambient temperature during physiological intervention studies. Unfortunately mice are then exposed to a temperature below their thermal neutral zone. This implies that their metabolism is chronically increased which is known to influence study outcomes. In chapter 4the second question; “how is the diet-induced metabolic response affected by housing at thermoneutrality?”was investigated. A 14-week dietary intervention with two semi-purified diets, a

low fat diet and a moderately high fat diet, was performed at 28°C in C57BL/6J mice. This resulted in a large diet-induced difference in bodyweight, adipose tissue mass, adipocyte size, and serum leptin level. But no differential effects of the diets were seen on serum glucose, free fatty acids, triacylglycerides, insulin, a panel of cardiovascular markers, and a number of (metabolic) parameters in liver and muscle.

Although adipose tissue mass and adipocyte size was increased significantly, there was no sign of inflammation or dysfunction in the adipose tissue. This study suggests that diet-induced obesity of C57BL/6J mice at thermoneutrality results in a suitable model for the metabolically ‘healthy’ obese (people who are significantly overweight but show none of the usual metabolic problems). Next to that, this study emphasizes the importance of consideration and control of housing temperature for mice, as it has profound effects on study outcomes.

The third and last question investigated was if oxygen restriction is able to induce inflammation in white adipose tissue. There is substantial evidence that white adipose tissue becomes hypoxic when excessively enlarged. Due to fast expansion of white adipose tissue the vasculature is not able to keep pace with growth. Next to that, adipocytes are able to increase in size beyond the limit of oxygen diffusion. To investigate if hypoxia was able to induce inflammation in white adipose tissue, the model for healthy obese adipocytes (developed in chapter 4) was used and exposed to ambient oxygen restriction (13%) to challenge adipose tissue metabolism. This resulted in the presence of systemic oxygen restriction as shown by increased levels of hemoglobin and hematocrit. Furthermore a switch to glycolytic metabolism, which is indicative for tissue hypoxia, was present. No differences in adipose tissue macrophage infiltration (as marker for inflammation) were found. But, serum branched chain amino acids and adipokines were affected. Branched chain amino acids were increased in mice exposed to oxygen restriction which shows resemblance with findings in humans where increased levels were found in lean versus obese people. The peptide hormone adiponectin was increased in serum, without differences in WAT expression. On the other hand, the peptide hormones CCDC3 and CCK showed decreased transcript levels in white adipose tissue without significant change in serum levels, although for CCDC3 a trend was seen. Together these results suggest that oxygen restriction does not induce inflammation in adipose tissue. However, it does affect adipokine regulation.

After performing these studies it was clear that composition of the diet has a major influence on outcome parameters of physiological studies as shown in chapter 2. To compare functional effects of different nutrients, it is important to use standardized purified diets. Not only the experimental intervention diet is of importance but also the reference control diet can influence outcomes. For example, when an intervention is performed with a high fat purified diet and the reference diet is chow this will lead to a difficult comparison. The content of chow is variable as it is grain or cereal based (ground corn, ground oats alfalfa meal, soybean meal and ground wheat). Nutritional adequacy is ensured by addition of vitamins, minerals, and fat. However, the exact amount of the various ingredients is frequently kept secret by the manufacturer. Next to that, due to the plant based origin of chow it will contain nutritive (protein, carbohydrate, fat) components but also non-nutritive components (phytochemicals). The content of the chow diet will vary from batch to batch as the nutritive and nonnutritive value will change between harvests. When using a chow reference diet in

comparison to a purified diet you will never know exactly what you are comparing, i.e. difference in amino acids or effects of phytochemicals etc. Therefore, a reference diet for physiology was designed (chapter 6) to improve comparison of study outcomes and to increase efficiency of resources and material. A key feature of the diet is the fixed protein concentration, which allows for an exchange of carbohydrate and fat in a high fat version of the diet.

To conclude, the work presented in this thesis provides clear insight in factors that are of importance for improvement of translatability of mouse studies to the human situation. It was shown that when investigating the weight balance many parameters, i.e. genetics, metabolic rate, environmental factors like ambient housing temperature and light and cognitive behavior, besides the diet and its composition are able to influence the outcome parameters. As most mouse experiments are performed

in a fixed environment with no choices of food and a standard temperature set to 22°C. This is clearly not reflective of humans under free living conditions. However, these fixed conditions are able to result in experiments that unravel underlying mechanisms of weight balance, which form the basis for discovering a solution to the obesity epidemic.

Moderate alcohol consumption, adiponectin, inflammation and type 2 diabetes risk : prospective cohort studies and randomized crossover trials
Joosten, M.M. - \ 2011
Wageningen University. Promotor(en): Renger Witkamp, co-promotor(en): H.F.J. Hendriks. - [S.l. : S.n. - ISBN 9789085858256 - 192
alcoholinname - diabetes mellitus - risico - genexpressie - vetweefsel - hormonen - alcohol intake - diabetes mellitus - risk - gene expression - adipose tissue - hormones
Background: Moderate alcohol consumption has been associated with a lower risk of type 2 diabetes in various populations. However, the underlying mechanisms are not entirely clear. The aims of this thesis were 1) to substantiate the evidence of the association between alcohol consumption and type 2 diabetes in observational research and 2) to examine physiological mechanisms in randomized trials with specific attention to adiponectin, inflammation and insulin sensitivity which may mediate the association between alcohol consumption and type 2 diabetes.

Methods: Two prospective cohort studies, one among 38,031 U.S. men (age: 45-75 y) of the Health Professionals Follow up Study (HPFS) and one among 35,625 Dutch men and women (age: 20-70 y) of the European Prospective Investigation into Cancer and Nutrition (EPIC)-NL cohort. Four randomized, crossover trials of eight to twelve weeks with consumption of 25-30 g alcohol/day in the form of vodka with orange juice, beer, or white wine (twice) compared to orange juice, alcohol free beer, white grape juice or water among 24 young men, 24 premenopausal and 36 and 22 postmenopausal women, respectively.

Results: A 7.5 g/day increase in alcohol consumption over four years was associated with lower diabetes risk among initial non-drinkers (hazard ratio [HR]: 0.78; 95% confidence interval (CI): 0.60, 1.00) and drinkers initially consuming <15 g/d (HR: 0.89; 95% CI: 0.83, 0.96) but not among men initially drinking ≥15 g/d (HR: 0.99; 95% CI: 0.95, 1.02) (Pinteraction < 0.01) in U.S. men. Among Dutch subjects with ≥3 out of 4 low-risk lifestyle behaviors, moderate alcohol consumption was associated with a lower risk of type 2 diabetes compared with abstention (HR: 0.56; 95% CI: 0.32, 1.00).
In the randomized crossover trials, alcohol consumption consistently increased circulating adiponectin levels by about 10% compared to abstention (P < 0.05) regardless of beverage type, gender or age. These increases were evident after a minimum of three weeks of alcohol consumption. Moderate alcohol consumption also increased expression of the gene encoding adiponectin in adipose tissue and lowered serum fasting insulin and triglyceride levels (all P < 0.05). An integrated approach of large-scale profiling of proteins and genes revealed that moderate alcohol consumption for four weeks altered gene expression profiles of white blood cells and circulating markers related to inflammation in men (all P < 0.05). However, we did not observe an attenuated inflammatory response after a low-dose in vivo endotoxin bolus, despite increased high-density lipoprotein cholesterol and apolipoprotein levels after four weeks of alcohol consumption compared to abstention. Six minutes of oral white wine exposure without swallowing substantially (-20%; P < 0.05) and temporarily (~20 min) decreased circulating free fatty acid concentrations compared with oral water exposure.

Conclusions: Moderate alcohol consumption was associated with a lower risk of type 2 diabetes compared with abstention. The association persisted among subjects already at low risk based on combined favorable lifestyle behaviors. Also, increases in alcohol consumption among initially rare and light drinking men were associated with higher adiponectin levels and lower risk of type 2 diabetes. Increased adiponectin levels, anti-inflammatory effects and decreased insulin and triglyceride levels, may partially explain the inverse association between moderate alcohol consumption and type 2 diabetes.

Als vet gaat ontsteken : hoe voeding kan leiden tot chronische ziektes
Wolkers, J. - \ 2010
WageningenWorld 2010 (2010)1. - ISSN 2210-7908 - p. 28 - 35.
voedselwetenschappen - ziekten - vetweefsel - ontsteking - levensstijl - voedselconsumptie - voeding en gezondheid - food sciences - diseases - adipose tissue - inflammation - lifestyle - food consumption - nutrition and health
Hart- en vaatziekten, astma, diabetes en zelfs kanker zouden wel eens één ding met elkaar gemeen kunnen hebben: een chronische ontstekingsreactie in het lichaam, die ontstaat in vetweefsel. Voeding speelt hierin een grote rol, blijkt uit nieuwe inzichten van Wageningse voedingswetenschappers.
Lichaam in balans
Keijer, J. - \ 2009
Wageningen : Wageningen Universiteit, Wageningen UR - ISBN 9789085852803
mens - dieren - energiebalans - homeostase - vetweefsel - quetelet index - obesitas - fysiologische functies - voedingsfysiologie - gezondheid - man - animals - energy balance - homeostasis - adipose tissue - body mass index - obesity - physiological functions - nutrition physiology - health
N-3 polyunsaturated fatty acids in adipose tissue and depression in different age groups from Crete
Mamalakis, G. - \ 2007
Wageningen University. Promotor(en): Daan Kromhout; A. Kafatos. - [S.l.] : S.n. - ISBN 9789085046622 - 176
depressie - meervoudig onverzadigde vetzuren - vetweefsel - epidemiologische onderzoeken - kreta - depression - polyenoic fatty acids - adipose tissue - epidemiological surveys - crete
In this thesis, the results of cross-sectional studies on the relationship of depression with adipose tissue n-3 polyunsaturated fatty acids have been described. The aim of this thesis is to investigate whether adipose tissue n-3 fatty acids, an objective index or biomarker of long-term or habitual n-3 fatty acid intake, relate to depression. The study populations in this thesis consisted of generally healthy adolescent, adult and elderly volunteers from the island of Crete. The results presented in this thesis demonstrated for the first time in the different age-groups studied, significant inverse relationships between depression and different adipose tissue n-3 fatty acids. Adipose tissue eicosapentaenoic acid (EPA) was significantly inversely associated with depression in adolescents. Similar relations were found for adipose tissue docosahexaenoic acid (DHA) in adults and for adipose tissue alpha-linolenic acid (ALA) in elderly subjects. Although the evidence is not strong enough to give a recommendation, it is possible that in addition to preventing cardiovascular diseases, frequent or regular consumption of fish/seafood may also help to prevent depression.
Characterization of the two PPAR target genes FIAF (Fasting-Induced Adipose Factor) and G0S2 (G0/G1 switch gene 2)
Zandbergen, F.J. - \ 2006
Wageningen University. Promotor(en): Michael Muller, co-promotor(en): Sander Kersten. - s.l. : S.n. - ISBN 9085043921 - 136
lipidenmetabolisme - obesitas - vetweefsel - genexpressie - vasten - hormonen - lipid metabolism - obesity - adipose tissue - gene expression - fasting - hormones
Hormonal regulation of puberty onset in female rats: is leptin a missing link?
Zeinoaldini, S. - \ 2005
Wageningen University. Promotor(en): D. van der Heide, co-promotor(en): H.J.M. van de Heijning. - Wageningen : Wageningen University - ISBN 9085042011 - 176
ratten - vrouwelijke dieren - polypeptiden - hormonen - puberteit - hormonale controle - vetweefsel - dierproeven - endocrinologie - rats - female animals - polypeptides - hormones - puberty - hormonal control - adipose tissue - animal experiments - endocrinology
Visceral fat and weight loss in obese subjects : relationship to serum lipids, energy expenditure and sex hormones
Leenen, R. - \ 1993
Agricultural University. Promotor(en): J.G.A.J. Hautvast; P. Deurenberg; J.C. Seidell. - S.l. : Leenen - ISBN 9789054850854 - 123
obesitas - overgewicht - vetweefsel - voeding - vetten - biometrie - geslachtshormonen - energiebehoeften - voedselhygiëne - voedingstoestand - consumptiepatronen - obesity - overweight - adipose tissue - nutrition - fats - biometry - sex hormones - energy requirements - food hygiene - nutritional state - consumption patterns

This thesis describes the relationships between visceral fat accumulation and serum lipids, energy expenditure, and sex hormone levels in healthy obese men and premenopausal women undergoing weight loss therapy. The subjects, aged 27-51 years, with an initial body mass index of 28-38 kg/m 2, received a controlled diet for 13 weeks providing a 4.2 MJ/day energy deficit. Magnetic resonance imaging was used to quantify fat depots.

In women but not in men, visceral fat accumulation was associated with a less favourable serum lipid profile independent of age and body fat percentage. In addition, in women only, visceral fat predominance was positively related to resting metabolic rate (RMR) and diet- induced thermogenesis (DIT) as well as to a relatively increased androgenicity. In obese men, no relationship could be found between visceral fat accumulation and any of the sex hormone levels.

The mean weight reduction of 12.2 ± 3.5 (SD) kg due to the energy-deficit diet, resulted in larger reductions in serum levels of total cholesterol, LDL cholesterol, and triglycerides and a larger increase in the HDL cholesterol/LDL cholesterol ratio in men compared with women. Men with an initially larger visceral fat depot than women did not lose more body weight, but they lost more visceral fat than women. Comparison of these average changes between both sexes suggests a potential role of visceral fat loss in improving the serum lipid profile. While in women, a loss of visceral fat was related to an increased HDL cholesterol, a more general beneficial effect of visceral fat loss was not seen using correlation analyses within each sex. In women but not in men, visceral fat accumulation before weight loss was associated with improvement of HDL cholesterol and triglyceride levels after weight loss. In women only, a reduction in the visceral fat depot also seems to be accompanied by a relative reduction in androgenicity regardless of total body fat loss.

In this study, the effect of weight loss alone on serum lipids could be separated from the effect of dietary fat modification usually accompanying a dietary weight loss treatment. The favourable effect of weight loss per se seems to be considerable in optimizing the serum lipid profile of obese subjects and even greater than that of dietary fat modification.

It is concluded that there may be gender differences in the associations between visceral fat accumulation and serum lipids, energy expenditure (RMR and DIT), and sex hormone levels in healthy moderately obese subjects. In addition, particularly healthy moderately obese women with a visceral fat predominance benefit from a dietary weight loss treatment with respect to their serum lipid profile and sex hormone levels. In healthy moderately obese men, the critical role of the visceral fat depot could not be confirmed.

Changes in body composition and fat distribution in response to weight loss and weight regain
Kooy, K. van der - \ 1993
Agricultural University. Promotor(en): J.G.A.J. Hautvast; P. Deurenberg; J.C. Seidell. - S.l. : Van der Kooy - ISBN 9789054850991 - 123
obesitas - overgewicht - voeding - vetten - biometrie - energiebehoeften - voedselhygiëne - voedingstoestand - consumptiepatronen - vetweefsel - obesity - overweight - nutrition - fats - biometry - energy requirements - food hygiene - nutritional state - consumption patterns - adipose tissue

This thesis describes the effects of weight loss and subsequent weight regain on body composition, fat distribution and resting energy expenditure in moderately obese men and moderately obese premenopausal women. Participants were subjected to a controlled 4.2 MJ/day energy deficit diet for 13 weeks, and re-examined more than one year after weight loss intervention. Five techniques to assess the changes in body composition after weight loss (on average 12.2 ± 3.7 kg (mean ± SD)) were compared. The results from densitometry (hydrostatic weighing) and the deuterium oxide dilution technique were similar, whereas, bioelectrical impedance and two anthropometric methods (skinfold thicknesses and body mass index) showed larger reductions in fat-free mass (FFM) than estimated by densitometry and the dilution technique. These findings were similar in both sexes. Magnetic resonance imaging (MRI) was used to assess the reductions after weight loss in the visceral and subcutaneous abdominal fat depots and the subcutaneous fat depot at trochanter level. The proportional reduction of fat was largest in the visceral depot (men 40%, women 33%) and less fat was lost subcutaneously, especially at trochanter level (men 29%, women 26%). The reductions in visceral fat as measured by MRI were compared with changes in anthropometric measurements. The change in waist-to-hip ratio (WHR) was not related to the change in visceral fat, and the change in sagittal-to-transverse abdominal diameter ratio was only moderately associated with visceral fat loss in both sexes. During the follow-up of 67 weeks after weight loss, 80% of the weight lost was regained on average. In men but not in women, the reduction in resting metabolic rate (RMR) after weight loss was larger than expected from the losses of FFM and fat mass. The RMR returned to baseline level in both sexes after weight regain. The reduction in RMR was not related to later weight regain. Percentage body fat and amount of visceral fat also nearly returned to the level similar to that before weight loss.

It is concluded that bioelectrical impedance and anthropometric measurements are not as good as densitometry or the deuterium-oxide dilution method for the evaluation of changes in body composition. Only approximate estimates of visceral fat can be achieved by anthropometry. As a consequence, the assessment of changes in visceral fat by anthropometry is limited. Finally, one weight cycle as observed in this study does not lead to a permanently reduced RMR, nor to a greater body fatness nor to an increase in visceral fat compared with initial levels.

Prediction of production : nutrition induced tissue partitioning in growing pigs
Greef, K.H. de - \ 1992
Agricultural University. Promotor(en): M.W.A. Verstegen; B. Kemp. - S.l. : De Greef - 117
voer - varkens - groei - ontwikkeling - biologie - biochemie - biofysica - moleculaire biologie - vetweefsel - modellen - onderzoek - feeds - pigs - growth - development - biology - biochemistry - biophysics - molecular biology - adipose tissue - models - research

In several swine growth models, a constant ratio is assumed between lipid deposition rate and protein deposition rate when pigs are fed below their protein deposition capacity. In the present thesis, it was studied whether there is an effect of energy intake, live weight and nutritional history on composition of growth in restrictedly fed pigs. Results showed that all three mentioned factors affected the composition of growth. Fatness of deposited tissue increased both with an increase in energy intake and with live weight. It was concluded that the composition of total tissue is not constant. It was derived that the composition of extra tissue, deposited due to extra energy intake is independent of energy intake. This extra tissue is consistently fatter than total deposited tissue. This explains the increase in fatness of pigs with each increase in energy intake. It was studied which factor (energy intake or body weight) is of major importance for the partitioning of tissue. Composition of growth was affected by energy intake to a considerably larger extent than by live weight. Furthermore, data on the partitioning of deposited protein and lipid within the body showed that, even at low energy intakes, the major part of extra tissue (due to extra energy intake) was deposited in non-lean carcass parts.

Overweight and fat distribution : associations with aspects of morbidity
Seidell, J.C. - \ 1986
Landbouwhogeschool Wageningen. Promotor(en): J.G.A.J. Hautvast; P. Deurenberg. - Wageningen : Seidell - 146
obesitas - overgewicht - vetweefsel - volksgezondheid - gezondheidszorg - obesity - overweight - adipose tissue - public health - health care
This thesis reports on the association between estimates of the amount and distribution of fat mass with aspects of morbidity in Dutch adults. A literature review on the current insights into these associations is included. The results of several cross-sectional and retrospective cohort studies are presented. The prevalence of severe overweight, defined as a Body Mass Index (BMI=kg/m 2) higher than 30 kg/m 2, is about 6% in women and 4% in men, while about 34% of the men and 24% of the women are moderately overweight (BMI 25-30 kg/m 2). Among overweight persons, especially when severely overweight, the prevalence and incidence of various chronic disorders and use of aspects of medical care was higher than in non-overweight persons. For gout and arteriosclerotic disease, overweight appeared to be a risk factor at lower levels of BMI in men than in women. The incidence was particularly high in men with an initial BMI between 27-30 kg/m 2. The association between BMI and subjective health was more pronounced in women than in men. This was true for certain somatic as well as psychosomatic complaints. Fat distribution, as measured with the waist-hip circumference ratio or waist-thigh circumference ratio, was shown to be related to the prevalence of certain chronic disorders in men and women. These associations were independent of age and BMI. A study in which Computed Tomography scans, taken at the level of the L4 vertebra, were related to anthropometric measurements, revealed that correlations of circumference ratios with the amount of intra-abdominal fat were higher than with subcutaneous abdominal fat.

It is concluded that overweight is related to aspects of morbidity but that it may be particularly relevant to include fat distribution measurements in the evaluation of health risks in overweight subjects.

Factoren die invloed hebben op de verdeling van het vetweefsel over verschillende vetdepots in runderkarkassen
Dijkstra, M. - \ 1979
Zeist : I.V.O. (Rapport / Instituut voor Veeteeltkundig Onderzoek ''Schoonoord'' no. B-138) - 13
rundvee - vetweefsel - groei - ontwikkeling - cattle - adipose tissue - growth - development
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