Intake of an Obesogenic Cafeteria Diet Affects Body Weight, Feeding Behavior, and Glucose and Lipid Metabolism in a Photoperiod-Dependent Manner in F344 Rats

We previously demonstrated that chronic exposure to different photoperiods induced marked variations in several glucose and lipid metabolism-related parameters in normoweight Fischer 344 (F344) rats. Here, we examined the effects of the combination of an obesogenic cafeteria diet (CAF) and the chronic exposure to three different day lengths (L12, 12 h light/day; L18, 18 h light/day; and L6, 6 h light/day) in this rat strain. Although no changes were observed during the first 4 weeks of adaptation to the different photoperiods in which animals were fed a standard diet, the addition of the CAF for the subsequent 7 weeks triggered profound physiologic and metabolic alterations in a photoperiod-dependent manner. Compared with L12 rats, both L6 and L18 animals displayed lower body weight gain and cumulative food intake in addition to decreased energy expenditure and locomotor activity. These changes were accompanied by differences in food preferences and by a sharp upregulation of the orexigenic genes Npy and Ghsr in the hypothalamus, which could be understood as a homeostatic mechanism for increasing food consumption to restore body weight control. L18 rats also exhibited higher glycemia than the L6 group, which could be partly attributed to the decreased pAkt2 levels in the soleus muscle and the downregulation of Irs1 mRNA levels in the gastrocnemius muscle. Furthermore, L6 animals displayed lower whole-body lipid utilization than the L18 group, which could be related to the lower lipid intake and to the decreased mRNA levels of the fatty acid transporter gene Fatp1 observed in the soleus muscle. The profound differences observed between L6 and L18 rats could be related with hepatic and muscular changes in the expression of circadian rhythm-related genes Cry1, Bmal1, Per2, and Nr1d1. Although further research is needed to elucidate the pathophysiologic relevance of these findings, our study could contribute to emphasize the impact of the consumption of highly palatable and energy dense foods regularly consumed by humans on the physiological and metabolic adaptations that occur in response to seasonal variations of day length, especially in diseases associated with changes in food intake and preference such as obesity and seasonal affective disorder

A mixture of four dietary fibres ameliorates adiposity and improves metabolic profile and intestinal health in cafeteria-fed obese rats: an integrative multi-omics approach

Aims: Atherosclerosis is the main pathological process contributing to cardiovascular disease, with diet being the most important factor involved. Although the lipidome of atheromatous plaque has been studied previously, the use of comparative lipidomics and metabolomics in plasma in early atherogenesis could lead to the discovery of plasma biomarkers that allow not only disease prediction but also measurement of disease progression. Methods and results: High-throughput techniques, such as liquid chromatography/mass spectrometry, allowed us to compare the circulating and aortic lipidome and plasma metabolome in order to look for new molecular targets involved in atherogenesis. To achieve this objective, we chose the hamster (Mesocricetus auratus) as the best small animal model for diet-induced early atherosclerosis, because its lipoprotein metabolism is similar to that of humans. The results revealed the existence of several, previously unreported, changes in lipid and amino-acid metabolism, the peroxisome proliferator-activated receptor γ pathway, and oxidative and endoplasmic reticulum stress, also involving cell senescence. Furthermore, as a proof of concept in the modelling of dietary influences in atherogenesis, we have measured the effect of a potential anti-atherogenic polyphenol extract on the reported pathways. Our results support a previously unknown role for taurocholic acid as a potential plasma biomarker of early atheromatous plaque formation. Conclusion: The use of comparative liquid chromatography/mass spectrometry-based lipidomics and metabolomics allows the discovery of novel pathways in atherogenesis, as well as new potential plasma biomarkers, which could allow us to predict disease in its early stages and measure its progression

[email protected]

La crononutrició estudia la relació entre els ritmes biològics i el metabolisme. Actualment, s’ha incorporat en el context de la nutrició personalitzada, per tal de millorar els consells dietètics i els seus resultats. La teoria de la Xenohormesis proposa que els animals poden reconèixer compostos bioactius de les plantes, principalment polifenols, com una senyal no-fòtica per detectar condicions ambientals adverses, permetent que reaccionin per avançat i millorant així la seva supervivència. En aquest context, l’objectiu principal d’aquesta tesi és avaluar si el consum de fruita dins o fora de la seva estació de maduració produeix efectes en diferents biomarcadors d’estacionalitat i en processos neuroendocrins en rates Fischer 344, utilitzant animals normopes i obesos. El consum de raïm, però no de cirera, en animals normopes durant la seva època (SD) produeix canvis importants en comportament i en despesa energètica, la qual cosa pot estar associada a canvis en mecanismes centrals controlats per l’estacionalitat, com ara el sistema dopaminèrgic o somatostatinèrgic. A més, considerant que aquests resultats podrien ser beneficiosos pel tractament de l’obesitat, animals alimentats amb dieta de cafeteria van ser estudiats en les mateixes condicions. Els resultats mostren que l’obesitat atenua els efectes del consum de fruita en el comportament i en els controladors d’estacionalitat, tant a nivell central com perifèric. Finalment, la comparació de la sensibilitat al fotoperíode entre els dos fenotips que consumien raïm va mostrar que l’obesitat bloqueja la resposta estacional de la prolactina, així com la resposta dels eixos adrenals, gonadals i tiroidals, mostrant insensibilitat tant a senyals fòtiques com no-fòtiques. El treball d’aquesta tesi mostra la importància de l’estacionalitat i el consum de determinats aliments per la modulació del cervell a través de la nutrició, i proporciona noves evidències per considerar l’adaptació estacional com un element de prevenció i tractament de malalties.La crononutrición estudia la relación entre los ritmos biológicos y el metabolismo. Actualmente, se ha incorporado en el contexto de la nutrición personalizada, para mejorar los consejos dietéticos y sus resultados. La teoría de la Xenohormesis propone que los animales pueden reconocer compuestos bioactivos de las plantas, principalmente polifenoles, como señales no-fóticas para detectar condiciones ambientales adversas, permitiendo reaccionar por adelantado i mejorando así su nivel de supervivencia. En este contexto, el objetivo principal de la tesis es evaluar si el consumo de fruta dentro o fuera de su estación produce efectos en los diferentes biomarcadores de estacionalidad y en procesos neuroendocrinos en ratas Fischer 344, utilizando animales normopeso y obesos. El consumo de uva, pero no de cereza, en animales normopeso durante su época (SD) produce cambios importantes en comportamiento y en gasto energético, cosa que puede estar asociada a cambios en mecanismos centrales controlados por la estacionalidad, como el sistema dopaminérgico y el somatostatinérgico. Además, considerando que estos resultados podrían ser beneficiosos para el tratamiento de la obesidad, animales alimentados con dieta de cafetería fueron estudiados en las mismas condiciones. Los resultados muestran que la obesidad atenúa los efectos del consumo de fruta en el comportamiento y en los marcadores de estacionalidad, tanto a nivel central como periférico. Finalmente, la comparación de la sensibilidad al fotoperiodo entre los dos fenotipos que consumían uva mostró que la obesidad bloquea la respuesta estacional de la prolactina, así como la respuesta de los ejes adrenales, gonadales y tiroideos, mostrando insensibilidad tanto a señales fóticas como no-fóticas. El trabajo de esta tesis muestra la importancia de la estacionalidad y el consumo de alimentos para la modulación del cerebro a través de la nutrición, y proporciona nuevas evidencias para considerar la adaptación estacional como un elemento preventivo y de tratamiento de enfermedades.Chrononutrition studies the relationship between biological rhythms and metabolism. Nowadays, it has been embraced within nutritional approaches in order to improve dietary advices and their final result. The Xenohormesis theory proposes that animals recognize bioactive compounds from plants, mainly polyphenols, as non-photic cues for checking environmental conditions, allowing them to respond in advance to environmental alterations and to improve their survival. In this framework, the main aim of the present thesis is to evaluate whether fruit consumption in or out of their natural season produce effects on different key biomarkers of seasonality and neuroendocrine processes in normoweight and cafeteria-fed obese Fischer 344 rats. We found that in healthy Fischer 344 rats, the oral consumption of red-grape, but not cherry, during its natural season characterized by a short day photoperiod produced behavioral changes, such as decreased locomotor activity and food consumption; and energy expenditure, which could be associated with changes observed on central mechanisms subjected to seasonal control, such as dopaminergic and somatostatinergic systems. Furthermore, considering that these results could be beneficial for the treatment of obesity, CAF fed animals were also studied at the same photoperiodic conditions and supplemented with the red-grape treatment. Results revealed that obesity dampens the effects of fruit consumption in behavior and in central and peripheral controllers of seasonality observed in the normoweight cohort. Finally, photoperiod sensitivity in both phenotypes consuming red-grape was assessed. Results revealed that obesity impairs seasonal control of prolactin release and the response to hypothalamic-pituitary-adrenal, hypothalamic-pituitary-gonadal and hypothalamic-pituitary-thyroidal axis to changes in photoperiod, therefore producing an insensitivity to photic and non-photic cues. This thesis work highlights the relevance of seasonality of fruits and its consumption for the modulation of brain function by nutrition, and furthermore, provides new evidences for considering seasonal adaptation as a relevant element for prevention and treatment of diseases

[email protected]

La crononutrició estudia la relació entre els ritmes biològics i el metabolisme. Actualment, s’ha incorporat en el context de la nutrició personalitzada, per tal de millorar els consells dietètics i els seus resultats. La teoria de la Xenohormesis proposa que els animals poden reconèixer compostos bioactius de les plantes, principalment polifenols, com una senyal no-fòtica per detectar condicions ambientals adverses, permetent que reaccionin per avançat i millorant així la seva supervivència. En aquest context, l’objectiu principal d’aquesta tesi és avaluar si el consum de fruita dins o fora de la seva estació de maduració produeix efectes en diferents biomarcadors d’estacionalitat i en processos neuroendocrins en rates Fischer 344, utilitzant animals normopes i obesos. El consum de raïm, però no de cirera, en animals normopes durant la seva època (SD) produeix canvis importants en comportament i en despesa energètica, la qual cosa pot estar associada a canvis en mecanismes centrals controlats per l’estacionalitat, com ara el sistema dopaminèrgic o somatostatinèrgic. A més, considerant que aquests resultats podrien ser beneficiosos pel tractament de l’obesitat, animals alimentats amb dieta de cafeteria van ser estudiats en les mateixes condicions. Els resultats mostren que l’obesitat atenua els efectes del consum de fruita en el comportament i en els controladors d’estacionalitat, tant a nivell central com perifèric. Finalment, la comparació de la sensibilitat al fotoperíode entre els dos fenotips que consumien raïm va mostrar que l’obesitat bloqueja la resposta estacional de la prolactina, així com la resposta dels eixos adrenals, gonadals i tiroidals, mostrant insensibilitat tant a senyals fòtiques com no-fòtiques. El treball d’aquesta tesi mostra la importància de l’estacionalitat i el consum de determinats aliments per la modulació del cervell a través de la nutrició, i proporciona noves evidències per considerar l’adaptació estacional com un element de prevenció i tractament de malalties.La crononutrición estudia la relación entre los ritmos biológicos y el metabolismo. Actualmente, se ha incorporado en el contexto de la nutrición personalizada, para mejorar los consejos dietéticos y sus resultados. La teoría de la Xenohormesis propone que los animales pueden reconocer compuestos bioactivos de las plantas, principalmente polifenoles, como señales no-fóticas para detectar condiciones ambientales adversas, permitiendo reaccionar por adelantado i mejorando así su nivel de supervivencia. En este contexto, el objetivo principal de la tesis es evaluar si el consumo de fruta dentro o fuera de su estación produce efectos en los diferentes biomarcadores de estacionalidad y en procesos neuroendocrinos en ratas Fischer 344, utilizando animales normopeso y obesos. El consumo de uva, pero no de cereza, en animales normopeso durante su época (SD) produce cambios importantes en comportamiento y en gasto energético, cosa que puede estar asociada a cambios en mecanismos centrales controlados por la estacionalidad, como el sistema dopaminérgico y el somatostatinérgico. Además, considerando que estos resultados podrían ser beneficiosos para el tratamiento de la obesidad, animales alimentados con dieta de cafetería fueron estudiados en las mismas condiciones. Los resultados muestran que la obesidad atenúa los efectos del consumo de fruta en el comportamiento y en los marcadores de estacionalidad, tanto a nivel central como periférico. Finalmente, la comparación de la sensibilidad al fotoperiodo entre los dos fenotipos que consumían uva mostró que la obesidad bloquea la respuesta estacional de la prolactina, así como la respuesta de los ejes adrenales, gonadales y tiroideos, mostrando insensibilidad tanto a señales fóticas como no-fóticas. El trabajo de esta tesis muestra la importancia de la estacionalidad y el consumo de alimentos para la modulación del cerebro a través de la nutrición, y proporciona nuevas evidencias para considerar la adaptación estacional como un elemento preventivo y de tratamiento de enfermedades.Chrononutrition studies the relationship between biological rhythms and metabolism. Nowadays, it has been embraced within nutritional approaches in order to improve dietary advices and their final result. The Xenohormesis theory proposes that animals recognize bioactive compounds from plants, mainly polyphenols, as non-photic cues for checking environmental conditions, allowing them to respond in advance to environmental alterations and to improve their survival. In this framework, the main aim of the present thesis is to evaluate whether fruit consumption in or out of their natural season produce effects on different key biomarkers of seasonality and neuroendocrine processes in normoweight and cafeteria-fed obese Fischer 344 rats. We found that in healthy Fischer 344 rats, the oral consumption of red-grape, but not cherry, during its natural season characterized by a short day photoperiod produced behavioral changes, such as decreased locomotor activity and food consumption; and energy expenditure, which could be associated with changes observed on central mechanisms subjected to seasonal control, such as dopaminergic and somatostatinergic systems. Furthermore, considering that these results could be beneficial for the treatment of obesity, CAF fed animals were also studied at the same photoperiodic conditions and supplemented with the red-grape treatment. Results revealed that obesity dampens the effects of fruit consumption in behavior and in central and peripheral controllers of seasonality observed in the normoweight cohort. Finally, photoperiod sensitivity in both phenotypes consuming red-grape was assessed. Results revealed that obesity impairs seasonal control of prolactin release and the response to hypothalamic-pituitary-adrenal, hypothalamic-pituitary-gonadal and hypothalamic-pituitary-thyroidal axis to changes in photoperiod, therefore producing an insensitivity to photic and non-photic cues. This thesis work highlights the relevance of seasonality of fruits and its consumption for the modulation of brain function by nutrition, and furthermore, provides new evidences for considering seasonal adaptation as a relevant element for prevention and treatment of diseases

Table_4_The Exposure to Different Photoperiods Strongly Modulates the Glucose and Lipid Metabolisms of Normoweight Fischer 344 Rats.doc

<p>Seasonal variations in day length trigger clear changes in the behavior, growth, food intake, and reproductive status of photoperiod-sensitive animals, such as Fischer 344 rats. However, there is little information about the effects of seasonal fluctuations in day length on glucose and lipid metabolisms and their underlying mechanisms in this model. To gain knowledge on these issues, three groups of male Fischer 344 rats were fed with a standard diet and exposed to different photoperiods for 14 weeks: normal photoperiod (L12, 12 h light/day), long photoperiod (L18, 18 h light/day), and short photoperiod (L6, 6 h light/day). A multivariate analysis carried out with 239 biometric, serum, hepatic and skeletal muscle parameters revealed a clear separation among the three groups. Compared with L12 rats, L6 animals displayed a marked alteration of glucose homeostasis and fatty acid uptake and oxidation, which were evidenced by the following observations: (1) increased circulating levels of glucose and non-esterified fatty acids; (2) a sharp down-regulation of the phosphorylated Akt2 levels, a downstream post-receptor target of insulin, in both the soleus and gastrocnemius muscles; (3) decreased expression in the soleus muscle of the glucose metabolism-related microRNA-194 and lower mRNA levels of the genes involved in glucose metabolism (Irs1, soleus, and Glut2, liver), β-oxidation (Had and Cpt1β, soleus) and fatty acid transport (Cd36, soleus, and liver). L18 animals also displayed higher blood glucose levels than L12 rats and profound changes in other glucose and lipid metabolism-related parameters in the blood, liver, and skeletal muscles. However, the mechanisms that account for the observed effects were less evident than those reported in L6 animals. In conclusion, exposure to different photoperiods strongly modulated glucose and lipid metabolisms in normoweight rats. These findings emphasize the relevance of circannual rhythms in metabolic homeostasis regulation and suggest that Fischer 344 rats are a promising animal model with which to study glucose- and lipid-related pathologies that are influenced by seasonal variations, such as obesity, cardiovascular disease and seasonal affective disorder.</p

The Exposure to Different Photoperiods Strongly Modulates the Glucose and Lipid Metabolisms of Normoweight Fischer 344 Rats

Seasonal variations in day length trigger clear changes in the behavior, growth, food intake, and reproductive status of photoperiod-sensitive animals, such as Fischer 344 rats. However, there is little information about the effects of seasonal fluctuations in day length on glucose and lipid metabolisms and their underlying mechanisms in this model. To gain knowledge on these issues, three groups of male Fischer 344 rats were fed with a standard diet and exposed to different photoperiods for 14 weeks: normal photoperiod (L12, 12 h light/day), long photoperiod (L18, 18 h light/day), and short photoperiod (L6, 6 h light/day). A multivariate analysis carried out with 239 biometric, serum, hepatic and skeletal muscle parameters revealed a clear separation among the three groups. Compared with L12 rats, L6 animals displayed a marked alteration of glucose homeostasis and fatty acid uptake and oxidation, which were evidenced by the following observations: (1) increased circulating levels of glucose and non-esterified fatty acids; (2) a sharp down-regulation of the phosphorylated Akt2 levels, a downstream post-receptor target of insulin, in both the soleus and gastrocnemius muscles; (3) decreased expression in the soleus muscle of the glucose metabolism-related microRNA-194 and lower mRNA levels of the genes involved in glucose metabolism (Irs1, soleus, and Glut2, liver), β-oxidation (Had and Cpt1β, soleus) and fatty acid transport (Cd36, soleus, and liver). L18 animals also displayed higher blood glucose levels than L12 rats and profound changes in other glucose and lipid metabolism-related parameters in the blood, liver, and skeletal muscles. However, the mechanisms that account for the observed effects were less evident than those reported in L6 animals. In conclusion, exposure to different photoperiods strongly modulated glucose and lipid metabolisms in normoweight rats. These findings emphasize the relevance of circannual rhythms in metabolic homeostasis regulation and suggest that Fischer 344 rats are a promising animal model with which to study glucose- and lipid-related pathologies that are influenced by seasonal variations, such as obesity, cardiovascular disease and seasonal affective disorder

Maternal Supplementation with a Cocoa Extract during Lactation Deeply Modulates Dams’ Metabolism, Increases Adiponectin Circulating Levels and Improves the Inflammatory Profile in Obese Rat Offspring

High-flavonoid cocoa consumption has been associated with beneficial properties. However, there are scarce data concerning the effects of maternal cocoa intake on dams and in their progeny. Here, we evaluated in rats whether maternal supplementation with a high-flavan-3-ol cocoa extract (CCX) during lactation (200 mg.kg−1.day−1) produced beneficial effects on dams and in their normoweight (STD-CCX group) and cafeteria-fed obese (CAF-CCX group) adult male offspring. Maternal intake of CCX significantly increased the circulating levels of adiponectin and decreased the mammary gland lipid content of dams. These effects were accompanied by increased energy expenditure and circulating free fatty acids, as well as by a higher expression of lipogenic and adiponectin-related genes in their mammary glands, which could be related to a compensatory mechanism to ensure enough lipid supply to the pups. CCX consumption programmed both offspring groups towards increased plasma total adiponectin levels, and decreased liver weight and lean/fat ratio. Furthermore, CAF-CCX progeny showed an improvement of the inflammatory profile, evidenced by the significant decrease of the monocyte chemoattractant protein-1 (MCP-1) circulating levels and the mRNA levels of the gene encoding the major histocompatibility complex, class II invariant chain (Cd74), a marker of M1 macrophage phenotype, in the epididymal white adipose tissue. Although further studies are needed, these findings can pave the way for using CCX as a nutraceutical supplement during lactation

Table_3_The Exposure to Different Photoperiods Strongly Modulates the Glucose and Lipid Metabolisms of Normoweight Fischer 344 Rats.doc

<p>Seasonal variations in day length trigger clear changes in the behavior, growth, food intake, and reproductive status of photoperiod-sensitive animals, such as Fischer 344 rats. However, there is little information about the effects of seasonal fluctuations in day length on glucose and lipid metabolisms and their underlying mechanisms in this model. To gain knowledge on these issues, three groups of male Fischer 344 rats were fed with a standard diet and exposed to different photoperiods for 14 weeks: normal photoperiod (L12, 12 h light/day), long photoperiod (L18, 18 h light/day), and short photoperiod (L6, 6 h light/day). A multivariate analysis carried out with 239 biometric, serum, hepatic and skeletal muscle parameters revealed a clear separation among the three groups. Compared with L12 rats, L6 animals displayed a marked alteration of glucose homeostasis and fatty acid uptake and oxidation, which were evidenced by the following observations: (1) increased circulating levels of glucose and non-esterified fatty acids; (2) a sharp down-regulation of the phosphorylated Akt2 levels, a downstream post-receptor target of insulin, in both the soleus and gastrocnemius muscles; (3) decreased expression in the soleus muscle of the glucose metabolism-related microRNA-194 and lower mRNA levels of the genes involved in glucose metabolism (Irs1, soleus, and Glut2, liver), β-oxidation (Had and Cpt1β, soleus) and fatty acid transport (Cd36, soleus, and liver). L18 animals also displayed higher blood glucose levels than L12 rats and profound changes in other glucose and lipid metabolism-related parameters in the blood, liver, and skeletal muscles. However, the mechanisms that account for the observed effects were less evident than those reported in L6 animals. In conclusion, exposure to different photoperiods strongly modulated glucose and lipid metabolisms in normoweight rats. These findings emphasize the relevance of circannual rhythms in metabolic homeostasis regulation and suggest that Fischer 344 rats are a promising animal model with which to study glucose- and lipid-related pathologies that are influenced by seasonal variations, such as obesity, cardiovascular disease and seasonal affective disorder.</p

Table_2_The Exposure to Different Photoperiods Strongly Modulates the Glucose and Lipid Metabolisms of Normoweight Fischer 344 Rats.doc

<p>Seasonal variations in day length trigger clear changes in the behavior, growth, food intake, and reproductive status of photoperiod-sensitive animals, such as Fischer 344 rats. However, there is little information about the effects of seasonal fluctuations in day length on glucose and lipid metabolisms and their underlying mechanisms in this model. To gain knowledge on these issues, three groups of male Fischer 344 rats were fed with a standard diet and exposed to different photoperiods for 14 weeks: normal photoperiod (L12, 12 h light/day), long photoperiod (L18, 18 h light/day), and short photoperiod (L6, 6 h light/day). A multivariate analysis carried out with 239 biometric, serum, hepatic and skeletal muscle parameters revealed a clear separation among the three groups. Compared with L12 rats, L6 animals displayed a marked alteration of glucose homeostasis and fatty acid uptake and oxidation, which were evidenced by the following observations: (1) increased circulating levels of glucose and non-esterified fatty acids; (2) a sharp down-regulation of the phosphorylated Akt2 levels, a downstream post-receptor target of insulin, in both the soleus and gastrocnemius muscles; (3) decreased expression in the soleus muscle of the glucose metabolism-related microRNA-194 and lower mRNA levels of the genes involved in glucose metabolism (Irs1, soleus, and Glut2, liver), β-oxidation (Had and Cpt1β, soleus) and fatty acid transport (Cd36, soleus, and liver). L18 animals also displayed higher blood glucose levels than L12 rats and profound changes in other glucose and lipid metabolism-related parameters in the blood, liver, and skeletal muscles. However, the mechanisms that account for the observed effects were less evident than those reported in L6 animals. In conclusion, exposure to different photoperiods strongly modulated glucose and lipid metabolisms in normoweight rats. These findings emphasize the relevance of circannual rhythms in metabolic homeostasis regulation and suggest that Fischer 344 rats are a promising animal model with which to study glucose- and lipid-related pathologies that are influenced by seasonal variations, such as obesity, cardiovascular disease and seasonal affective disorder.</p