Effects of maternal high-fat/high sucrose diet on hepatic lipid metabolism in rat offspring.

Maternal obesity and/or high-fat diet during pregnancy predispose the offspring to metabolic disease. It is however unclear how pre-natal and post-natal exposure respectively affect the risk of hepatic steatosis and the trajectory towards non-alcoholic steatohepatitis in the offspring. We investigate hepatic lipid metabolism and how these factors are related to metabolic outcome in new born and young rats. Rat dams were exposed to a high-fat/high sucrose (HFHS) diet for 17 weeks prior to mating and during pregnancy. After birth, female offspring were killed and male offspring were cross-fostered, creating four groups; Control-born pups lactated by control (CC) or HFHS dams (CH) and HFHS-born pups lactated by control (HC) or HFHS dams (HH). At 4 weeks of age, pups were killed and metabolic markers in plasma were assayed, together with hepatic lipid composition and expression of relevant genes. Female HFHS neonates had smaller livers at birth (P < .05), a reduced hepatic lipid content (P < .05) and altered lipid composition. The post-natal environment dominated the metabolic profile in the male offspring at 4 weeks of age. Offspring exposed to a HFHS environment post-natally had increased adiposity (P < .0001), increased hepatic triacylglycrol accumulation (P < .0001), and an altered lipid profile with elevated n-6 polyunsaturated fatty acid (PUFA) levels (P < .0001) and a reduction in ceramide (P < .001) and monounsaturated fatty acid (MUFA) (P < .0001). In summary, maternal HFHS diet during gestation affects the hepatic lipid profile in neonates. The pre-natal exposure becomes less pronounced in young male offspring at 4 weeks of age, where the post-natal diet has the largest impact.

Changes in long-chain fatty acid composition of milk fat globule membrane and expression of mammary lipogenic genes in dairy cows fed sunflower seeds and rumen-protected choline.

The aim of this experiment was to investigate the effect of dietary supplementation of crushed high oleic sunflower seeds (HOS) and rumen-protected choline (RPC) on the fatty acid (FA) profile of phospholipids and sphingomyelin and mammary transcription of genes that are important for milk fat synthesis and de novo synthesis of sphingolipids. Twenty-four cows were divided into four groups that either received an unsupplemented diet (Control), the Control diet supplemented with 50 g RPC per day, a diet supplemented with HOS at 10% of dry matter, or RPC and HOS in combination (RPC + HOS). RPC supplementation had no effect on the FA composition of milk or sphingomyelin. Cows receiving RPC and RPC + HOS had increased incorporation of C22:5 (n-3) into phospholipids. Milk FA proportion of C18:0 and C18:1 isomers was increased in cows receiving HOS (HOS and RPC + HOS). Sphingomyelin proportion of C22:0 was increased in cows receiving HOS and RPC + HOS, at the expense of C23:0. HOS supplementation further increased the proportion of unsaturated fatty acids (UFA) in milk phospholipids. HOS supplementation increased mammary transcription of UDP-glucose ceramide glycosyltransferase (UGCG), sterol response element-binding protein cleavage-activating protein (SCAP) and peroxisome proliferation-activated receptor Gamma subunit C 1b (PPARGC1b), and reduced transcription of insulin induced gene 1 (INSIG1) and fatty acid-binding protein 3 (FABP3). Dietary supplementation of RPC increased mammary transcription of fatty acid desaturase 1 (FADS1) and longevity assurance gene 2 (LASS2), and reduced transcription of sphingomyelin synthase (SGMS). The results show that the FA profile of milk phospholipids is sensitive to dietary lipid supplementation and, to a minor degree, RPC supplementation. Furthermore, transcription of genes that are important for milk fat synthesis and sphingolipids synthesis is affected by dietary supplementation of RPC and HOS.

Optimization of tolerability and efficacy of the novel dual amylin and calcitonin receptor agonist KBP-089 through dose escalation and combination with a GLP-1 analog.

Amylin and GLP-1 agonism induce a well-known anorexic effect at dose initiation, which is managed by dose escalation. In this study we investigated how to optimize tolerability while maintaining efficacy of a novel, highly potent dual amylin and calcitonin receptor agonist (DACRA), KBP-089. Furthermore, we tested the GLP-1 add-on potential of KBP-089 in high-fat diet (HFD)-fed rats. KBP-089 potently activated both the amylin and calcitonin receptors in vitro and demonstrated a prolonged receptor activation as well as a potent reduction of acute food intake. HFD rats dosed every day or every second day obtained equal weight loss at study end, albeit with an uneven reduction in both food intake and body weight in rats dosed every second day. In a 4-fold dose escalation, KBP-089 induced a transient reduction in food intake at every escalation step, with reducing magnitude over time, and the following treatment with 2.5, 10, and 40 µg/kg resulted in an ~15% vehicle-corrected weight loss, a corresponding reduction in adipose tissue (AT), and, in all treatment groups, improved oral glucose tolerance (P < 0.01). Twofold and linear escalations suppressed body weight evenly with no significant reduction in food intake at either escalation step. KBP-089 (1.25 µg/kg) and liraglutide (50 µg/kg) reduced 24-h food intake by 29% and 37% compared with vehicle, respectively; however, when they were combined, 24-h food intake was reduced by 87%. Chronically, KBP-089 (1.25 µg/kg) and liraglutide (50 µg/kg) lowered body weight 8% and 2% in HFD rats, respectively, whereas the combination resulted in a 12% body weight reduction. Moreover, the combination improved glucose tolerance (P < 0.05). In conclusion, DACRAs act complementarily with GLP-1 on food intake and body weight. Furthermore, on escalation, KBP-089 was well tolerated and induced and sustained a significant weight loss and a reduction in AT in lean and HFD rats, underscoring the potential of KBP-089 as an anti-obesity agent.

Effects of Gliadin consumption on the Intestinal Microbiota and Metabolic Homeostasis in Mice Fed a High-fat Diet.

Dietary gluten causes severe disorders like celiac disease in gluten-intolerant humans. However, currently understanding of its impact in tolerant individuals is limited. Our objective was to test whether gliadin, one of the detrimental parts of gluten, would impact the metabolic effects of an obesogenic diet. Mice were fed either a defined high-fat diet (HFD) containing 4% gliadin (n = 20), or a gliadin-free, isocaloric HFD (n = 20) for 23 weeks. Combined analysis of several parameters including insulin resistance, histology of liver and adipose tissue, intestinal microbiota in three gut compartments, gut barrier function, gene expression, urinary metabolites and immune profiles in intestinal, lymphoid, liver and adipose tissues was performed. Mice fed the gliadin-containing HFD displayed higher glycated hemoglobin and higher insulin resistance as evaluated by the homeostasis model assessment, more hepatic lipid accumulation and smaller adipocytes than mice fed the gliadin-free HFD. This was accompanied by alterations in the composition and activity of the gut microbiota, gut barrier function, urine metabolome, and immune phenotypes within liver and adipose tissue. Our results reveal that gliadin disturbs the intestinal environment and affects metabolic homeostasis in obese mice, suggesting a detrimental effect of gluten intake in gluten-tolerant subjects consuming a high-fat diet.

A study of associations between early DHA status and fatty acid desaturase (FADS) SNP and developmental outcomes in children of obese mothers.

DHA from diet or endogenous synthesis has been proposed to affect infant development, however, results are inconclusive. In this study, we aim to verify previously observed fatty acid desaturase gene cluster (FADS) SNP-specific associations with erythrocyte DHA status in 9-month-old children and sex-specific association with developmental outcomes. The study was performed in 166 children (55 % boys) of obese mothers. Erythrocyte fatty acid composition was analysed in blood-samples obtained at 9 months of age, and developmental outcomes assessed by the Ages and Stages Questionnaire at 3 years. Erythrocyte DHA level ranged from 4·4 to 9·9 % of fatty acids, but did not show any association with FADS SNP or other potential determinants. Regression analysis showed associations between erythrocyte DHA and scores for personal-social skills (ß 1·8 (95 % CI 0·3, 3·3), P=0·019) and problem solving (ß 3·4 (95 % CI 1·2, 5·6), P=0·003). A tendency was observed for an association in opposite direction between minor alleles (G-variant) of rs1535 and rs174575 and personal-social skills (P=0·062 and 0·068, respectively), which became significant when the SNP were combined based on their previously observed effect on erythrocyte DHA at 9 months of age (ß 2·6 (95 % CI 0·01, 5·1), P=0·011). Sex-SNP interaction was indicated for rs174575 genotype on fine motor scores (P=0·016), due to higher scores among minor allele carrying girls (P=0·043), whereas no effect was seen among boys. In conclusion, DHA-increasing FADS SNP and erythrocyte DHA status were consistently associated with improved personal-social skills in this small cohort of children of obese mothers irrespective of sex, but the sample was too small to verify potential sex-specific effects.

Gene expression profiling in persons with multiple chemical sensitivity before and after a controlled n-butanol exposure session.

OBJECTIVES: To investigate the pathophysiological pathways leading to symptoms elicitation in multiple chemical sensitivity (MCS) by comparing gene expression in MCS participants and healthy controls before and after a chemical exposure optimised to cause symptoms among MCS participants.The first hypothesis was that unexposed and symptom-free MCS participants have similar gene expression patterns to controls and a second hypothesis that MCS participants can be separated from controls based on differential gene expression upon a controlled n-butanol exposure. DESIGN: Participants were exposed to 3.7 ppm n-butanol while seated in a windowed exposure chamber for 60 min. A total of 26 genes involved in biochemical pathways found in the literature have been proposed to play a role in the pathogenesis of MCS and other functional somatic syndromes were selected. Expression levels were compared between MCS and controls before, within 15 min after being exposed to and 4 hours after the exposure. SETTINGS: Participants suffering from MCS and healthy controls were recruited through advertisement at public places and in a local newspaper. PARTICIPANTS: 36 participants who considered themselves sensitive were prescreened for eligibility. 18 sensitive persons fulfilling the criteria for MCS were enrolled together with 18 healthy controls. OUTCOME MEASURES: 17 genes showed sufficient transcriptional level for analysis. Group comparisons were conducted for each gene at the 3 times points and for the computed area under the curve (AUC) expression levels. RESULTS: MCS participants and controls displayed similar gene expression levels both at baseline and after the exposure and the computed AUC values were likewise comparable between the 2 groups. The intragroup variation in expression levels among MCS participants was noticeably greater than the controls. CONCLUSIONS: MCS participants and controls have similar gene expression levels at baseline and it was not possible to separate MCS participants from controls based on gene expression measured after the exposure.

A novel dual amylin and calcitonin receptor agonist, KBP-089, induces weight loss through a reduction in fat, but not lean mass, while improving food preference.

BACKGROUND AND PURPOSE: Obesity and associated co-morbidities, such as type 2 diabetes and non-alcoholic fatty liver disease, are major health challenges. Hence, there is an important need to develop weight loss therapies with the ability to reduce the co-morbidities. EXPERIMENTAL APPROACH: The effect of the dual amylin and calcitonin receptor agonist (DACRA), KBP-089, on body weight, glucose homeostasis and fatty acid accumulation in liver and muscle tissue and on food preference was investigated. Furthermore, we elucidated weight-independent effects of KBP-089 using a weight-matched group. KEY RESULTS: Rats fed a high-fat diet were treated, s.c., with KBP-089 0.625, 1.25, 2.5 µg·kg-1 or vehicle. KB-089 induced in a dose-dependent and sustained weight loss (~17% by 2.5 µg·kg-1 ). Moreover, KBP-089 reduced fat depot size and reduced lipid accumulation in muscle and liver. In Zucker Diabetic Fatty rats, KBP-089 improved glucose homeostasis through improved insulin action. To obtain a weight-matched group, significantly less food was offered (9% less than in the KBP-089 group). Weight matching led to improved glucose homeostasis by reducing plasma insulin; however, these effect were inferior compared to those of KBP-089. In the food preference test, rats fed a normal diet obtained 74% of their calories from chocolate. KBP-089 reduced total caloric intake and induced a relative increase in chow consumption while drastically reducing chocolate consumption compared with vehicle. CONCLUSIONS AND IMPLICATIONS: The novel DACRA, KBP-089, induces a sustained weight loss, leading to improved metabolic parameters including food preference, and these are beyond those observed simply by diet-induced weight loss.

Supplementation of docosahexaenoic acid (DHA), vitamin D3 and uridine in combination with six weeks of cognitive and motor training in prepubescent children: a pilot study.

BACKGROUND: Learning and memory have been shown to be influenced by combination of dietary supplements and exercise in animal models, but there is little available evidence from human subjects. The aim of this pilot study was to investigate the effect of combining a motor- and cognitive exercise program with dietary supplementation consisting of 500 mg docosahexaenoic acid (DHA), 10 µg vitamin D3 and 1000 mg uridine (DDU-supplement) in 16 prepubescent children (age 8-11 years). METHODS: We designed a randomized, placebo-controlled, double-blinded study lasting 6 weeks in which DDU-supplement or placebo was ingested daily. During the intervention period, all children trained approximately 30 min 3 days/week using an internet-based cognitive and motor training program (Mitii). Prior to and post the intervention period dietary record, blood sampling, physical exercise tests and motor and cognitive tests were performed. RESULTS: Fourteen of the 16 children completed the intervention and ingested the supplement as required. 6 weeks DDU-supplementation resulted in a significant increase in the blood concentration of vitamin D2+3 and DHA (p = 0.023 and p < 0.001, respectively). Power calculation based on one of the cognitive tasks revealed a proper sample size of 26 children. CONCLUSION: All children showed improved performance in the trained motor- and cognitive tasks, but it was not possible to demonstrate any significant effects on the cognitive tests from the dietary supplementation. However, DDU-supplementation did result in increased blood concentration of DHA and vitamin D2+3. TRIAL REGISTRATION: Clinical registration ID: NCT02426554 (clinical Trial.gov). January 2015 retrospectively registered.

A safflower oil based high-fat/high-sucrose diet modulates the gut microbiota and liver phospholipid profiles associated with early glucose intolerance in the absence of tissue inflammation.

SCOPE: Omega-6 (n-6) PUFA-rich diets are generally considered obesogenic in rodents. Here, we examined how long-term intake of a high-fat/high-sucrose (HF/HS) diet based on safflower oil affected metabolism, inflammation, and gut microbiota composition. METHODS AND RESULTS: We fed male C57BL/6J mice a HF/HS diet based on safflower oil-rich in n-6 PUFAs-or a low-fat/low-sucrose diet for 40 wk. Compared to the low-fat/low-sucrose diet, intake of the safflower-based HF/HS diet only led to moderate weight gain, while glucose intolerance developed at week 5 prior to signs of inflammation, but concurrent with increased levels of linoleic acid and arachidonic acid in hepatic phospholipids. Intake of the HF/HS diet resulted in early changes in the gut microbiota, including an increased abundance of Blautia, while late changes coincided with altered inflammatory profiles and increased fasting plasma insulin. Analysis of immune cells in visceral fat and liver revealed no differences between diets before week 40, where the number of immune cells decreased in the liver of HF/HS-fed mice. CONCLUSION: We suggest that a diet-dependent increase in the n-6 to omega-3 (n-3) PUFA ratio in hepatic phospholipids together with gut microbiota changes contributed to early development of glucose intolerance without signs of inflammation.

Environmental spread of microbes impacts the development of metabolic phenotypes in mice transplanted with microbial communities from humans.

Microbiota transplantation to germ-free animals is a powerful method to study involvement of gut microbes in the aetiology of metabolic syndrome. Owing to large interpersonal variability in gut microbiota, studies with broad coverage of donors are needed to elucidate the establishment of human-derived microbiotas in mice, factors affecting this process and resulting impact on metabolic health. We thus transplanted faecal microbiotas from humans (16 obese and 16 controls) separately into 64 germ-free Swiss Webster mice caged in pairs within four isolators, with two isolators assigned to each phenotype, thereby allowing us to explore the extent of microbial spread between cages in a well-controlled environment. Despite high group-wise similarity between obese and control human microbiotas, transplanted mice in the four isolators developed distinct gut bacterial composition and activity, body mass gain, and insulin resistance. Spread of microbes between cages within isolators interacted with establishment of the transplanted microbiotas in mice, and contributed to the transmission of metabolic phenotypes. Our findings highlight the impact of donor variability and reveal that inter-individual spread of microbes contributes to the development of metabolic traits. This is of major importance for design of animal studies, and indicates that environmental transfer of microbes between individuals may affect host metabolic traits.

Plasma amino acid levels are elevated in young, healthy low birth weight men exposed to short-term high-fat overfeeding.

Low birth weight (LBW) individuals exhibit a disproportionately increased, incomplete fatty acid oxidation and a decreased glucose oxidation, compared with normal birth weight (NBW) individuals, and furthermore have an increased risk of developing insulin resistance and type 2 diabetes. We hypothesized that changes in amino acid metabolism may occur parallel to alterations in fatty acid and glucose oxidation, and could contribute to insulin resistance. Therefore, we measured fasting plasma levels of 15 individual or pools of amino acids in 18 LBW and 25 NBW men after an isocaloric control diet and after a 5-day high-fat, high-calorie diet. We demonstrated that LBW and NBW men increased plasma alanine levels and decreased valine and leucine/isoleucine levels in response to overfeeding. Also, LBW men had higher alanine, proline, methionine, citrulline, and total amino acid levels after overfeeding compared with NBW men. Alanine and total amino acid levels tended to be negatively associated with the insulin-stimulated glucose uptake after overfeeding. Therefore, the higher amino acid levels in LBW men could be a consequence of their reduction in skeletal muscle insulin sensitivity due to overfeeding with a possible increased skeletal muscle proteolysis and/or could potentially contribute to an impaired insulin sensitivity. Furthermore, the alanine level was negatively associated with the plasma acetylcarnitine level and positively associated with the hepatic glucose production after overfeeding. Thus, the higher alanine level in LBW men could be accompanied by an increased anaplerotic formation of oxaloacetate and thereby an enhanced tricarboxylic acid cycle activity and as well an increased gluconeogenesis.

Plasma acylcarnitine profiling indicates increased fatty acid oxidation relative to tricarboxylic acid cycle capacity in young, healthy low birth weight men.

We hypothesized that an increased, incomplete fatty acid beta-oxidation in mitochondria could be part of the metabolic events leading to insulin resistance and thereby an increased type 2 diabetes risk in low birth weight (LBW) compared with normal birth weight (NBW) individuals. Therefore, we measured fasting plasma levels of 45 acylcarnitine species in 18 LBW and 25 NBW men after an isocaloric control diet and a 5-day high-fat, high-calorie diet. We demonstrated that LBW men had higher C2 and C4-OH levels after the control diet compared with NBW men, indicating an increased fatty acid beta-oxidation relative to the tricarboxylic acid cycle flux. Also, they had higher C6-DC, C10-OH/C8-DC, and total hydroxyl-/dicarboxyl-acylcarnitine levels, which may suggest an increased fatty acid omega-oxidation in the liver. Furthermore, LBW and NBW men decreased several acylcarnitine levels in response to overfeeding, which is likely a result of an upregulation of fatty acid oxidation due to the dietary challenge. Moreover, C10-OH/C8-DC and total hydroxyl-/dicarboxyl-acylcarnitine levels tended to be negatively associated with the serum insulin level, and the total hydroxyl-/dicarboxyl-acylcarnitine level additionally tended to be negatively associated with the hepatic insulin resistance index. This indicates that an increased fatty acid omega-oxidation could be a compensatory mechanism to prevent an accumulation of lipid species that impair insulin signaling.

Human gut microbes impact host serum metabolome and insulin sensitivity.

Insulin resistance is a forerunner state of ischaemic cardiovascular disease and type 2 diabetes. Here we show how the human gut microbiome impacts the serum metabolome and associates with insulin resistance in 277 non-diabetic Danish individuals. The serum metabolome of insulin-resistant individuals is characterized by increased levels of branched-chain amino acids (BCAAs), which correlate with a gut microbiome that has an enriched biosynthetic potential for BCAAs and is deprived of genes encoding bacterial inward transporters for these amino acids. Prevotella copri and Bacteroides vulgatus are identified as the main species driving the association between biosynthesis of BCAAs and insulin resistance, and in mice we demonstrate that P. copri can induce insulin resistance, aggravate glucose intolerance and augment circulating levels of BCAAs. Our findings suggest that microbial targets may have the potential to diminish insulin resistance and reduce the incidence of common metabolic and cardiovascular disorders.

The dual amylin- and calcitonin-receptor agonist KBP-042 increases insulin sensitivity and induces weight loss in rats with obesity.

OBJECTIVE: In this study, KBP-042, a dual amylin- and calcitonin-receptor agonist, was investigated as a treatment of obesity and insulin resistance in five different doses (0.625 µg/kg-10 µg/kg) compared with saline-treated and pair-fed controls. METHODS: Rats with obesity received daily s.c. administrations for 56 days, and glucose tolerance was assessed after one acute injection, 3 weeks of treatment, and again after 7 weeks of treatment. To assess the effect on insulin sensitivity, rats received 5 µg/kg KBP-042 for 21 days before hyperinsulinemic-euglycemic clamp. RESULTS: KBP-042 induced a sustained weight loss of up to 20% without any significant weight reduction in the pair-fed groups. Decreases in adipose tissues and lipid deposition in the liver were observed, while plasma adiponectin was increased and plasma leptin levels were decreased. Acute administration of KBP-042 led to impaired glucose tolerance and increased plasma lactate, while this diabetogenic effect was reversed by chronic treatment. Finally, assessment of insulin sensitivity using the hyperinsulinemic-euglycemic clamp showed that KBP-042 increased the glucose infusion rate. CONCLUSIONS: The study indicates that KBP-042 combines two highly relevant features, namely weight loss and insulin sensitivity, and is thus an excellent candidate for chronic treatment of obesity and insulin resistance.

Fish oil supplementation from 9 to 18 months of age affects the insulin-like growth factor axis in a sex-specific manner in Danish infants.

Several studies have investigated the effects of fish oil (FO) on infant growth, but little is known about the effects of FO and sex on insulin-like growth factor-1 (IGF-1), the main regulator of growth in childhood. We explored whether FO v. sunflower oil (SO) supplementation from 9 to 18 months of age affected IGF-1 and its binding protein-3 (IGFBP-3) and whether the potential effects were sex specific. Danish infants (n 115) were randomly allocated to 5 ml/d FO (1·2 g/d n-3 long-chain PUFA (n-3 LCPUFA)) or SO. We measured growth, IGF-1, IGFBP-3 and erythrocyte EPA, a biomarker of n-3 LCPUFA intake and status, at 9 and 18 months. Erythrocyte EPA increased strongly with FO compared with SO (P<0·001). There were no effects of FO compared with SO on IGF-1 in the total population, but a sex × group interaction (P=0·02). Baseline-adjusted IGF-1 at 18 months was 11·1 µg/l (95% CI 0·4, 21·8; P=0·04) higher after FO compared with SO supplementation among boys only. The sex × group interaction was borderline significant in the model of IGFBP-3 (P=0·09), with lower IGFBP-3 with FO compared with SO among girls only (P=0·03). The results were supported by sex-specific dose-response associations between changes in erythrocyte EPA and changes in IGF-1 and IGFBP-3 (both P<0·03). Moreover, IGF-1 was sex specifically associated with BMI and length. In conclusion, FO compared with SO resulted in higher IGF-1 among boys and lower IGFBP-3 among girls. The potential long-term implications for growth and body composition should be investigated further.

Lipid hydrolysis products affect the composition of infant gut microbial communities in vitro.

Some lipid hydrolysis products such as medium-chained NEFA (MC-NEFA), sphingosine and monoacylglycerols (MAG) possess antibacterial activity, while others, including oleic acid, are essential for the optimal growth of Lactobacillus species. Thus, changes in the concentrations of NEFA and MAG in the distal ileum and colon can potentially selectively modulate the composition of the gut microbiota, especially in early life when lipid absorption efficacy is reduced. As medium-chained fatty acids are enriched in mothers' milk, such effects may be highly relevant during gut colonisation. In the present study, we examined the effect of selected NEFA, MAG and sphingosine on the composition of faecal microbial communities derived from infants aged 2-5 months during a 24 h anaerobic in vitro fermentation. We tested lipid mixtures in the concentration range of 0-200 µm, either based on MC-NEFA (10 : 0 to 14 : 0 and MAG 12 : 0) or long-chained NEFA (LC-NEFA; 16 : 0 to 18 : 1 and MAG 16 : 0) with and without sphingosine, representing lipid hydrolysis products characteristic for intestinal hydrolysis of breast milk lipids. Ion Torrent sequencing of the bacterial 16S ribosomal RNA gene revealed that the relative abundance of lactic acid-producing genera, including Lactobacillus and Bifidobacterium, was generally increased in the presence of 50 µm or higher concentrations of MC-NEFA. For Bifidobacterium, the same effect was also observed in the presence of a mixture containing LC-NEFA with sphingosine. On the contrary, the relative abundance of Enterobacteriaceae was significantly decreased in the presence of both lipid mixtures. Our findings suggest that the high concentration of medium-chained fatty acids in breast milk might have functional effects on the establishment of the gut microbiota in early life.

Whey-reduced weight gain is associated with a temporary growth reduction in young mice fed a high-fat diet.

Whey protein consumption reportedly alleviates parameters of the metabolic syndrome. Here, we investigated the effects of whey protein isolate (whey) in young mice fed a high-fat diet. We hypothesized that whey as the sole protein source reduced early weight gain associated with retarded growth and decreased concentration of insulin-like growth factor-1. Moreover, we hypothesized that these changes were explained by increased nitrogen loss via elevated urea production and/or increased energy expenditure. Male 5-week-old C57BL/6 mice were fed high-fat diets with the protein source being either whey, casein or a combination of both for 5 weeks. After 1, 3 or 5 weeks, respectively, the mice were subjected to a meal challenge with measurements of blood and urinary urea before and 1 and 3 h after eating a weighed meal of their respective diets. In a subset of mice, energy expenditure was measured by indirect calorimetry during the first week of dietary intervention. Observed exclusively during the first week of intervention, whey significantly reduced body length (P<.01) and weight gain (P<.001) correlating positively with plasma concentrations of insulin-like growth factor-1. The combination diet displayed intermediate results indicating an interactive effect. Urea production, urea cycle activity, food intake and energy expenditure were unaffected by protein source. In conclusion, whey decreased growth-related parameters exclusively during the first week of dietary intervention. The early effect of whey could not be explained by food intake, energy expenditure, urea production or urea cycle activity but was correlated with plasma levels of insulin-like growth factor-1.

Reduced ex vivo stimulated IL-6 response in infants randomized to fish oil from 9 to 18 months, especially among PPARG2 and COX2 wild types.

We investigated whether n-3 LCPUFA affected immune function in late infancy and explored effect-modification by single nucleotide polymorphisms (SNPs) and links to intestinal microbiota. Infants (n=105) were randomized to fish oil (FO, 1.2g/d n-3 LCPUFA) or sunflower oil (SO)-supplements from age 9-18 months. Immune function was assessed by ex vivo cytokine production in stimulated blood and plasma immunoglobulin E (IgE). We genotyped functional SNPs in PPARG2 and COX2 and analyzed fecal microbiota by 16S-rRNA terminal restriction fragment length polymorphism. FO compared to SO reduced Lactobacillus paracasei-stimulated IL-6 at 18 months (P=0.03, n=104). This effect was most pronounced among infants wild-type for PPARG2-Pro12Ala and/or COX2-T8473C (P<0.05). Predominant bacterial fragments were associated with 18 months IgE in all infants (P=0.004) (bp100) and with IL-6 production among infants weaned before 9 months (P=0.047) (bp102). Thus, FO reduced IL-6 in a genotype-modified manner. The microbiota was partly linked to IL-6 and IgE, not directly to FO.

Acute and perinatal programming effects of a fat-rich diet on rat muscle mitochondrial function and hepatic lipid accumulation.

OBJECTIVE: Maternal high-fat intake during pregnancy may have long-term consequences in the offspring. Since this might relate to the capacity of mitochondrial metabolic adaptation and hepatic lipid metabolism, we investigated how maternal high-fat intake affected mitochondrial function and hepatic steatosis in the offspring. DESIGN: Sprague-Dawley rats were fed a high-fat (20% w/w) or a control diet (chow, C) from 10 days before pregnancy and throughout lactation. At weaning the litters were split into two groups; one was continued on the maternal diet and the other was fed low-fat chow. SAMPLE: Skeletal muscle mitochondria and liver lipids. METHODS: Mitochondrial respiration and hepatic lipid content were determined during and after weaning, on days 20 and 70 postpartum. MAIN OUTCOME MEASURES: Mitochondrial function and hepatic lipids. RESULTS: At 20 days, maternal high-fat diet caused increased Vo2max with pyruvate as substrate (p=0.047), at 70 days, pups born by C-dams, but not those born by high-fat-dams, showed increased oxidation of palmitoylcarnitine in the absence of ADP (p=0.018). Rates of ADP-stimulated oxygen consumption, maximal respiratory capacity and mitochondrial respiratory control ratio with pyruvate, increased post weaning (p<0.001), whereas respiratory control ratio with palmitoylcarnitine decreased (p=0.013). The increase in respiratory control ratio was most pronounced in pups from C-dams (p=0.05). The high-fat-diet caused pronounced hepatic steatosis in pups at weaning (p<0.001), without concomitant ceramide accumulation, while high-fat-feeding after weaning induced triacylglycerol and ceramide accumulation (p<0.01), regardless of maternal diet. CONCLUSION: Intake of a fat-rich diet during pregnancy and lactation reduced the age-induced increases in un-coupled fat oxidation.