High-fat diet consumption by male rat offspring of obese mothers exacerbates adipose tissue hypertrophy and metabolic alterations in adult life.

Obese mothers' offspring develop obesity and metabolic alterations in adulthood. Poor postnatal dietary patterns also contribute to obesity and its comorbidities. We aimed to determine whether in obese mothers' offspring an adverse postnatal environment, such as high-fat diet (HFD) consumption (second hit) exacerbates body fat accumulation, metabolic alterations and adipocyte size distribution. Female Wistar rats ate chow (C-5 %-fat) or HFD (maternal obesity (MO)-25 %-fat) from weaning until the end of lactation. Male offspring were weaned on either control (C/C and MO/C, maternal diet/offspring diet) or HFD (C/HF and MO/HF) diet. At 110 postnatal days, offspring were killed. Fat depots were excised to estimate adiposity index (AI). Serum glucose, triglyceride, leptin, insulin, insulin resistance index (HOMA-IR), corticosterone and dehydroepiandrosterone (DHEA) were determined. Adipocyte size distribution was evaluated in retroperitoneal fat. Body weight was similar in C/C and MO/C but higher in C/HF and MO/HF. AI, leptin, insulin and HOMA-IR were higher in MO/C and C/HF v. C/C but lower than MO/HF. Glucose increased in MO/HF v. MO/C. C/HF and MO/C had higher triglyceride and corticosterone than C/C, but lower corticosterone than MO/HF. DHEA and the DHEA/corticosterone ratio were lower in C/HF and MO/C v. C/C, but higher than MO/HF. Small adipocyte proportion decreased while large adipocyte proportions increased in MO/C and C/HF v. C/C and exacerbated in MO/HF v. C/HF. Postnatal consumption of a HFD by the offspring of obese mothers exacerbates body fat accumulation as well as the decrease of small and the increase of large adipocytes, which leads to larger metabolic abnormalities.

Maternal Stress during Pregnancy in Mice Induces Sex-Dependent Behavioral Alterations in Offspring along with Impaired Serotonin and Kynurenine Pathways of Tryptophan Metabolism.

Maternal stress during pregnancy results in increased risk of developing psychiatric disorders in the offspring including anxiety, depression, schizophrenia, and autism. However, the mechanisms underlying this disease susceptibility remain largely to be determined. In this study, the involvement of the serotonin (5-HT) and kynurenine (KYN) pathways of tryptophan metabolism on the behavioral deficits induced by maternal stress during the late phase of gestation in mice was investigated. Adult offspring born to control or restraint-stressed dams were exposed to the elevated plus-maze and tail suspension tests. Metabolites of the KYN and 5-HT pathways were measured in the hippocampus and brainstem by ultra-performance liquid chromatography tandem mass spectrometry. Female, but not male, prenatally stressed (PNS) offspring displayed a depressive-like phenotype, mainly when in proestrus/diestrus, along with reduced hippocampal 5-HT levels and high 5-HT turnover rate in the hippocampus and brainstem. In contrast, male PNS mice showed enhanced anxiety-like behaviors and higher hippocampal and brainstem quinolinic acid levels compared to male offspring born to nonstressed dams. These results indicate that maternal stress affects the behavior and brain metabolism of tryptophan in the offspring in a sex-dependent manner and suggest that alterations in both the 5-HT and KYN pathways may underlie the emotional dysfunctions observed in individuals exposed to stress during in utero development.

High-fat and combined high-fat-high-fructose diets impair episodic-like memory and decrease glutamate and glutamine in the hippocampus of adult mice.

BACKGROUND: Diet-induced obesity is associated with premature cognitive decline. Elevated consumption of fats and sugars in humans and rodents has been associated with deficits in recognition memory, which is modulated by the hippocampus. Alterations in excitatory and inhibitory neurotransmitters in this area have been observed after hypercaloric diets, but the effects on episodic-like memory are not conclusive. OBJECTIVE: To investigate the effects of hypercaloric diets on memory and their relationship with γ-aminobutyric acid (GABA), glutamate and glutamine and their genetic expression in the hippocampus. DESIGN: A control diet (CD), a high-fat diet (HFD) and a combined high-fat-high-fructose diet (HFFrD) were administered to 30 C57BL/6 adult mice for 10 weeks. The discrimination indexes and exploration time of the novel object recognition (NOR) and novel object location (NOL) tasks were evaluated and GABA, glutamate and glutamine concentrations and their genetic expression were obtained from the hippocampus. RESULTS: The HFFrD induced lower discrimination indexes, decreased exploration time in the recognition memory tasks, and lowered the concentrations of glutamate and glutamine, and HFD increased their expression in the hippocampus. CONCLUSIONS: These findings suggest that a possible adaptative long-term mechanism in the hippocampal neurotransmitters, and this possibility may underlie the episodic-like memory deficits in mice fed HFD and HFFrD.

Maternal obesity accelerates rat offspring metabolic ageing in a sex-dependent manner.

KEY POINTS: Maternal obesity predisposes to metabolic dysfunction in male and female offspring Maternal high-fat diet consumption prior to and throughout pregnancy and lactation accelerates offspring metabolic ageing in a sex-dependent manner This study provides evidence for programming-ageing interactions ABSTRACT: Human epidemiological studies show that maternal obesity (MO) shortens offspring life and health span. Life course cellular mechanisms involved in this developmental programming-ageing interaction are poorly understood. In a well-established rat MO model, female Wistar rats ate chow (controls (C)) or high energy, obesogenic diet to induce MO from weaning through pregnancy and lactation. Females were bred at postnatal day (PND) 120. Offspring (F1 ) of mothers on control diet (CF1 ) and MO diet (MOF1 ) delivered spontaneously at terms. Both CF1 and MOF1 ate C diet from weaning throughout the study. Offspring were killed at PND 36, 110, 450 and 650. We determined body and liver weights, liver and serum metabolite concentrations, hormones and oxidative stress biomarkers. Male and female CF1 body weight, total fat, adiposity index, serum leptin, insulin, insulin resistance, and liver weight, fat, triglycerides, malondialdehyde, reactive oxygen species and nitrotyrosine all rose with differing ageing trajectories. Female CF1 triglycerides were unchanged with age. Age-related increases were greater in MOF1 than CF1 in both sexes for all variables except glucose in males and females and cholesterol in males. Cholesterol fell in CF1 females but not MOF1 . Serum corticosterone levels were higher in male and female MOF1 than CF1 and declined with age. DHEA serum levels were lower in male and female MOF1 than CF1 . Liver antioxidant enzymes decreased with age (CF1 and MOF1 ). CONCLUSIONS: exposure to the developmental challenge of MO accelerates progeny ageing metabolic and endocrine profiles in a sex specific manner, providing evidence for programming-ageing interactions.

Maternal obesity has sex-dependent effects on insulin, glucose and lipid metabolism and the liver transcriptome in young adult rat offspring.

KEY POINTS: Maternal high-fat diet consumption predisposes to metabolic dysfunction in male and female offspring at young adulthood. Maternal obesity programs non-alcoholic fatty liver disease (NAFLD) in a sex-dependent manner. We demonstrate sex-dependent liver transcriptome profiles in rat offspring of obese mothers. In this study, we focused on pathways related to insulin, glucose and lipid signalling. These results improve understanding of the mechanisms by which a maternal high-fat diet affects the offspring. ABSTRACT: Maternal obesity (MO) predisposes offspring (F1) to obesity, insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD). MO's effects on the F1 liver transcriptome are poorly understood. We used RNA-seq to determine the liver transcriptome of male and female F1 of MO and control-fed mothers. We hypothesized that MO-F1 are predisposed to sex-dependent adult liver dysfunction. Female Wistar rat mothers ate a control (C) or obesogenic (MO) diet from the time they were weaned through breeding at postnatal day (PND) 120, delivery and lactation. After weaning, all male and female F1 ate a control diet. At PND 110, F1 serum, liver and fat were collected to analyse metabolites, histology and liver differentially expressed genes. Male and female MO-F1 showed increased adiposity index, triglycerides, insulin and homeostatic model assessment vs. C-F1 with similar body weight and glucose serum concentrations. MO-F1 males presented greater physiological and histological NAFLD characteristics than MO-F1 females. RNA-seq revealed 1365 genes significantly changed in male MO-F1 liver and only 70 genes in female MO-F1 compared with controls. GO and KEGG analysis identified differentially expressed genes related to metabolic processes. Male MO-F1 liver showed the following altered pathways: insulin signalling (22 genes), phospholipase D signalling (14 genes), NAFLD (13 genes) and glycolysis/gluconeogenesis (7 genes). In contrast, few genes were altered in these pathways in MO-F1 females. In summary, MO programs sex-dependent F1 changes in insulin, glucose and lipid signalling pathways, leading to liver dysfunction and insulin resistance.

Maternal obesity in the rat impairs male offspring aging of the testicular antioxidant defence system.

A high-fat diet during intrauterine development predisposes offspring (F1) to phenotypic alterations, such as lipid synthesis imbalance and increased oxidative stress, causing changes in male fertility. The objective of this study was to evaluate the effects of maternal obesity during pregnancy and lactation on antioxidant enzymes in the F1 testes. Female Wistar rats (F0) were fed either a control (C, 5% fat) or an obesogenic (MO, maternal obesity, 25% fat) diet from weaning and throughout subsequent pregnancy and lactation. F1 offspring were weaned to the control diet. Testes were retrieved at 110, 450 and 650 postnatal days (PND) for real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and immunohistochemical (IHC) antioxidant enzyme analyses. Catalase was similar between groups by RT-qPCR, whereas by IHC it was higher in the MO group at all ages than in the C group. Superoxide dismutase 1 (SOD1) had lower expression at PND 110 in MO than in C by both techniques; at PND 450 and 650 by immunoanalysis SOD1 was higher in MO than in C. Glutathione peroxidase 1 (GPX1), GPX2 and GPX4 by RT-qPCR were similar between groups and ages; by IHC GPX1/2 was higher in MO than in C, whereas GPX4 showed the opposite result at PND 110 and 450. In conclusion, antioxidant enzymes in the rat testes are modified with age. Maternal obesity negatively affects the F1 testicular antioxidant defence system, which, in turn, can explain the decrease in reproductive capacity.

Resveratrol partially prevents oxidative stress and metabolic dysfunction in pregnant rats fed a low protein diet and their offspring.

Protein restriction in pregnancy produces maternal and offspring metabolic dysfunction potentially as a result of oxidative stress. Data are lacking on the effects of inhibition of oxidative stress. We hypothesized that maternal resveratrol administration decreases oxidative stress, preventing, at least partially, maternal low protein-induced maternal and offspring metabolic dysfunction. In the present study, pregnant wistar rats ate control (C) (20% casein) or a protein-restricted (R) (10% casein) isocaloric diet. Half of each group received resveratrol orally, 20 mg kg(-1) day(-1), throughout pregnancy. Post-delivery, mothers and offspring ate C. Oxidative stress biomarkers and anti-oxidant enzymes were measured in placenta, maternal and fetal liver, and maternal serum corticosterone at 19 days of gestation (dG). Maternal (19 dG) and offspring (postnatal day 110) glucose, insulin, triglycerides, cholesterol, fat and leptin were determined. R mothers showed metabolic dysfunction, increased corticosterone and oxidative stress and reduced anti-oxidant enzyme activity vs. C. R placental and fetal liver oxidative stress biomarkers and anti-oxidant enzyme activity increased. R offspring showed higher male and female leptin, insulin and corticosterone, male triglycerides and female fat than C. Resveratrol decreased maternal leptin and improved maternal, fetal and placental oxidative stress markers. R induced offspring insulin and leptin increases were prevented and other R changes were offspring sex-dependent. Resveratrol partially prevents low protein diet-induced maternal, placental and sex-specific offspring oxidative stress and metabolic dysfunction. Oxidative stress is one mechanism programming offspring metabolic outcomes. These studies provide mechanistic evidence to guide human pregnancy interventions when fetal nutrition is impaired by poor maternal nutrition or placental function.

Ovarian hormones and prolactin increase renal NaCl cotransporter phosphorylation.

Unique situations in female physiology require volume retention. Accordingly, a dimorphic regulation of the thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC) has been reported, with a higher activity in females than in males. However, little is known about the hormones and mechanisms involved. Here, we present evidence that estrogens, progesterone, and prolactin stimulate NCC expression and phosphorylation. The sex difference in NCC abundance, however, is species dependent. In rats, NCC phosphorylation is higher in females than in males, while in mice both NCC expression and phosphorylation is higher in females, and this is associated with increased expression and phosphorylation of full-length STE-20 proline-alanine-rich kinase (SPAK). Higher expression/phosphorylation of NCC was corroborated in humans by urinary exosome analysis. Ovariectomy in rats resulted in decreased expression and phosphorylation of the cotransporter and promoted the shift of SPAK isoforms toward the short inhibitory variant SPAK2. Conversely, estradiol or progesterone administration to ovariectomized rats restored NCC phosphorylation levels and shifted SPAK expression and phosphorylation towards the full-length isoform. Estradiol administration to male rats induced a significant increase in NCC phosphorylation. NCC is also modulated by prolactin. Administration of this peptide hormone to male rats induced increased phosphorylation of NCC, an effect that was observed even using the ex vivo kidney perfusion strategy. Our results indicate that estradiol, progesterone, and prolactin, the hormones that are involved in sexual cycle, pregnancy and lactation, upregulate the activity of NCC.

Late-in-life Exercise Ameliorates the Aging Trajectory Metabolism Programmed by Maternal Obesity in Rats: It is Never Too Late.

BACKGROUND: Maternal obesity (MO) has been shown to adversely affect metabolic, oxidative, reproductive, and cognitive function in offspring. However, it is unclear whether lifestyle modification can ameliorate the metabolic and organ dysfunction programmed by MO and prevent the effects of metabolic syndrome in adulthood. This study aimed to evaluate whether moderate voluntary exercise in the offspring of rats born to obese mothers can ameliorate the adverse effects of MO programming on metabolism and liver function in mid-adulthood. METHODS: Offspring of control (CF1) and MOF1 mothers were fed with a control diet from weaning. Adult males and females participated in 15 min exercise sessions five days/week. Metabolic parameters were analyzed before and after the exercise intervention. Liver oxidative stress biomarkers and antioxidant enzymes were analyzed before and after the intervention. RESULTS: Males showed that CF1ex ran more than MOF1ex and increased the distance covered. In contrast, females in both groups ran similar distances and remained constant but ran more distance than males. At PND 300 and 450, male and female MOF1 had higher leptin, triglycerides, insulin, and HOMA-IR levels than CF1. However, male MOF1ex had lower triglycerides, insulin, and HOMA-IR levels than MOF1. Improvements in liver fat and antioxidant enzymes were observed in CF1ex and MOF1ex males and females compared to their respective CF1 and MOF1 groups. CONCLUSION: These findings suggest that moderate voluntary exercise, even when started in mid-adulthood, can improve metabolic outcomes and delay accelerated metabolic aging in MO-programmed rats in a sex-dependent manner.

Impaired Ischemia-Reperfusion Responses in the Hearts of Aged Male and Female Offspring of Obese Rats.

Maternal obesity predisposes offspring (F1) to cardiovascular disease. To evaluate basal heart function and ischemia-reperfusion (IR) responses in F1 males and females of obese mothers, female Wistar rats (F0) were fed chow or an obesogenic (MO) diet from weaning through pregnancy and lactation. Non-sibling F1 males and females were weaned to chow at postnatal day (PND) 21 and euthanized at PND 550. Offspring of MO mothers (MOF1) rarely survive beyond PND 650. Hearts were immediately isolated from euthanized F1s and subjected to 30 min ischemia with 20 min reperfusion. Retroperitoneal fat, serum triglycerides, glucose, insulin, and insulin resistance were measured. Baseline left ventricular developed pressure (LVDP) was lower in male and female MOF1 than in controls. After global ischemia, LVDP in control (C) male and female F1 recovered 78 and 83%, respectively, while recovery in MO male and female F1 was significantly lower at 28 and 52%, respectively. Following the IR challenge, MO hearts showed a higher functional susceptibility to reperfusion injury, resulting in lower cardiac reserve than controls in both sexes. Female hearts were more resistant to IR. Retroperitoneal fat was increased in male MOF1 vs. CF1. Circulating triglycerides and insulin resistance were increased in male and female MOF1 vs. CF1. These data show that MO programming reduces F1 cardiac reserve associated with age-related insulin resistance in a sex-specific manner.

Maternal Obesity Programs the Premature Aging of Rat Offspring Liver Mitochondrial Electron Transport Chain Genes in a Sex-Dependent Manner.

We investigated whether maternal obesity affects the hepatic mitochondrial electron transport chain (ETC), sirtuins, and antioxidant enzymes in young (110 postnatal days (PND)) and old (650PND) male and female offspring in a sex- and age-related manner. Female Wistar rats ate a control (C) or high-fat (MO) diet from weaning, through pregnancy and lactation. After weaning, the offspring ate the C diet and were euthanized at 110 and 650PND. The livers were collected for RNA-seq and immunohistochemistry. Male offspring livers had more differentially expressed genes (DEGs) down-regulated by both MO and natural aging than females. C-650PND vs. C-110PND and MO-110PND vs. C-110PND comparisons revealed 1477 DEGs in common for males (premature aging by MO) and 35 DEGs for females. Analysis to identify KEGG pathways enriched from genes in common showed changes in 511 and 3 KEGG pathways in the male and female livers, respectively. Mitochondrial function pathways showed ETC-related gene down-regulation. All ETC complexes, sirtuin2, sirtuin3, sod-1, and catalase, exhibited gene down-regulation and decreased protein expression at young and old ages in MO males vs. C males; meanwhile, MO females down-regulated only at 650PND. Conclusions: MO accelerates the age-associated down-regulation of ETC pathway gene expression in male offspring livers, thereby causing sex-dependent oxidative stress, premature aging, and metabolic dysfunction.

Developmental Programming-Aging Interactions Have Sex-Specific and Developmental Stage of Exposure Outcomes on Life Course Circulating Corticosterone and Dehydroepiandrosterone (DHEA) Concentrations in Rats Exposed to Maternal Protein-Restricted Diets.

The steroids corticosterone and dehydroepiandrosterone (DHEA) perform multiple life course functions. Rodent life-course circulating corticosterone and DHEA trajectories are unknown. We studied life course basal corticosterone and DHEA in offspring of rats fed protein-restricted (10% protein, R) or control (20% protein, C), pregnancy diet first letter, and/or lactation second letter, producing four offspring groups-CC, RR, CR, and RC. We hypothesize that 1. maternal diet programs are sexually dimorphic, offspring life course steroid concentrations, and 2. an aging-related steroid will fall. Both changes differ with the plastic developmental period offspring experienced R, fetal life or postnatally, pre-weaning. Corticosterone was measured by radioimmunoassay and DHEA by ELISA. Steroid trajectories were evaluated by quadratic analysis. Female corticosterone was higher than male in all groups. Male and female corticosterone were highest in RR, peaked at 450 days, and fell thereafter. DHEA declined with aging in all-male groups. DHEA: corticosterone fell in three male groups but increased in all-female groups with age. In conclusion, life course and sexually dimorphic steroid developmental programming-aging interactions may explain differences in steroid studies at different life stages and between colonies experiencing different early-life programming. These data support our hypotheses of sex and programming influences and aging-related fall in rat life course serum steroids. Life course studies should address developmental programming-aging interactions.

Programming Mechanism of Adipose Tissue Expansion in the Rat Offspring of Obese Mothers Occurs in a Sex-Specific Manner.

We investigated whether excessive retroperitoneal adipose tissue (AT) expansion programmed by maternal obesity (MO) affects adipocyte size distribution and gene expression in relation to adipocyte proliferation and differentiation in male and female offspring (F1) from control (F1C) and obese (F1MO) mothers. Female Wistar rats (F0) ate a control or high-fat diet from weaning through pregnancy and lactation. F1 were weaned onto a control diet and euthanized at 110 postnatal days. Fat depots were weighed to estimate the total AT. Serum glucose, triglyceride, leptin, insulin, and the insulin resistance index (HOMA-IR) were determined. Adipocyte size and adipogenic gene expression were examined in retroperitoneal fat. Body weight, retroperitoneal AT and adipogenesis differed between male and female F1Cs. Retroperitoneal AT, glucose, triglyceride, insulin, HOMA-IR and leptin were higher in male and female F1MO vs. F1C. Small adipocytes were reduced in F1MO females and absent in F1MO males; large adipocytes were increased in F1MO males and females vs. F1C. Wnt, PI3K-Akt, and insulin signaling pathways in F1MO males and Egr2 in F1MO females were downregulated vs. F1C. MO induced metabolic dysfunction in F1 through different sex dimorphism mechanisms, including the decreased expression of pro-adipogenic genes and reduced insulin signaling in males and lipid mobilization-related genes in females.

Resveratrol Supplementation in Obese Pregnant Rats Improves Maternal Metabolism and Prevents Increased Placental Oxidative Stress.

Maternal obesity (MO) causes maternal and fetal oxidative stress (OS) and metabolic dysfunction. We investigated whether supplementing obese mothers with resveratrol improves maternal metabolic alterations and reduces OS in the placenta and maternal and fetal liver. From weaning through pregnancy female Wistar rats ate chow (C) or a high-fat diet (MO). One month before mating until 19 days' gestation (dG), half the rats received 20 mg resveratrol/kg/d orally (Cres and MOres). At 19dG, maternal body weight, retroperitoneal fat adipocyte size, metabolic parameters, and OS biomarkers in the placenta and liver were determined. MO mothers showed higher body weight, triglycerides and leptin serum concentrations, insulin resistance (IR), decreased small and increased large adipocytes, liver fat accumulation, and hepatic upregulation of genes related to IR and inflammatory processes. Placenta, maternal and fetal liver OS biomarkers were augmented in MO. MOres mothers showed more small and fewer large adipocytes, lower triglycerides serum concentrations, IR and liver fat accumulation, downregulation of genes related to IR and inflammatory processes, and lowered OS in mothers, placentas, and female fetal liver. Maternal resveratrol supplementation in obese rats improves maternal metabolism and reduces placental and liver OS of mothers and fetuses in a sex-dependent manner.

Maternal obesity (MO) programs morphological changes in aged rat offspring small intestine in a sex dependent manner: Effects of maternal resveratrol supplementation.

Maternal obesity (MO) leads to offspring metabolic problems. The mechanisms involved are multifactorial. The small intestine plays an important role in the absorption of nutrients and is modified as we age. Few studies have explored MO programming effects on offspring (F1) small intestine morphology. The aim of this study was to investigate MO effects on old adult F1 intestinal morphology, and whether any F1 intestinal changes due to MO were modified by maternal resveratrol supplementation. From weaning throughout pregnancy and lactation, female Wistar rats (F0) ate standard chow (controls, C: 5%-fat) or high-fat diet (MO: 25%-fat). One month before mating at postnatal day (PND) 120 through lactation half of each group received 20 mg/kg/day of resveratrol orally (Cres or MOres). After weaning F1 were fed with chow diet until the end of the study at PND 650. Body weight, percent of fat, glucose, cholesterol and triglyceride serum concentrations were determined. F1 small intestinal samples were collected for histological analysis. Male F1 body weight was higher in MO and MOres compared with C and Cres. Female F1 body weight and percent of fat was higher in MO than C and MOres. Triglyceride concentrations were higher in MO and MOres male F1 compared with C and Cres. There were no differences among groups in female triglyceride concentrations. Male F1 duodenal villus height was smaller in MO compared with MOres. Female F1 duodenal and jejunal crypt depth was smaller in MO compared with C and was greater compared with MOres. Female F1 villus height in jejunum was greater in MO compared with MOres. In conclusion, exposure to the developmental challenge of MO changed the aged F1 intestinal morphological and metabolic profiles. Maternal resveratrol supplementation ameliorated these effects in an F1 sex dependent manner.

Different Protein Sources in the Maternal Diet of the Rat during Gestation and Lactation Affect Milk Composition and Male Offspring Development during Adulthood.

Protein sources in maternal diet are important for mammary gland differentiation and milk protein; however, few studies have examined the metabolic and cellular adaptations of mothers based on protein source diets during pregnancy and lactation, and leptin concentration in offspring. We evaluated metabolic parameters and maternal key organs and milk components in mothers at the end of lactation, who were fed different sources of proteins. In postnatal day 110 and 250, we studied development parameters and leptin in male offspring. Female rats received a Vegetal (V) or Animal (A) diet during pregnancy and lactation. After weaning, male offspring ate V diet until postnatal day 250, which yielded two groups: Vv and Av. Milk dry, protein and fat were analyzed. Maternal metabolic parameters, leptin, and liver, adipose tissue and mammary gland histological analyses were studied. Body weight, food intake and leptin were analyzed in offspring at two ages. Adipose tissue weight and cells size and liver fat, mammary gland apoptosis, weight, milk protein and leptin were higher in A vs V. Maternal liver and milk dry were lower in A vs V. All offspring parameters were higher in Av vs Vv at postnatal day 110; however, at postnatal day 250, leptin was higher in Av vs Vv. Maternal serum and milk leptin had a positive correlation with offspring serum leptin at both ages. Consumption of animal protein-based diets by mothers during developmental periods affects specific maternal organs and changes milk composition during lactation, leading to a hyperleptinemic phenotype in male offsprings.

DHA Supplementation of Obese Rats throughout Pregnancy and Lactation Modifies Milk Composition and Anxiety Behavior of Offspring.

We investigated if supplementing obese mothers (MO) with docosahexaenoic acid (DHA) improves milk long-chain polyunsaturated fatty acid (LCPUFA) composition and offspring anxiety behavior. From weaning throughout pregnancy and lactation, female Wistar rats ate chow (C) or a high-fat diet (MO). One month before mating and through lactation, half the mothers received 400 mg DHA kg-1 d-1 orally (C+DHA or MO+DHA). Offspring ate C after weaning. Maternal weight, total body fat, milk hormones, and milk nutrient composition were determined. Pups' milk nutrient intake was evaluated, and behavioral anxiety tests were conducted. MO exhibited increased weight and total fat, and higher milk corticosterone, leptin, linoleic, and arachidonic acid (AA) concentrations, and less DHA content. MO male and female offspring had higher ω-6/ ω-3 milk consumption ratios. In the elevated plus maze, female but not male MO offspring exhibited more anxiety. MO+DHA mothers exhibited lower weight, total fat, milk leptin, and AA concentrations, and enhanced milk DHA. MO+DHA offspring had a lower ω-6/ω-3 milk intake ratio and reduced anxiety vs. MO. DHA content was greater in C+DHA milk vs. C. Supplementing MO mothers with DHA improves milk composition, especially LCPUFA content and ω-6/ω-3 ratio reducing offspring anxiety in a sex-dependent manner.

Aging Endocrine and Metabolic Phenotypes Are Programmed by Mother's Age at Conception in a Sex-Dependent Fashion in the Rat.

Programming of offspring life-course health by maternal nutrition and stress are well studied. At postnatal day 850, we evaluated male and female steroid levels and metabolism in aged offspring of primigravid sister rats bred at 70, 90, 150, or 300 days' life. At 850 days life, male offspring corticosterone was similar regardless of maternal age. Female corticosterone was highest in offspring of 70- and 300-day mothers. Serum dehydroepiandrosterone:corticosterone was lowest in both sexes of offspring of 70- and 300-day mothers. Male and female fat depots were smaller in offspring of 150- than 70- and 90-day mothers. Insulin, glucose, and homeostatic model assessment were similar in all male offspring but higher in female offspring of 70-day mothers than other ages. We conclude, maternal age affects offspring aging in an offspring sex-dependent manner and merits consideration in designing and interpreting programming studies.

Leuconostoc mesenteroides subsp. mesenteroides SD23 Prevents Metabolic Dysfunction Associated with High-Fat Diet-Induced Obesity in Male Mice.

High-fat diet (HFD) consumption induces obesity and increases blood glucose, insulin resistance, and metabolic disorders. Recent studies suggest that probiotics might be a novel approach to counteract these effects in the treatment of obesity. Here, we evaluated the effect of Leuconostoc mesenteroides subsp. mesenteroides SD23 on obesity-related metabolic dysfunction. In the present study, mice were randomly divided into four dietary groups: standard diet (C), HFD (OB), standard diet with L. mesenteroides SD23 (CP), and HFD with L. mesenteroides SD23 (OBP). Diets were maintained for 14 weeks. Animal weight was monitored and biochemical and histological analyses were performed after intervention. OB showed metabolic dysfunction, and increased the number of larger adipocytes compared to C. OB induced liver tumor necrosis factor-α (TNF-α) expression, increased cholesterol, leptin, and glucose levels compared to C. OBP reduced body weight, glucose, cholesterol, and leptin levels and improved glucose tolerance compared to OB. OBP also reduced liver steatosis, the number of larger adipocytes in adipose tissue, and reduced the villus height in the small intestine. OBP decreased expression of TNF-α and increased expression of IL-10 in liver. The parameters evaluated in the CP were similar to the C. This study provides novel evidence that dietary intervention with L. mesenteroides SD23 improves metabolic dysfunction related to obesity in HFD-fed mice.

Impact of Leuconostoc SD23 intake in obese pregnant rats: benefits for maternal metabolism.

Maternal obesity (MO) during pregnancy and lactation leads to maternal and offspring metabolic dysfunction. Recent research has suggested that probiotics might be a novel approach to counteract these unwanted MO effects. The aim of this research was to analyze the impact of Leuconostoc SD23, a probiotic isolated from aguamiel (traditional Mexican drink), on MO metabolism in rats at the end of lactation (21 days). From weaning through lactation, control female Wistar rats (C) ate chow (5% fat) or high-energy obesogenic diet (MO; 25% fat). Half the C and MO mothers received a daily dose (1 × 1010 CFU/ml) of probiotic orally, control with probiotic (CP) and MO with probiotic (MOP), 1 month before mating and through pregnancy and lactation. Histological analyses of the liver, white adipose tissue and small intestine, body composition, glucose, insulin, triglycerides, and leptin were determined in mothers at the end of lactation. Maternal weight during pregnancy was greater in MO than C mothers, but similar at the end of lactation. Probiotic intervention had no effect on maternal weight. However, at the end of lactation, percentage of body fat was higher in MO than C, CP, and MOP. Serum glucose, homeostasis model assessment of insulin resistance, and triglycerides were higher in MO versus C, CP, and MOP. MO small intestine villus height was higher versus MOP, C, and CP. Leuconostoc SD23 did not present adverse effects in C. Conclusions: maternal administration of Leuconostoc SD23 has beneficial effects on maternal metabolism, which holds possibilities for preventing adverse offspring metabolic programming.