Intake of different types of seafood and meat and risk of type 2 diabetes in women: a prospective study supported by a dietary intervention in mice.

Detailed knowledge regarding the associations between intake of different types of seafood and meat and the risk of type 2 diabetes (T2D), and insight into possible mechanisms are warranted. In this study we aimed to evaluate the associations between intake of different types of seafood and meat and the subsequent risk of T2D using the Norwegian Mother, Father, and Child Cohort Study (MoBa), and furthermore, by using a mouse model to gain further insight into possible molecular mechanisms contributing to the associated metabolic changes. Women in MoBa who were free of pharmacologically treated diabetes at baseline (n = 60,777) were prospectively evaluated for incident T2D, identified on the basis of medication usages > 90 days after delivery, ascertained by the Norwegian Prescription Database. Dietary intake was obtained with a validated 255-item food frequency questionnaire which assessed habitual diet during the first 4-5 months of pregnancy. Metabolic phenotypes and plasma metabolome were investigated in female mice fed isocaloric diets with different types of seafood and meat mimicking the dietary intake in the human cohort. During maximum 10-year and mean (SD) 7.2 (1.6) years follow-up time, 681 (1.1%) women developed pharmacologically treated T2D. All statistical models identified a higher risk of T2D with increased shellfish intake, whereas no associations were observed for total seafood, fatty fish, total meat and red meat in the adjusted models. In mice, the shellfish-based western diet induced reduced glucose tolerance and insulin secretion compared to the diet based on lean fish, and we identified a number of metabolites elevated in plasma from shellfish-fed mice that correlated with glucose intolerance. Mice fed a western diet based on meat also exhibited reduced glucose tolerance in comparison to lean fish fed mice, whereas mice fed fatty fish, total seafood or red meat did not differ from lean fish fed mice. We observed a diet-specific metabolic signature in plasma demonstrating five distinct metabolite profiles in mice fed shellfish, fatty fish, total seafood/lean fish, a mixed diet and meat. In conclusion, these findings demonstrate that different types of seafood have different outcome on T2D risk. In women, intake of shellfish was associated with higher risk of T2D. In female mice, a shellfish enriched diet reduced glucose tolerance and altered the abundance of several distinct plasma metabolites correlating with glucose tolerance.

Host-gut microbiota interactions shape parasite infections in farmed Atlantic salmon.

Animals and their associated microbiota share long evolutionary histories. However, it is not always clear how host genotype and microbiota interact to affect phenotype. We applied a hologenomic approach to explore how host-microbiota interactions shape lifetime growth and parasite infection in farmed Atlantic salmon (Salmo salar). Multi-omics data sets were generated from the guts of 460 salmon, 82% of which were naturally infected with an intestinal cestode. A single Mycoplasma bacterial strain, MAG01, dominated the gut metagenome of large, non-parasitized fish, consistent with previous studies showing high levels of Mycoplasma in the gut microbiota of healthy salmon. While small and/or parasitized salmon also had high abundance of MAG01, we observed increased alpha diversity in these individuals, driven by increased frequency of low-abundance Vibrionaceae and other Mycoplasma species that carried known virulence genes. Colonization by one of these cestode-associated Mycoplasma strains was associated with host individual genomic variation in long non-coding RNAs. Integrating the multi-omic data sets revealed coordinated changes in the salmon gut mRNA transcriptome and metabolome that correlated with shifts in the microbiota of smaller, parasitized fish. Our results suggest that the gut microbiota of small and/or parasitized fish is in a state of dysbiosis that partly depends on the host genotype, highlighting the value of using a hologenomic approach to incorporate the microbiota into the study of host-parasite dynamics.IMPORTANCEStudying host-microbiota interactions through the perspective of the hologenome is gaining interest across all life sciences. Intestinal parasite infections are a huge burden on human and animal health; however, there are few studies investigating the role of the hologenome during parasite infections. We address this gap in the largest multi-omics fish microbiota study to date using natural cestode infection of farmed Atlantic salmon. We find a clear association between cestode infection, salmon lifetime growth, and perturbation of the salmon gut microbiota. Furthermore, we provide the first evidence that the genetic background of the host may partly determine how the gut microbiota changes during parasite-associated dysbiosis. Our study therefore highlights the value of a hologenomic approach for gaining a more in-depth understanding of parasitism.

One-Year Treatment with Olanzapine Depot in Female Rats: Metabolic Effects.

BACKGROUND: Antipsychotic drugs can negatively affect the metabolic status of patients, with olanzapine as one of the most potent drugs. While patients are often medicated for long time periods, experiments in rats typically run for 1 to 12 weeks, showing olanzapine-related weight gain and increased plasma lipid levels, with transcriptional upregulation of lipogenic genes in liver and adipose tissue. It remains unknown whether metabolic status will deteriorate with time. METHODS: To examine long-term metabolic effects, we administered intramuscular long-acting injections of olanzapine (100 mg/kg BW) or control substance to female rats for up to 13 months. RESULTS: Exposure to olanzapine long-acting injections led to rapid weight gain, which was sustained throughout the experiment. At 1, 6, and 13 months, plasma lipid levels were measured in separate cohorts of rats, displaying no increase. Hepatic transcription of lipid-related genes was transiently upregulated at 1 month. Glucose and insulin tolerance tests indicated insulin resistance in olanzapine-treated rats after 12 months. CONCLUSION: Our data show that the continuous increase in body weight in response to long-term olanzapine exposure was accompanied by surprisingly few concomitant changes in plasma lipids and lipogenic gene expression, suggesting that adaptive mechanisms are involved to reduce long-term metabolic adverse effects of this antipsychotic agent in rats.

Mechanisms Preserving Insulin Action during High Dietary Fat Intake.

Prolonged intervention studies investigating molecular metabolism are necessary for a deeper understanding of dietary effects on health. Here we provide mechanistic information about metabolic adaptation to fat-rich diets. Healthy, slightly overweight men ingested saturated or polyunsaturated fat-rich diets for 6 weeks during weight maintenance. Hyperinsulinemic clamps combined with leg balance technique revealed unchanged peripheral insulin sensitivity, independent of fatty acid type. Both diets increased fat oxidation potential in muscle. Hepatic insulin clearance increased, while glucose production, de novo lipogenesis, and plasma triacylglycerol decreased. High fat intake changed the plasma proteome in the immune-supporting direction and the gut microbiome displayed changes at taxonomical and functional level with polyunsaturated fatty acid (PUFA). In mice, eucaloric feeding of human PUFA and saturated fatty acid diets lowered hepatic triacylglycerol content compared with low-fat-fed control mice, and induced adaptations in the liver supportive of decreased gluconeogenesis and lipogenesis. Intake of fat-rich diets thus induces extensive metabolic adaptations enabling disposition of dietary fat without metabolic complications.

Opposite Regulation of Insulin Sensitivity by Dietary Lipid Versus Carbohydrate Excess.

To understand the mechanisms in lipid-induced insulin resistance, a more physiological approach is to enhance fatty acid (FA) availability through the diet. Nine healthy men ingested two hypercaloric diets (in 75% excess of habitual caloric intake) for 3 days, enriched in unsaturated FA (78 energy % [E%] fat) (UNSAT) or carbohydrates (80 E% carbohydrate) (CHO) as well as a eucaloric control diet (CON). Compared with CON, the UNSAT diet reduced whole-body and leg glucose disposal during a hyperinsulinemic-euglycemic clamp, while decreasing hepatic glucose production. In muscle, diacylglycerol (DAG) and intramyocellular triacylglycerol were increased. The accumulated DAG was sn-1,3 DAG, which is known not to activate PKC, and insulin signaling was intact. UNSAT decreased PDH-E1α protein content and increased inhibitory PDH-E1α Ser300 phosphorylation and FA oxidation. CHO increased whole-body and leg insulin sensitivity, while increasing hepatic glucose production. After CHO, muscle PDH-E1α Ser300 phosphorylation was decreased, and glucose oxidation increased. After UNSAT, but not CHO, muscle glucose-6-phosphate content was 103% higher compared with CON during the clamp. Thus, PDH-E1α expression and covalent regulation, and hence the tricarboxylic acid cycle influx of pyruvate-derived acetyl-CoA relative to ß-oxidation-derived acetyl-CoA, are suggested to impact on insulin-stimulated glucose uptake. Taken together, the oxidative metabolic fluxes of glucose and FA are powerful and opposite regulators of insulin action in muscle.

Circulating FGF21 in humans is potently induced by short term overfeeding of carbohydrates.

OBJECTIVE: Fibroblast-growth factor 21 (FGF21) is thought to be important in metabolic regulation. Recently, low protein diets have been shown to increase circulating FGF21 levels. However, when energy contribution from dietary protein is lowered, other macronutrients, such as carbohydrates, must be increased to meet eucaloric balance. This raises the possibility that intake of a diet rich in carbohydrates may induce an increase in plasma FGF21 levels per se. Here we studied the role of dietary carbohydrates on the levels of circulating FGF21 and concomitant physiologic effects by feeding healthy men a carbohydrate rich diet without reducing protein intake. METHODS: A diet enriched in carbohydrates (80 E% carbohydrate; CHO) and a eucaloric control diet (CON) were provided to nine healthy men for three days. The energy intake during the CHO diet was increased (+75% energy) to ensure similar dietary protein intake in CHO and CON. To control for the effect of caloric surplus, we similarly overfed (+75% energy) the same subjects for three days with a fat-rich diet (78 E% fat; FAT), consisting of primarily unsaturated fatty acids. The three diets were provided in random order. RESULTS: After CHO, plasma FGF21 concentration increased 8-fold compared to CON (329 ± 99 vs. 39 ± 9 pg ml-1, p < 0.05). In contrast, after FAT only a non-significant tendency (p = 0.073) to an increase in plasma FGF21 concentration was found. The increase in FGF21 concentration after CHO correlated closely (r = 0.88, p < 0.01) with increased leg glucose uptake (62%, p < 0.05) and increased hepatic glucose production (17%, p < 0.01), indicating increased glucose turnover. Plasma fatty acid (FA) concentration was decreased by 68% (p < 0.01), supported by reduced subcutaneous adipose tissue HSL Ser660 phosphorylation (p < 0.01) and perilipin 1 protein content (p < 0.01), pointing to a suppression of adipose tissue lipolysis. Concomitantly, a 146% increase in the plasma marker of hepatic de novo lipogenesis C16:1 n-7 FA (p < 0.01) was observed together with 101% increased plasma TG concentration (p < 0.001) in association with CHO intake and increased plasma FGF21 concentration. CONCLUSION: Excess dietary carbohydrate, but not fat, led to markedly increased FGF21 secretion in humans, notably without protein restriction, and affected glucose and lipid homeostais.

Links between Dietary Protein Sources, the Gut Microbiota, and Obesity.

The association between the gut microbiota and obesity is well documented in both humans and in animal models. It is also demonstrated that dietary factors can change the gut microbiota composition and obesity development. However, knowledge of how diet, metabolism and gut microbiota mutually interact and modulate energy metabolism and obesity development is still limited. Epidemiological studies indicate an association between intake of certain dietary protein sources and obesity. Animal studies confirm that different protein sources vary in their ability to either prevent or induce obesity. Different sources of protein such as beans, vegetables, dairy, seafood, and meat differ in amino acid composition. Further, the type and level of other factors, such as fatty acids and persistent organic pollutants (POPs) vary between dietary protein sources. All these factors can modulate the composition of the gut microbiota and may thereby influence their obesogenic properties. This review summarizes evidence of how different protein sources affect energy efficiency, obesity development, and the gut microbiota, linking protein-dependent changes in the gut microbiota with obesity.