The Journal of Nutritional Biochemistry

Maternal n-3 PUFA (omega-3) deficiency can affect brain development in utero and postnatally. Despite the evidence, the impacts of n-3 PUFA deficiency on the expression of neurogenesis genes in the postnatal brain remained elusive. Since postnatal brain development requires PUFAs via breast milk, we examined the fatty acid composition of breast milk and hippocampal expression of neurogenesis genes in n-3 PUFA deficient 21d mice. In addition, expression of fatty acid desaturases, elongases, signalling receptors of free fatty acids, insulin and leptin, and glucose transporters were measured. Among the genes involved in neurogenesis, the expression of brain-specific tenascin-R (TNR) was downregulated to a greater extent ([~]31 folds), followed by adenosine A2A receptor (A2AAR), dopamine receptor D2 (DRD2), glial cell line-derived neurotrophic factor (GDNF) expression in the n-3 PUFA deficient hippocampus (p<0.05). Increasing dietary LA to ALA (50:1) elevated ARA to DHA ratio by [~]8 folds in the n-3 PUFA deficient breast milk, with an overall increase of total n-6/n-3 PUFAs by [~]15:1 (p<0.05) compared to n-3 PUFA sufficient (LA to ALA: 2:1) diet. The n-3 PUFA deficient brain exhibited upregulation of FADS1, FADS2, ELOVL2, ELOVL5, ELOVL6, GPR40, GPR120, LEPR, IGF1 and downregulation of GLUT1, GLUT3, and GLUT4 mRNA expression (p<0.05). Maternal n-3 PUFA deficiency affects the expression of key neurogenesis genes in the offspring with concomitant expression of desaturases and elongases genes suggesting the importance of dietary n-3 PUFA for neurodevelopment.

ScopeWe explored the influence of DHA on cardiometabolic and cognitive phenotypes, and multiomic alterations in the brain under two metabolic conditions to understand context-specific nutritional effects. Methods and ResultsRats were randomly assigned to a DHA-rich or a control chow diet while drinking water or high fructose solution, followed by profiling of metabolic and cognitive phenotypes and the transcriptome and DNA methylome of the hypothalamus and hippocampus. DHA reduced serum triglyceride and improved insulin resistance and memory exclusively in the fructose-consuming rats. In hippocampus, DHA affected genes related to synapse functions in the chow group but immune functions in the fructose group; in hypothalamus, DHA altered immune pathways in the chow group but metabolic pathways in the fructose group. Network modeling revealed context-specific regulators of DHA effects, including Klf4 and Dusp1 for chow condition and Lum, Fn1, and Col1a1 for fructose condition in hippocampus, as well as Cyr61, JunB, Ier2, and Pitx2 under chow condition and Hcar1, Cdh1, and Osr1 under fructose condition in hypothalamus. ConclusionDHA exhibits differential influence on epigenetic loci, genes, pathways, and metabolic and cognitive phenotypes under different dietary contexts, supporting population stratification in DHA studies to achieve precision nutrition.

Nonalcoholic fatty liver disease (NAFLD) and Metabolic syndrome (MS) have become a global health concern as incidence of these metabolic disorders is growing rapidly in developing countries particularly in the Middle East, South America and Africa. Studies have shown that protein restriction is associated with increased risk of metabolic diseases, possibly through effects on fatty acid (FA) metabolism. In the present study, we investigated whether a low protein diet modulates FA metabolism and whether methyl donor supplementation can ameliorate these effects and improve metabolic health. Male C57BL/6 mice were fed either a low protein diet (LPD, 90 g/kg protein, n=8), a LPD supplemented with methyl donors (MD-LPD; choline chloride, betaine, methionine, folic acid, vitamin B12, n=8) or normal protein diet (NPD, 180 g/kg protein, n=8) for 7 weeks prior to analysis of serum fatty acid profiles by GC FID and MS and liver fatty acid synthesis and uptake gene expression by RT-qPCR. We observed significant depletion of serum C15:0 and C17:0 in LPD-fed males compared to NPD. Serum long chain saturated FAs C18:0 and C24:0 were increased in LPD male mice compared to NPD. Gene expression analysis revealed an upregulation of hepatic cluster of differentiation 36 (CD36) expression in LPD mice compared to NPD suggesting increased fat uptake in the liver. However, when LPD diet was supplemented with methyl donors, we observed either no change in serum C15: 0 and an increased serum C17:0 compared to LPD with no methyl donor supplementation. Again, methyl donor supplementation upregulated fatty acid desaturase 1 (FADS1), thioredoxin-1 (TRX1) and catalase (CAT) expression in the liver of MD-LPD fed mice compared to LPD mice. Altogether, our study revealed that odd chain fatty acids (OCFA)s are key early markers observed in a suboptimal diet-induced metabolic changes and may be potential targets to improve metabolic health outcomes.

ObjectiveTo assess peripheral lymphocyte DNA methylation profiles in prediabetes using a high fat-diet-fed C57BL/6 animal model. We further evaluated whether low dose-aspirin, or low-dose aspirin in combination with metformin, could modulate global DNA methylation levels in peripheral blood lymphocytes.\n\nMethodsTwenty-eight (28) male C57BL/6 mice were used in two experimental phases. The first experiment involved animals (n=16) which were randomised to receive a low-fat diet (LFD) or high-fat diet (HFD) (n = 8/group) for 10 weeks. Whereas in the second experiment, HFD-fed mice (n=15) were randomised into 3 treatment groups, a low-dose aspirin (LDA), LDA and metformin group, and a clopidogrel group. DNA methylation profiles of were determined using flow cytometry.\n\nResultsThe HFD group showed moderate weight gain and elevated postprandial blood glucose levels when compared to the LFD group after 2 weeks of HFD-feeding (p < 0.05). Interestingly, the HFD group had elevated levels of T cells expressing high levels %5-methylcytosine (p<0, 05). Notably, these elevated levels were lowered by short-term low-dose aspirin treatment.\n\nDiscussionT cells are involved in the propagation of the inflammatory response. Persistent T cell activation promotes chronic inflammation and insulin resistance. Low-dose aspirin may be effective in modulating T cell-specific global methylation.

Semi-synthetic and grain-based diets are common rodent diets for biomedical research. Both diet types are considered nutritionally adequate to support breeding, growth, and long life, yet there are fundamental differences between them that may affect metabolic processes. We have characterized the effects of diet type on breeding outcomes, metabolic phenotype, and microbiota profile in adult mice. Healthy 8-week-old female and male C57BL/6J mice were fed a semi-synthetic or a grain-based diet for 12 weeks and changes in body weight and body composition were monitored. Breeding outcomes were determined. Body fat accumulation of female mice was lower on the semi-synthetic diet than on the grain-based diet. Pregnancy rate and newborn pup survival appeared to be lower in mice exposed to semi-synthetic diet compared to grain-based diet. Both female and male mice showed a profound change in fecal microbiota alpha and beta diversity depending on diet type. Our study shows that type of rodent diet may affect breeding outcomes whilst influencing metabolism and health of female laboratory mice. These factors have the potential to influence other experimental outcomes and the results suggest that semi-synthetic and grain-based diets are not interchangeable in research using rodent models. Careful consideration and increased understanding of the consequences of diet choice would lead to improvements in experimental design and reproducibility of study results.

ScopeMetabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic hepatic liver disease. An imbalance diet, rich in lipids and sugars and low in fibre, is a key contributing factor. However, there is limited knowledge about how soluble and fermentable dietary fibres, compared to insoluble and non-fermentable fibres, differently affect liver metabolism through their interactions with the intestinal microbiota. Methods and resultsMale mice housed at thermoneutrality were fed a Western Diet (WD) supplemented with fermentable inulin or non-fermentable cellulose for 18 weeks. Inulin supplementation mitigated WD-induced obesity, glucose intolerance, dyslipidemia and protected against WD-induced hepatic steatosis compared to cellulose. Hepatic gene expression changes induced by WD were attenuated with inulin. Additionally, inulin preserved gut microbiota composition and metabolism, indicating greater resilience against diet-induced perturbations. ConclusionThese findings suggest that soluble dietary fibres like inulin confer superior metabolic and hepatic benefits over insoluble fibres by modulating the gut microbiota-liver axis, highlighting their potential role in MASLD management.

Obesity is a multifactorial condition influenced not only by diet composition but also by food processing. While high-fat and high-sugar diets are widely used in rodent models of metabolic syndrome, the independent effects of diet purification remain poorly understood. This study evaluated the impact of a grain-based control (C/GB), a balanced semi-purified (B/SP), and a high-fat/high-sugar semi-purified (HFS/SP) diet on obesity development and metabolic alterations in adult male Wistar rats over 10 weeks. Morphometric, biochemical, histological, metabolic, and oxidative parameters were assessed. Rats fed the B/SP diet exhibited greater body weight and adiposity despite similar caloric intake, yet these changes were largely compensatory, with enhanced fat mobilization, redistribution toward subcutaneous depots, and improved antioxidant defenses. In contrast, HFS/SP-fed rats consumed fewer calories but developed visceral adiposity without additional body weight, in association with reduced fat mobilization and oxidation. Only the HFS/SP group displayed features of metabolic syndrome, including impaired glucose control, dyslipidemia, hepatic steatosis, and systemic as well as tissue oxidative stress. The liver emerged as a central organ mediating oxidative burden, reinforcing its key role in obesity-related metabolic impairment. In conclusion, our findings demonstrate that both nutrient composition and diet purification shape distinct obesity phenotypes, but only high-fat/high-sugar intake determines the risk of metabolic dysfunction. HIGHLIGHTS* Diet purification contributes to adipose tissue and weight gain. * Diet purification alone does not induce metabolic damage. * Diet composition is the main contributor to the development of metabolic syndrome.

Aims/IntroductionThe {omega}3 polyunsaturated fatty acids in fish oil enhance heat production in adipocytes and exert anti-obesity effects, but the effects of fish oil on heat production in diet-induced obese (DIO) mice are unclear. In this study, we examined whether diets containing fish oil increased the expression of heat-producing genes in adipose tissue and increased body temperature in DIO mice, resulting in weight loss. We also examined fibroblast growth factor 21 (FGF21) levels in blood and the expression of the FGF21 gene in adipose tissue of DIO mice fed fish oil. Materials and MethodsC57BL6/J mice were fed a lard-based high-fat diet for 8 weeks starting at 5 weeks of age and then divided into two groups: one group was fed a fish oil-based high-fat diet, and the other group was fed a lard-based high-fat diet continuously for another 8 weeks. Mice fed a control diet for 16 weeks from the age of 5 weeks served as the control group. Mice were dissected at 21 weeks and used for analysis. ResultsMice fed a fish oil-based high-fat diet lost body weight gain, adipose tissue weight gain, and reduced insulin/leptin resistance. In addition, the rectal temperatures of mice fed a fish oil-based high-fat diet remained higher. The administration of fish oil increased the expression of heat-producing genes in brown adipose tissue (BAT) but did not alter heat-producing genes in inguinal white adipose tissue (WAT). In DIO mice fed a fish oil-based high-fat diet, the FGF21 expression in BAT increased. Furthermore, {beta}klotho expression in BAT increased and the blood FGF21 concentration was decreased compared to mice fed a lard-based high-fat diet. ConclusionsIn DIO mice, fish oil was shown to increase rectal temperature and ameliorate obesity. Furthermore, fish oil enhanced heat production in BAT, but not WAT, in DIO mice.

BackgroundObesogenic diets (ODs) are known to trigger metabolic and inflammatory disturbances. However, the effects of short-term OD withdrawal on systemic and neuroinflammatory parameters remain unclear. ObjectivesThis study investigated the short-term effects of OD withdrawal on metabolic, inflammatory, and anxiety-like behaviours in young male Wistar rats. MethodsThree-week-old male Wistar rats were fed either a control (Ct, n=5) or high-sugar/high-fat (HSHF) diet for 14 days. Animals in the HSHF group were further divided into no-withdrawal (NWt, n=5) and withdrawal (Wt, n=5) groups, where Wt received a control diet for 48 hours. Food intake, body mass, adiposity, serum metabolic parameters, hepatic energy stores, inflammatory markers (serum, liver, hypothalamus, hippocampus, mesenteric fat), and oxidative stress markers in the hippocampus were measured. Anxiety-like behaviour was assessed using the elevated plus maze. ResultsOD intake significantly increased caloric intake, visceral adiposity, hepatic glycogen, and TAG levels. The 48-hour withdrawal reduced TAG, induced hyperinsulinemia and hypoglycaemia, and heightened inflammation in mesenteric fat, serum, and the hippocampus. Oxidative stress markers (SOD and MDA) increased in the hippocampus, correlating with elevated serum corticosterone and heightened anxiety-like behaviour in the Wt group compared to the other groups. ConclusionShort-term withdrawal after only two weeks of OD intake exacerbates systemic and neuroinflammation, hippocampal oxidative stress, and anxiety-like behaviours, indicating rapid negative responses to dietary transition. These findings highlight the metabolic and behavioural challenges associated with short-term OD withdrawal and highlight the need for adjunct interventions to mitigate its adverse effects.

Pregnancy can alter gut microbiota composition, but how an obesogenic diet impacts maternal gut microbiota, and the extent to which this influences offspring microbiome can be obscured by confounding factors. This study examined changes in gut microbiota composition across pre-pregnancy, gestation and lactation in rat dams fed either a high-fat, high-sugar Cafeteria (Caf) diet or Chow. Microbiome development was assessed in their offspring weaned onto chow. Caf diet consumption during pregnancy increased weight gain and adiposity, and compromised subsequent maternal nursing behaviour. - and {beta} diversity measures in Caf-fed dams showed a different trajectory across the progression of pregnancy, with no change in Bacteroidetes and Firmicutes abundance compared with Chow dams. Offspring born to Caf dams exhibited greater adiposity and plasma leptin at weaning and 14 weeks of age than those born to Chow dams. Maternal Caf diet induced clear differences in {beta} diversity in weanlings but not diversity. SourceTracker analysis revealed similarities in the gut microbiota of Chow weanlings and maternal gut microbiota in lactation, whereas the microbiota of Caf weanlings was similar to the maternal gut microbiota during gestation. Maternal Caf diet exerted only marginal effects on gut microbiota composition in 14-week-old offspring.

Hormesis is defined as dose response phenomenon characterized by low-dose stimulation and high-dose inhibition (Calabrese & Mattson, 2017). To date, low doses of several stressors (intermittent fasting, caloric restriction or selected phytochemicals) have been shown to exert beneficial effects on health (Martin et al., 2006). In the present study, we aimed to determine hormetic factors in a series of diets used in mice. We found that animals fed high-sugar diet (HSD) or high-fat diet (HFD) containing relatively high amounts of mono- and disaccharides become obese compared to animals fed standard diet (STAND) or ketogenic diet (KD) containing low doses of these compounds. Underlying the observed metabolic phenotype may be changes in the composition of the intestinal microbiota, showing u-shaped features in selected species. It is noteworthy that a short-term dietary regimen of several weeks resulted in difficulties in achieving effective scores on a complex cognitive test based on spatial procedural acquisition in the HSD and HFD groups. Our data identify dietary mono- and disaccharide content (commonly known as sugars) as a critical hormetic factor with beneficial/harmful effects at multiple levels of body function.

BackgroundCircadian rhythm disruption (CRD) is a risk factor for irritable bowel syndrome (IBS), but the mechanism linking CRD to intestinal barrier dysfunction remains unclear. This preclinical study aimed to clarify whether CRD impairs intestinal barrier integrity via gut microbiota dysbiosis and the "apoptosis-inflammation-oxidative stress" cascade. MethodsTwenty-four male C57BL/6 mice were randomized into control (12h light/dark, n=12) and CRD (21-day continuous light, n=12) groups. Circadian disruption was verified via locomotor activity, serum melatonin/serotonin, and clock gene expression. Intestinal barrier function, microbiota, apoptosis, inflammation, and oxidative stress were assessed using FITC-dextran permeability, 16S rRNA sequencing, Western blotting (WB), TUNEL, and ELISA. ResultsCRD increased intestinal permeability (+114.7%, p<0.001), shortened villi (-25.6%, p=0.018), downregulated tight junction proteins (ZO-1, Occludin, p<0.05), and altered microbiota (family-level: decreased Prevotellaceae, increased Bacteroidaceae, p<0.05). It also activated the apoptosis-inflammation-oxidative stress cascade (Caspase-3/{beta}-actin: +1.4-fold, IL-1{beta}: +44.1%, MDA: +50%, CAT: -90%, all p<0.05). ConclusionsCRD impairs intestinal barrier integrity via gut microbiota dysbiosis and the apoptosis-inflammation-oxidative stress cascade. These preclinical findings identify gut microbiota and the apoptosis-inflammation-oxidative stress cascade as potential targets for further investigating IBS associated with CRD.

Uterine Natural Killer (uNK) cells, predominant leukocytes in mouse and human pregnant uteruses, play crucial roles in angiogenesis and pregnancy protection. In mice, DBA lectin-reactive uNK cells expressing Gal-N-Ac sugar exhibit angiogenic functions essential for pregnancy maintenance. This study compares the impact of different nutritional imbalances on mouse pregnancy and the activation of angiogenic DBA+ uNK cells to safeguard against pregnancy complications. High Fat (HF), High Carbohydrate (HC), High Protein (HP), and Food Restriction (FR) diets were administered from gestation day (GD) 1 to GD10 or until parturition. HF and HC diets led to reduced expression of DBA-identified N-acetyl-D-galactosamine, akin to LPS-induced inflammation, and decreased uNK perforin levels. Additionally, HF and HC diets resulted in elevated endometrial cleaved caspase-3 and decreased smooth muscle alpha-actin, causing blood vessel wall thinning without jeopardizing pregnancy term. FR impaired uNK differentiation, manifesting as an "all-or-none" phenomenon with 50% pregnancy failure. Our findings highlight the intricate relationship between nutritional imbalances and mouse pregnancy outcomes. Notably, high-fat diets elicited pronounced responses from DBA+ uNK cells, while high-protein diets had relatively weaker effects. This study underscores the importance of comprehending uNK cell dynamics in maintaining pregnancy homeostasis under diverse dietary conditions, paving the way for elucidating molecular mechanisms governing these interactions. By shedding light on these complex relationships, this research offers valuable insights for improving maternal and fetal health in the context of nutritional interventions during pregnancy.

Obesity has been associated with dysbiosis, but innate mechanisms linking intestinal epithelial cell subsets and obesity remain poorly understood. Using mice lacking Paneth cells (Sox9{Delta}IEC mice), small intestinal epithelial cells specialized in the production of antimicrobial products and cytokines, we show that dysbiosis alone does not induce obesity or metabolic disorders. Loss of Paneth cells reduced ILC3 and increased ILC2 numbers in the intestinal lamina propria. High-fat diet (HFD) induced higher weight gain and more severe metabolic disorders in Sox9{Delta}IEC mice. Further, HFD enhances the number of ILC1 in the intestinal lamina propria of Sox9{Delta}IEC mice and increases intestinal permeability and the accumulation of immune cells (inflammatory macrophages and T cells, and B cells) in abdominal fat tissues of obese Sox9{Delta}IEC. Transplantation of fecal materials from Sox9{Delta}IEC mice in germ-free mice before HFD further confirmed the regulatory role of Paneth cells for gut ILC subsets and the development of obesity.

The modern dietary exposome is calorie dense and poor in nutritional quality resulting in high prevalence of fatty liver disease and an increasing incidence of cardiometabolic disease and cancer. We investigated the impact of dietary composition on the interaction between the liver and haematopoietic systems in mice. Using xenograft and chemical-induced liver cancer models, we find that liver tumours per se have a minimal impact on haematopoietic stem and progenitor cell (HSPC) responses. In contrast, alterations in dietary composition have profound effects on the liver-bone marrow axis. Specifically, exposure to sucrose with or without dietary cholesterol has minimal impact on the HSPC response, while perturbations in bile acid biosynthesis synergises with excess dietary cholesterol to enhance HSPC responses. Pharmacological restoration of bile acid biosynthesis partially reversed these effects. We conclude that the crosstalk between liver and bone marrow, and subsequent HSPC responses is regulated by bile acid biosynthesis.

BackgroundThromboinflammation of adipose tissue involves accumulation of pro-fibrinogenic factors to adipose tissue in obesity, which promotes immune cell infiltration, affects weight gain and can lead to metabolic dysfunction. The role of neutrophil genes in inflammation are frequently investigated using MRP8-Cre mice to generate neutrophil-specific knockouts. Recent study demonstrated that MRP8-Cre mice have off-target deletions in Serpine1 and Ap1s1 genes. Serpine1, encoding plasminogen activator inhibitor-1, is a key anti-fibrinolytic factor linked to thromboinflammation and metabolic dysfunctions in obesity. In this study, we provide evidence suggesting a critical limitation in using MRP8-Cre model to study adipose tissue, weight-related dysfunctions and/or metabolic disorders. MethodsMRP8-Cre and F13a1-/-MRP8 mice were placed on either control diet or high-fat diet for 16 weeks, with body weight monitored weekly. The expression of Serpine 1, Ap1s1 and Adgre1 (macrophage marker) genes in inguinal and epididymal adipose tissues were analyzed using qRT-PCR and compared to the wild-type mice. ResultsMRP8-Cre shows no Serpine1 or Ap1s1 expression in inguinal and epididymal adipose tissues. MRP8-Cre mouse is resistant to weight gain on obesogenic diet and does not show macrophage marker in adipose tissue compared to control obesity model. The resistance to weight gain translates to a neutrophil knockout model, F13a1-/-MRP8 that was not expected to show resistance to weight gain as its global knockout does not exhibit this phenotype. ConclusionOur work suggests that MRP8-Cre model may not be suitable to investigate metabolic outcomes of neutrophil genes, or pathologies that have underlying etiology in thomboinflammation.

The gut ecosystem is shaped by multiple factors with the immune system being one of the major determinants in shaping its composition in health and disease. On the other hand, the immune system regulates its responses through the action of the sympathetic nervous system (SNS) in part through beta-adrenergic receptors 1/2 (ADRB1/2). In the past years, a clear link has been established between the immune system, SNS, and the modification of nutrient absorption by the gut microbiota in the development of diet-induced obesity. We have previously shown in male mice transplanted with bone marrow cells ADRB1/2 knock-out mice (KD) showed mild immunosuppression and microbiota changes. Post-recovery, mice were challenged with high-fat diet (HFD) for two weeks ad libitum. Our findings show that KD mice are protected against diet-induced adiposity and weight gain. Additionally, these mice showed an increase in residual calorific values and a decreased expression of the fatty acid transporter FAT/CD36. Suggesting a decreased absorption of lipids in the KD mice. Gut microbiota analysis showed that KD microbiota composition on a HFD remained stable with a significant enrichment in the Bacteroidetes phylum, which is depleted in obesity. This was associated with a switch from triglycerides to diglyceride fecal profile. Moreover, microbiome culture showed a decrease in triglycerides after an incubation with 0.1% of HFD lipid extract. Suggesting a potential role of the Bacteroidetes phylum in the metabolism of these lipids. Our findings demonstrate not only that the gut microbiota can modify nutrient absorption and susceptibility to diet-induced obesity but also that the immune system contributes to selective depletion of microbial members that would otherwise thrive on dietary lipids. Revealing a novel mechanism by which host immunity sculpts the gut ecosystem in ways that influence metabolic outcomes.

Dietary trans 10, cis 12-conjugated linoleic acid (t10c12-CLA) is a potential candidate in anti-obesity trials. A transgenic mouse was previously successfully established to determine the anti-obesity properties of t10c12-CLA in male mice that could produce endogenous t10c12-CLA. To test whether there is a different impact of t10c12-CLA on lipid metabolism in both sexes, this study investigated the adiposity and metabolic profiles of female Pai mice that exhibited a dose-dependent expression of foreign Pai gene and a shift of t10c12-CLA content in tested tissues. Compared to their gender-match wild-type littermates, Pai mice had no fat reduction but exhibited enhanced lipolysis and thermogenesis by phosphorylated hormone-sensitive lipase and up-regulating uncoupling proteins in brown adipose tissue. Simultaneously, Pai mice showed hepatic steatosis and hypertriglyceridemia by decreasing gene expression involved in lipid and glucose metabolism. Further investigations revealed that t10c10-CLA induced excessive prostaglandin E2, adrenaline, corticosterone, glucagon and inflammatory factors in a dose-dependent manner, resulting in less heat release and oxygen consumption in Pai mice. Moreover, fibroblast growth factor 21 overproduction only in monoallelic Pai/wt mice indicates that it was sensitive to low doses of t10c12-CLA. These results suggest that chronic t10c12-CLA has system-wide effects on female health via synergistic actions of various hormones.

Loss of ovarian function is associated with increased visceral fat. In this study, we aimed to study the effects of caloric restriction (CR) on metabolism in ovariectomized mice. Female, 8-12-month-old mice were divided into three groups: OVX (ovariectomized mice), OVXR (40% CR) and Sham. CR increased insulin sensitivity and glucose tolerance. AMPK phosphorylation was observed in the liver of OVXR mice. CR also increased hepatic cholesterol and triglyceride levels. The reductions in the level of TBARS in the serum and liver and of H2O2 in the liver of OVXR mice suggested alterations in the redox state of the liver. Although expression of catalase protein was reduced by CR, expression of superoxide dismutase was not altered by CR. Although interleukin IL-6 and IL-10 levels in OVXR mice were similar to those in Sham mice, macrophage infiltration was reduced in OVXR mice. OVXR mice had increased sirtuin1 levels and decreased sirtuin3 levels in the liver. In conclusion, CR improved the condition of ovariectomized mice by reducing adiposity and increasing insulin sensitivity and glucose tolerance through a mechanism that may involve AMPK.

ObjectiveMaternal malnutrition increases susceptibility to sepsis and mortality in neonates. The reason for this increased susceptibility remains unknown. We aimed to evaluate bacterial burden and serum cytokine levels in septic neonatal mice born to dams with malnutrition. Methods6-week-old C57BL/6 dams were placed on a low-fat (LFD) (10% kcal from fat), control (CD) (18% kcal from fat), or high-fat (HFD) (60% kcal from fat) diet for 3 weeks prior to breeding. Sepsis was induced in P4-P6 offspring via intraperitoneal Staphylococcus epidermidis injection. Mice were monitored for survival. At 12h after sepsis, serum and peritoneal wash fluid were collected for bacterial count and serum cytokine levels. In the absence of infection, P4-P6 offspring had untargeted serum metabolomics performed. ResultsSeptic offspring of dams fed LFD and HFD had significantly higher mortality than offspring of dams fed CD. There was no difference in serum or peritoneal wash bacterial loads. Maternal diet and Staphylococcus epidermidis sepsis caused changes in basal serum cytokine levels, with HFD causing decreased cytokine elevation during sepsis. Maternal LFD and HFD altered similar metabolomic pathways in offspring. ConclusionMaternal LFD and HFD decrease survival during neonatal sepsis and alter serum cytokines and the metabolome, supporting a role for maternal nutrition in neonatal immune function and infection susceptibility.