Brain-Derived Neurotrophic Factor as a Potential Mediator of the Beneficial Effects of Myo-Inositol Supplementation during Suckling in the Offspring of Gestational-Calorie-Restricted Rats.

This study aims to investigate the potential mechanisms underlying the protective effects of myo-inositol (MI) supplementation during suckling against the detrimental effects of fetal energy restriction described in animal studies, particularly focusing on the potential connections with BDNF signaling. Oral physiological doses of MI or the vehicle were given daily to the offspring of control (CON) and 25%-calorie-restricted (CR) pregnant rats during suckling. The animals were weaned and then fed a standard diet until 5 months of age, when the diet was switched to a Western diet until 7 months of age. At 25 days and 7 months of age, the plasma BDNF levels and mRNA expression were analyzed in the hypothalamus and three adipose tissue depots. MI supplementation, especially in the context of gestational calorie restriction, promoted BDNF secretion and signaling at a juvenile age and in adulthood, which was more evident in the male offspring of the CR dams than in females. Moreover, the CR animals supplemented with MI exhibited a stimulated anorexigenic signaling pathway in the hypothalamus, along with improved peripheral glucose management and enhanced browning capacity. These findings suggest a novel connection between MI supplementation during suckling, BDNF signaling, and metabolic programming, providing insights into the mechanisms underlying the beneficial effects of MI during lactation.

Supplementation with the Prebiotic High-Esterified Pectin Improves Blood Pressure and Cardiovascular Risk Biomarker Profile, Counteracting Metabolic Malprogramming.

Supplementation with the prebiotic pectin is associated with beneficial health effects. We aimed to characterize the cardioprotective actions of chronic high-esterified pectin (HEP) supplementation (10%) in a model of metabolic malprogramming in rats, prone to obesity and associated disorders: the progeny of mild calorie-restricted dams during the first half of pregnancy. Results show that pectin supplementation reverses metabolic malprogramming associated with gestational undernutrition. In this sense, HEP supplementation improved blood pressure, reduced heart lipid content, and regulated cardiac gene expression of atrial natriuretic peptide and lipid metabolism-related genes. Moreover, it caused an elevation in circulating levels of fibroblast growth factor 21 and a higher expression of its co-receptor ß-klotho in the heart. Most effects are correlated with the gut levels of beneficial bacteria promoted by HEP. Therefore, chronic HEP supplementation shows cardioprotective actions, and hence, it is worth considering as a strategy to prevent programmed cardiometabolic alterations.

Myo-Inositol Supplementation in Suckling Rats Protects against Adverse Programming Outcomes on Hypothalamic Structure Caused by Mild Gestational Calorie Restriction, Partially Comparable to Leptin Effects.

We studied whether myo-inositol supplementation throughout lactation, alone and combined with leptin, may reverse detrimental effects on hypothalamic structure and function caused by gestational calorie gestation (CR) in rats. Candidate early transcript-based biomarkers of metabolic health in peripheral blood mononuclear cells (PBMC) were also studied. Offspring of dams exposed to 25% gestational CR and supplemented during lactation with physiological doses of leptin (CR-L), myo-inositol (CR-M), the combination (CR-LM), or the vehicle (CR-V) as well as control rats (CON-V) were followed and sacrificed at postnatal day 25. Myo-inositol and the combination increased the number of neurons in arcuate nucleus (ARC) (only in females) and paraventricular nucleus, and myo-inositol (alone) restored the number of αMSH+ neurons in ARC. Hypothalamic mRNA levels of Lepr in CR-M and Insr in CR-M and CR-LM males were higher than in CR-V and CON-V, respectively. In PBMC, increased expression levels of Lrp11 and Gls in CR-V were partially normalized in all supplemented groups (but only in males for Gls). Therefore, myo-inositol supplementation throughout lactation, alone and combined with leptin, reverts programmed alterations by fetal undernutrition on hypothalamic structure and gene expression of potential early biomarkers of metabolic health in PBMC, which might be attributed, in part, to increased leptin sensitivity.

Sex-Specific Effects of Myo-Inositol Ingested During Lactation in the Improvement of Metabolic Health in Adult Rats.

SCOPE: To examine the effects of myo-inositol supplementation during lactation in male and female rats on metabolic parameters and its potential to reverse metabolic alterations associated with a moderate gestational calorie restriction. METHODS AND RESULTS: The offspring of control and 25% gestational calorie-restricted rats are supplemented with myo-inositol or vehicle throughout lactation and exposed to a Western diet (WD) from 5 to 7 months of age. Blood parameters are measured and gene expression and protein levels in retroperitoneal white adipose tissue (rWAT) and liver are analyzed. In male offspring, but not in females, myo-inositol supplementation resulted in lower fasting triglyceride and insulin levels and HOMA-IR at 7 months, and reversed the alterations in these parameters due to gestational calorie restriction. The expression pattern of key genes in metabolism in rWAT and liver support the beneficial effect of myo-inositol supplementation in reversing metabolic alterations programmed by gestational calorie restriction in male rats. CONCLUSIONS: Myo-inositol supplementation at physiological doses during lactation improves metabolic health and prevents the programmed trend to develop insulin resistance and hypertriglyceridemia in male rats acquired by inadequate fetal nutrition and exacerbated by a diabetogenic diet in adulthood. The absence of clear effects in females deserves further investigation.

Regulation of thermogenic capacity in brown and white adipocytes by the prebiotic high-esterified pectin and its postbiotic acetate.

OBJECTIVES: High-esterified pectin (HEP) is a prebiotic able to modulate gut microbiota, associated with health-promoting metabolic effects in glucose and lipid metabolism and adipostatic hormone sensitivity. Possible effects regulating adaptive thermogenesis and energy waste are poorly known. Therefore, we aimed to study how physiological supplementation with HEP is able to affect microbiota, energy metabolism and adaptive thermogenic capacity, and to contribute to the healthier phenotype promoted by HEP supplementation, as previously shown. We also attempted to decipher some of the mechanisms involved in the HEP effects, including in vitro experiments. SUBJECTS AND EXPERIMENTAL DESIGN: We used a model of metabolic malprogramming consisting of the progeny of rats with mild calorie restriction during pregnancy, both under control diet and an obesogenic (high-sucrose) diet, supplemented with HEP, combined with in vitro experiments in primary cultured brown and white adipocytes treated with the postbiotic acetate. RESULTS: Our main findings suggest that chronic HEP supplementation induces markers of brown and white adipose tissue thermogenic capacity, accompanied by a decrease in energy efficiency, and prevention of weight gain under an obesogenic diet. We also show that HEP promotes an increase in beneficial bacteria in the gut and peripheral levels of acetate. Moreover, in vitro acetate can improve adipokine production, and increase thermogenic capacity and browning in brown and white adipocytes, respectively, which could be part of the protection mechanism against excess weight gain observed in vivo. CONCLUSION: HEP and acetate stand out as prebiotic/postbiotic active compounds able to modulate both brown-adipocyte metabolism and browning and protect against obesity.

Biomarkers of Nutrition and Health: New Tools for New Approaches.

A main challenge in nutritional studies is the valid and reliable assessment of food intake, as well as its effects on the body. Generally, food intake measurement is based on self-reported dietary intake questionnaires, which have inherent limitations. They can be overcome by the use of biomarkers, capable of objectively assessing food consumption without the bias of self-reported dietary assessment. Another major goal is to determine the biological effects of foods and their impact on health. Systems analysis of dynamic responses may help to identify biomarkers indicative of intake and effects on the body at the same time, possibly in relation to individuals' health/disease states. Such biomarkers could be used to quantify intake and validate intake questionnaires, analyse physiological or pathological responses to certain food components or diets, identify persons with specific dietary deficiency, provide information on inter-individual variations or help to formulate personalized dietary recommendations to achieve optimal health for particular phenotypes, currently referred as "precision nutrition." In this regard, holistic approaches using global analysis methods (omics approaches), capable of gathering high amounts of data, appear to be very useful to identify new biomarkers and to enhance our understanding of the role of food in health and disease.

High-Esterified Pectin Reverses Metabolic Malprogramming, Improving Sensitivity to Adipostatic/Adipokine Hormones.

Detrimental metabolic programming has become a determinant factor in obesity propensity and the development of metabolic disorders; therefore, the search of nutritional strategies to reverse it is very relevant. Pectin is a prebiotic with health-promoting effects, such as control of glucose homeostasis and lipid metabolism, although other possible health effects and the prevention of obesity have been poorly studied. We studied the effects of chronic physiological supplementation with high-esterified pectin (HEP) in the reversion of metabolic nutrition-sensitive malprogramming associated with gestational undernutrition. As a model of nutrition-sensitive malprogramming, we used the progeny of rats with mild calorie restriction (CR) during pregnancy and analyzed their performance under metabolic stress (high-sucrose diet). We focused on the study of the sensitivity to the main adipostatic/adipokine hormones, i.e., leptin, insulin, and adiponectin, at both peripheral (liver and circulating parameters) and central (hypothalamus) levels. Our main findings suggest that chronic HEP supplementation is able to prevent weight/fat gain, to substantially reverse the detrimental malprogramming caused by the CR condition, to improve general health circulating markers, to modulate oxidative/lipogenic balance in the liver and energy metabolism regulators in the hypothalamus, and to restore/improve adipostatic/adipokine sensitivity affected by maternal calorie restriction, both peripherally and centrally. HEP stands out as a food component potentially useful against the development of metabolic disorders and obesity.

Combination of Capsaicin and Hesperidin Reduces the Effectiveness of Each Compound To Decrease the Adipocyte Size and To Induce Browning Features in Adipose Tissue of Western Diet Fed Rats.

We explored the potential of hesperidin and capsaicin, separately and in combination, to induce white adipose tissue (WAT) browning and to help body weight management in Western diet-fed rats. Adult male Wistar rats were fed for 8 weeks with Western diet and treated daily with hesperidin (100 mg/kg/day), capsaicin (4 mg/kg/day), hesperidin (100 mg/kg/day) + capsaicin (4 mg/kg/day), or the vehicle. Hesperidin and capsaicin separately, but not (or to a lesser extent) the combination, resulted in a decreased size of adipocytes and induced emergence of multilocular brown-like adipocytes positive for UCP1 and CIDEA in retroperitoneal WAT. Expression levels of browning markers, such as Prdm16, in inguinal WAT also increased with capsaicin treatment compared with the vehicle (145% ± 17% vs 92% ± 21%, P < 0.05), but no significant effects were found with the combination (106% ± 12%). Thus, the combination of both bioactives reduces the effectiveness of each compound to decrease the adipocyte size and induce WAT browning.

Leptin Intake at Physiological Doses Throughout Lactation in Male Wistar Rats Normalizes the Decreased Density of Tyrosine Hydroxylase-Immunoreactive Fibers in the Stomach Caused by Mild Gestational Calorie Restriction.

Introduction: Gestational under nutrition in rats has been shown to decrease expression of sympathetic innervation markers in peripheral tissues of offspring, including the stomach. This has been linked to lower gastric secretion and decreased circulating levels of ghrelin. Considering the critical role of leptin intake during lactation in preventing obesity and reversing adverse developmental programming effects, we aimed to find out whether leptin supplementation may reverse the above mentioned alterations caused by mild gestational calorie restriction. Methods: Three groups of male rats were studied at a juvenile age (25 days old) and during adulthood (3 and 6 months old): the offspring of ad libitum fed dams (controls), the offspring of dams that were diet restricted (20%) from days 1 to 12 of gestation (CR), and CR rats supplemented with a daily oral dose of leptin (equivalent to 5 times the average amount they could receive each day from maternal milk) throughout lactation (CR-Leptin). The density of TyrOH-immunoreactive (TyrOH+) fibers and the levels of Tyrosine hydroxylase (TyrOH)-used as potential markers of functional sympathetic innervation-were measured in stomach. Plasma leptin and ghrelin levels were also determined. Results: Twenty five-day-old CR rats, but not CR-Leptin rats, displayed lower density of TyrOH+ fibers (-46%) and TyrOH levels (-47%) in stomach compared to controls. Alterations in CR animals were mitigated at 6 months of age, and differences were not significant. Adult CR-Leptin animals showed higher plasma ghrelin levels than CR animals, particularly at 3 months (+16%), and a lower leptin/ghrelin ratio (-28 and -37% at 3 and 6 months, respectively). Conclusion: Leptin intake during lactation is able to reverse the alterations in the density of TyrOH+ fibers in the stomach and normalize the increased leptin/ghrelin ratio linked to a mild gestational calorie restriction in rats, supporting the relevance of leptin as an essential nutrient during lactation.

Screening of potential anti-adipogenic effects of phenolic compounds showing different chemical structure in 3T3-L1 preadipocytes.

This study was designed to analyze the anti-adipogenic effect of fifteen phenolic compounds from various chemical groups in 3T3-L1 pre-adipocytes. Cells were treated with 25 µM, 10 µM or 1 µM of apigenin, luteolin, catechin, epicatechin, epigallocatechin, genistein, daizein, naringenin, hesperidin, quercetin, kaempferol, resveratrol, vanillic acid, piceatannol and pterostilbene for 8 days. At 25 µM lipid accumulation was reduced by all the compounds, with the exception of catechin, epicatechin and epigallocatechin. At a dose of 10 µM apigenin, luteolin, naringenin, hesperidin, quercetin and kaempferol induced significant reductions, and at 1 µM only naringenin, hesperidin and quercetin were effective. The expression of c/ebpα was not. C/ebpß was significantly reduced by genistein and kaempferol, pparγ by genistein and pterostilbene, srebp1c by luteolin, genistein, hesperidin, kaempferol, pterostilbene and vanillic acid, and lpl by kaempferol. In conclusion, the most effective phenolic compounds are naringenin, hesperidin and quercetin. Differences were found in terms of effects on the expression of genes involved in adipogenesis among the analyzed compounds.

[CONSENSUS ON FATS AND OILS IN THE DIET OF S ISH ADULTS; POSITION PAPER OF THE SPANISH FEDERATION OF FOOD, NUTRITION AND DIETETICS SOCIETIES]. / CONSENSO SOBRE LAS GRASAS Y ACEITES EN LA ALIMENTACIÓN DE LA POBLACIÓN ESPAÑOLA ADULTA; POSTURA DE LA FEDERACIÓN ESPAÑOLA DE SOCIEDADES DE ALIMENTACIÓN, NUTRICIÓN Y DIETÉTICA (FESNAD).

The quality of dietary fat critically influences health. In this consensus document the scientific evidence relating effects of dietary fat quantity and quality on cardiovascular risk is reviewed and recommendations for the Spanish adult population are issued. As a novelty in nutrition guidelines, emphasis is made more on parent foods than on fatty acids per se. In summary, replacing saturated fatty acids (SFA) for monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) reduces cardiovascular risk. Recent data suggest that SFA proper may be harmful or not depending on the parent food, a reason why an intake threshold is not established, but consumption of foods containing excess SFA, such as butter, some processed meats, and commercial confectionery and fried foods is discouraged. The established threshold of <1 % of energy intake as trans FA, well known to be harmful for cardiovascular risk, is fulfilled in Spain due in part to its present low levels in margarines. MUFA are beneficial or neutral for cardiovascular risk depending on their dietary sources (virgin olive oil versus other fats), and no intake limitations are established.n-6 PUFA are cardioprotective and recommended intakes (5-10 % of energy) are not always fulfilled in the Spanish population, thus increased consumption of their vegetable food sources (seeds, derived oils, and margarines)is encouraged. Marine n-3 PUFA are also cardioprotective and the recommendation stands to eat fatty fish≥2 servings/weeks to reach intake levels of at least 250 mg/day. Increasing evidence suggests that alpha-linolenic acid (ALA), the vegetable n-3 PUFA, is also cardioprotective,but the parent foods (walnuts, soy products,green-leaf vegetables) may provide benefits beyond ALA itself. Finally, low-fat (high carbohydrate, particularly when having a high glycemic index) diets appear to lack cardiovascular preventive effects, while high-fat,high-vegetable fat dietary patterns such as the Mediterranean diet, are protective, a reason why no upper limit on fat intake is established for the Spanish population.This position statement targets dietitians, nutritionists and other health professionals involved in dietary counsel so they can deliver it rightly and according to the last scientific evidence.

La calidad de la grasa dietética tiene una profunda influencia sobre la salud. En este documento de consenso se evalúa la evidencia científica relativa a los efectos de la cantidad y calidad de la grasa alimentaria sobre la salud cardiovascular y se emiten recomendaciones para la población española adulta. Como novedad en unas guías nutricionales, se hace menos hincapié en los ácidos grasos per se que en los alimentos que los contienen. En resumen, sustituir ácidos grasos saturados (AGS) por monoinsaturados (AGM) y poliinsaturados (AGP) reduce el riesgo cardiovascular. Datos recientes sugieren que la ingesta de AGS per se es nociva solo en función del alimento que los contiene, por lo que no parece oportuno establecer un umbral de ingesta, pero se desaconsejan alimentos que los contienen en exceso, como la mantequilla y algunos derivados cárnicos, bollería y fritos comerciales. El límite de.

Consenso sobre las grasas y aceites en la alimentación de la población española adulta; postura de la Federación Española de Sociedades de Alimentación, Nutrición y Dietética (FESNAD) / Consensus on fats and oils in the diet of spanish adults; position paper of the spanish federation of food, nutrition and dietetics societies

La calidad de la grasa dietética tiene una profunda influencia sobre la salud. En este documento de consenso se evalúa la evidencia científica relativa a los efectos de la cantidad y calidad de la grasa alimentaria sobre la salud cardiovascular y se emiten recomendaciones para la población española adulta. Como novedad en unas guías nutricionales, se hace menos hincapié en los ácidos grasos per se que en los alimentos que los contienen. En resumen, sustituir ácidos grasos saturados (AGS) por monoinsaturados (AGM) y poliinsaturados (AGP) reduce el riesgo cardiovascular. Datos recientes sugieren que la ingesta de AGS per se es nociva solo en función del alimento que los contiene, por lo que no parece oportuno establecer un umbral de ingesta, pero se desaconsejan alimentos que los contienen en exceso, como la mantequilla y algunos derivados cárnicos, bollería y fritos comerciales. El límite de su bajo nivel actual en las margarinas. Los AGM son beneficiosos o neutros para el riesgo cardiovascular según su fuente dietética (aceite de oliva virgen frente a otras grasas), y no se establecen limitaciones de ingesta. Los AGP n-6 son cardioprotectores y el nivel recomendable de ingesta (5-10 % de la energía) no siempre se cumple en la población española, que debería aumentar el consumo de sus fuentes vegetales (semillas, aceites derivados y margarinas). Los AGP n-3 de origen marino son cardioprotectores y se recomienda consumir pescado graso ≥2 veces/semana para cumplir con la recomendación de al menos 250 mg/día. Existen evidencias crecientes de que el ácido alfa-linolénico (ALA), el AGP n-3 de origen vegetal, también es cardioprotector, pero los alimentos que lo contienen (nueces, soja, vegetales de hoja verde) pueden ser beneficiosos más allá del propio ALA. Finalmente, las dietas bajas en grasa (altas en hidratos de carbono, particularmente aquellas con un alto índice glicémico) carecen de efecto preventivo cardiovascular, mientras que las altas en grasa de origen vegetal, como la dieta mediterránea, son protectoras, razón por la que en España no parece necesario establecer un dintel superior de ingesta de grasa. Este documento de consenso se dirige a dietistas, nutricionistas y otros profesionales que dan consejo dietético para que puedan hacerlo de una manera razonada y acorde con la última evidencia científica (AU)

The quality of dietary fat critically influences health. In this consensus document the scientific evidence relating effects of dietary fat quantity and quality on cardiovascular risk is reviewed and recommendations for the Spanish adult population are issued. As a novelty in nutrition guidelines, emphasis is made more on parent foods than on fatty acids per se. In summary, replacing saturated fatty acids (SFA) for monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) reduces cardiovascular risk. Recent data suggest that SFA proper may be harmful or not depending on the parent food, a reason why an intake threshold is not established, but consumption of foods containing excess SFA, such as butter, some processed meats, and commercial confectionery and fried foods is discouraged. The established threshold of known to be harmful for cardiovascular risk, is fulfilled in Spain due in part to its present low levels in margarines. MUFA are beneficial or neutral for cardiovascular risk depending on their dietary sources (virgin olive oil versus other fats), and no intake limitations are established. n-6 PUFA are cardioprotective and recommended intakes (5-10 % of energy) are not always fulfilled in the Spanish population, thus increased consumption of their vegetable food sources (seeds, derived oils, and margarines) is encouraged. Marine n-3 PUFA are also cardioprotective and the recommendation stands to eat fatty fish ≥2 servings/weeks to reach intake levels of at least 250 mg/day. Increasing evidence suggests that alpha-linolenic acid (ALA), the vegetable n-3 PUFA, is also cardioprotective, but the parent foods (walnuts, soy products, green-leaf vegetables) may provide benefits beyond ALA itself. Finally, low-fat (high carbohydrate, particularly when having a high glycemic index) diets appear to lack cardiovascular preventive effects, while high-fat, high-vegetable fat dietary patterns such as the Mediterranean diet, are protective, a reason why no upper limit on fat intake is established for the Spanish population. This position statement targets dietitians, nutritionists and other health professionals involved in dietary counsel so they can deliver it rightly and according to the last scientific evidence (AU)

Pectin supplementation in rats mitigates age-related impairment in insulin and leptin sensitivity independently of reducing food intake.

SCOPE: This study investigates whether pectin supplementation in adult rats can ameliorate age-associated disturbances in peripheral insulin and leptin actions. METHODS AND RESULTS: Seven-month-old male Wistar rats were divided into three groups: control (rats fed ad libitum a standard-diet), pectin (rats fed ad libitum a standard-diet supplemented with 10% pectin), and pair-fed (rats pair-fed to the pectin group). They were sacrificed after 1 month. Pectin and pair-fed rats showed lower body weight gain and food intake than controls and underwent a decrease in leptin levels and an increase in adiponectin levels. Pectin-treated animals, but not pair-fed ones, showed lower body-fat content and HOMA-IR index after dietary intervention. Compared to controls, pectin-treated rats showed a decline in the expression of genes related to energy uptake (WAT) and lipogenesis (WAT and liver), and increased expression levels of lipolysis- and fatty-acid oxidation-related genes (liver). Some of the changes were not evidenced in the pair-fed group. These effects appear to be associated with improved leptin signaling. CONCLUSION: Ten percent pectin supplementation for 1 month in adult rats decreases body-fat content and ameliorates age-related insulin and leptin resistance more intensely than what could be attributed to the decrease in energy intake, overall contributing to better metabolic health.

Blood cell transcriptomic-based early biomarkers of adverse programming effects of gestational calorie restriction and their reversibility by leptin supplementation.

The challenge of preventing major chronic diseases requires reliable, early biomarkers. Gestational mild undernutrition in rats is enough to program the offspring to develop later pathologies; the intake of leptin, a breastmilk component, during lactation may reverse these programming effects. We used these models to identify, in peripheral blood mononuclear cells (PBMCs), transcriptomic-based early biomarkers of programmed susceptibility to later disorders, and explored their response to neonatal leptin intake. Microarray analysis was performed in PBMCs from the offspring of control and 20% gestational calorie-restricted dams (CR), and CR-rats supplemented with physiological doses of leptin throughout lactation. Notably, leptin supplementation normalised 218 of the 224 mRNA-levels identified in PBMCs associated to undernutrition during pregnancy. These markers may be useful for early identification and subsequent monitoring of individuals who are at risk of later diseases and would specifically benefit from the intake of appropriate amounts of leptin during lactation.

Oral leptin treatment in suckling rats ameliorates detrimental effects in hypothalamic structure and function caused by maternal caloric restriction during gestation.

A poor prenatal environment brings about perturbations in leptin surge and hypothalamic circuitry that program impaired ability to regulate energy homeostasis in adulthood. Here, using a rat model of moderate maternal caloric restriction during gestation, we aimed to investigate whether leptin supplementation with physiological doses throughout lactation is able to ameliorate the adverse developmental malprogramming effects exerted in offspring hypothalamus structure and function. Three groups of male and female rats were studied: the offspring of ad libitum fed dams (controls), the offspring of 20% calorie restricted dams during the first part of pregnancy (CR), and CR rats supplemented with physiological doses of leptin throughout lactation (CR-Leptin). Animals were sacrificed on postnatal day 25. Morphometric and immunohistochemical studies on arcuate (ARC) and paraventicular (PVN) nucleus were performed and hypothalamic expression levels of selected genes were determined. In CR males, leptin treatment restored, at least in part, the number of immunoreactive neuropeptide Y (NPY(+)) cells in ARC, the total number of cells in PVN, hypothalamic NPY, cocaine- and amphetamine-regulated transcript (CART) and suppressor of cytokine signalling-3 (SOCS-3) mRNA levels, and plasma leptin levels, which were decreased in CR animals. CR-Leptin males showed higher hypothalamic long-form leptin receptor (ObRb) mRNA levels, compared to control and CR animals. In CR females, leptin treatment reverted the increased number of cells in ARC and cell density in ARC and PVN, and reduced hypothalamic SOCS-3 mRNA expression to levels similar to controls. Leptin treatment also reverted the increased relative area of NPY(+) fibers in the PVN occurring in CR animals. In conclusion, leptin supplementation throughout lactation is able to revert, at least partly, most of the developmental effects on hypothalamic structure and function caused by moderate maternal caloric restriction during gestation, and hence making this metabolic malprogramming reversible to some extent.

Maternal dietary fat affects milk fatty acid profile and impacts on weight gain and thermogenic capacity of suckling rats.

We aimed to assess the effects of maternal supplementation with the main fat sources used in the human Western diet (olive oil, butter, margarine) on milk FA composition and on plasma FA profile of offspring, and to determine whether it may influence body-weight-gain (BWG) and adiposity of offspring during the suckling period. Wistar rats were supplemented with the different fat sources from day 14 of gestation and throughout lactation. Olive oil-supplemented dams showed the highest proportion of oleic-acid in milk, with no changes in plasma. Their offspring also showed the highest proportion of this FA in plasma, lower BWG during the suckling period, and higher levels of UCP1 in brown adipose tissue (BAT) at weaning. Margarine-supplemented dams showed the highest percentage of PUFA in milk, and a similar tendency was found in plasma of their offspring. Butter-supplemented dams displayed higher proportion of saturated FA (SFA) in milk compared to other fat-supplemented dams, but lower than controls. Control offspring also showed higher proportion of SFA in plasma and greater BWG during the suckling period than fat-supplemented groups. Significant correlations were found between the relative content of some milk FA and BWG of offspring, in particular, oleic-acid levels correlated negatively with BWG and positively with UCP1 levels. These results show that maternal dietary source of fat affects milk FA composition and circulating FA profile, as could be expected, but also BWG and thermogenic capacity of offspring during the suckling period. An effect of oleic-acid stimulating BAT thermogenic capacity of suckling pups is proposed.

Metabolic programming of sirtuin 1 (SIRT1) expression by moderate energy restriction during gestation in rats may be related to obesity susceptibility in later life.

In rats, 20% gestational energy restriction programmes offspring for higher food intake, which in adulthood results in higher body weight in males but not in females. Here, we aimed to assess whether the effects of moderate energy restriction during gestation and the sex-related outcomes on adult body weight may be related to the metabolic programming of sirtuin expression in different tissues. For this purpose, 25-d-old offspring of control and 20% energy-restricted (ER) rats (from days 1-12 of pregnancy) were studied. Body weight and the weight of white adipose tissue (WAT) depots and liver were recorded and mRNA expression of sirtuin 1 (SIRT1) and selected genes in the WAT, liver, muscle and hypothalamus were analysed. No differences were found in body weight or the weight of WAT and liver between the control and ER animals. A similar pattern of SIRT1 mRNA expression was found in the WAT, liver and skeletal muscle of ER animals, but in a sex-dependent manner: ER males showed lower SIRT1 mRNA levels than the controls, while no differences were found in females. A sex-different pattern was also observed in the hypothalamus. ER males, but not females, also showed lower mRNA levels of adipose TAG lipase (ATGL) and uncoupling protein 2 in WAT and of sterol response element binding protein 1c and stearoyl-CoA desaturase-1 in the liver. Both sexes of ER animals showed lower mRNA levels of 5' adenosine monophosphate-activated protein kinase and ATGL in the liver. In conclusion, moderate maternal energy restriction during gestation programmes a particular, sex-dependent gene expression profile of SIRT1 in different peripheral tissues, which may be related to obesity predisposition in adulthood; therefore SIRT1 expression emerges as a potential early biomarker of obesity susceptibility.

Maternal supplementation with an excess of different fat sources during pregnancy and lactation differentially affects feeding behavior in offspring: putative role of the leptin system.

SCOPE: This study investigates the lasting effects of maternal supplementation with different fat sources during pregnancy and lactation on feeding behavior and energy homeostasis of their offspring, and its relation to hypothetical effects in the development of main central structures involved in leptin signaling. METHODS AND RESULTS: Offspring of dams supplemented with olive oil, butter, or margarine during late pregnancy and lactation were fed with normal fat (NF) diet until 4-month-old, and then with NF or high fat (HF) diet until 6-month-old. Results showed that 21-day-old margarine group pups presented a higher cell number in the arcuate nucleus (ARC) (females) and higher hypothalamic ObRb/SOCS3 mRNA ratio (males). In adulthood, and under HF diet, they displayed a lower body weight (both genders) and body fat (males) than the butter group, a lower preference for fat food (both genders), and lower leptin levels than the olive oil (both genders) and butter (males) groups. CONCLUSIONS: Maternal supplementation with different fat sources during the perinatal period may affect the development of hypothalamic structures and hence predisposition to obesity. Margarine, compared with other fats, may program the offspring for increased leptin sensitivity and a lower preference for fat food, thus providing relative protection against body weight gain in adulthood, particularly under an obesogenic environment.

Impaired insulin and leptin sensitivity in the offspring of moderate caloric-restricted dams during gestation is early programmed.

We aimed to assess the mechanisms responsible for hyperphagia and metabolic alterations caused by maternal moderate caloric restriction during gestation. Male and female offspring of control and 20% caloric-restricted rats (CR) were studied. They were fed a normal-fat diet until 4 months of age and then moved to a high-fat diet until 6 months of age. Blood parameters and expression of selected genes in hypothalamus, retroperitoneal white adipose tissue (rWAT) and liver were analyzed at 25 days and 6 months of age. Plasma leptin was measured during suckling. Levels of proteins involved in insulin and leptin signaling were determined at 6 months of age. CR ate more calories than controls, but only males gained more weight. A peak in plasma leptin was found in 9-day-old controls, but was absent in CR. Twenty-five-day-old CR showed lower insulin receptor mRNA levels in hypothalamus, rWAT and liver, and long-form leptin receptor (ObRb) in hypothalamus. At the age of 6 months, homeostatic model assessment for insulin resistance index was higher in CR than controls, and CR males also displayed hyperleptinemia. Adult CR also showed lower ObRb mRNA levels in the hypothalamus (only females, but both showed altered neuropeptide Y/proopiomelanocortin mRNA ratio), rWAT and liver (males), and a decrease of protein kinase C zeta levels in rWAT (females) and liver (males) and of phosphorylated signal transducer and activator of transcription 3 in liver (females). These results suggest that CR animals are programmed for insulin and central leptin resistance, which may explain the dysregulation of appetite and other metabolic alterations, favoring obesity development, although only manifested in males. These early programming effects could be associated with the absence of leptin surge during lactation.