RESUMEN
Obesity is a significant risk factor for several chronic diseases. However, pre-menopausal females are protected against high-fat diet (HFD)-induced obesity and its adverse effects. The pregnane X receptor (PXR, NR1I2), a xenobiotic-sensing nuclear receptor, promotes short-term obesity-associated liver disease only in male mice but not in females. Therefore, the current study investigated the metabolic and pathophysiological effects of a long-term 52-week HFD in female wild-type (WT) and PXR-KO mice and characterized the PXR-dependent molecular pathways involved. After 52 weeks of HFD ingestion, the body and liver weights and several markers of hepatotoxicity were significantly higher in WT mice than in their PXR-KO counterparts. The HFD-induced liver injury in WT female mice was also associated with upregulation of the hepatic mRNA levels of peroxisome proliferator-activated receptor gamma (Pparg), its target genes, fat-specific protein 27 (Fsp27), and the liver-specific Fsp27b involved in lipid accumulation, apoptosis, and inflammation. Notably, PXR-KO mice displayed elevated hepatic Cyp2a5 (anti-obesity gene), aldo-keto reductase 1b7 (Akr1b7), glutathione-S-transferase M3 (Gstm3) (antioxidant gene), and AMP-activated protein kinase (AMPK) levels, contributing to protection against long-term HFD-induced obesity and inflammation. RNA sequencing analysis revealed a general blunting of the transcriptomic response to HFD in PXR-KO compared to WT mice. Pathway enrichment analysis demonstrated enrichment by HFD for several pathways, including oxidative stress and redox pathway, cholesterol biosynthesis, and glycolysis/gluconeogenesis in WT but not PXR-KO mice. In conclusion, this study provides new insights into the molecular mechanisms by which PXR deficiency protects against long-term HFD-induced severe obesity and its adverse effects in female mice.
Asunto(s)
Dieta Alta en Grasa , Hígado , Masculino , Femenino , Ratones , Animales , Receptor X de Pregnano/genética , Receptor X de Pregnano/metabolismo , Dieta Alta en Grasa/efectos adversos , Ratones Endogámicos C57BL , Aumento de Peso , Obesidad/metabolismo , Inflamación/metabolismo , Ratones NoqueadosRESUMEN
BACKGROUND: The role of diet on Coronavirus Disease 2019 (COVID-19) is emerging. We investigated the association between usual diet before the onset of the pandemic and risk and severity of subsequent SARS-CoV-2 infection. METHODS: We included 42,935 participants aged 55-99 y in 2 ongoing cohort studies, the Nurses' Health Study II and Health Professionals Follow-up Study, who completed a series of COVID-19 surveys in 2020 and 2021. Using data from FFQs before COVID-19, we assessed diet quality using the Alternative Healthy Eating Index (AHEI)-2010, the alternative Mediterranean Diet (AMED) score, an Empirical Dietary Index for Hyperinsulinemia (EDIH), and an Empirical Dietary Inflammatory Pattern (EDIP). We calculated multivariable-adjusted ORs and 95% CIs for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and severity of COVID-19 after controlling for demographic, medical, and lifestyle factors. RESULTS: Among 19,754 participants tested for SARS-CoV-2, 1941 participants reported a positive result. Of these, 1327 reported symptoms needing assistance and another 109 were hospitalized. Healthier diets, represented by higher AHEI-2010 and AMED scores and lower EDIH and EDIP scores, were associated with lower likelihood of SARS-CoV-2 infection (quartile 4 compared with quartile 1: OR: 0.80; 95% CI: 0.69, 0.92 for AHEI-2010; OR: 0.78; 95% CI: 0.67, 0.92 for AMED; OR: 1.36; 95% CI: 1.16, 1.57 for EDIH; and OR: 1.13; 95% CI: 0.99, 1.30 for EDIP; all P-trend ≤ 0.01). In the analysis of COVID-19 severity, participants with healthier diet had lower likelihood of severe infection and were less likely to be hospitalized owing to COVID-19. However, associations were no longer significant after controlling for BMI and pre-existing medical conditions. CONCLUSIONS: Diet may be an important modifiable risk factor for SARS-CoV-2 infection, as well as for severity of COVID-19. This association is partially mediated by BMI and pre-existing medical conditions.
Asunto(s)
COVID-19 , Dieta Mediterránea , Hiperinsulinismo , Humanos , SARS-CoV-2 , COVID-19/epidemiología , Estudios de Seguimiento , PandemiasRESUMEN
BACKGROUND: Gut microbiota composition as influenced by long-term diet may be associated with the risk of adult chronic diseases. Thus, establishing the relation of long-term diet, particularly starting from early life, with adult microbiota composition would be an important research advance. OBJECTIVE: We aimed to investigate the association of long-term intake of energy, carbohydrate, fiber, protein, and fat from infancy to late adolescence with microbiota composition in adulthood. METHODS: Within the prospective DOrtmund Nutritional and Anthropometric Longitudinally Designed (DONALD) Study, we sampled stool 1 or 2 times within 1 y from 128 adults (median age: 29 y). Microbiota composition was profiled by 16S ribosomal RNA sequencing. Annual dietary records from age 1 to 18 y were retrieved. We estimated trajectories of energy, energy-adjusted carbohydrate, fiber, protein, and fat intake with multilevel models, producing predicted intake at age 1 y and rates of change in intake. A multivariate, zero-inflated, logistic-normal model was used to model the association between intake trajectories and the composition of 158 genera in single-sampled individuals. Associations found in this model were confirmed in double-sampled individuals using a zero-inflated Beta regression model. RESULTS: Adjusting for covariates and temporal differences in microbiota composition, long-term carbohydrate intake was associated with 3 genera. Specifically, carbohydrate intake at age 1 y was negatively associated with Phascolarctobacterium [coefficient = -4.31; false discovery rate (FDR)-adjusted P = 0.006] and positively associated with Dialister (coefficient = 3.06; FDR-adjusted P = 0.003), and the rate of change in carbohydrate intake was positively associated with Desulfovibrio (coefficient = 13.16; FDR-adjusted P = 0.00039). Energy and other macronutrients were not associated with any genus. CONCLUSIONS: This work links long-term carbohydrate intake to microbiota composition. Considering the associations of high carbohydrate intake and microbiota composition with some diseases, these findings could inform the development of gut microbiota-targeted dietary recommendations for disease prevention.
Asunto(s)
Envejecimiento , Bacterias/clasificación , Fenómenos Fisiológicos Nutricionales Infantiles , Carbohidratos de la Dieta/administración & dosificación , Microbioma Gastrointestinal , Adolescente , Adulto , Bacterias/genética , Niño , Preescolar , ADN Bacteriano/genética , Heces/microbiología , Humanos , Lactante , ARN Bacteriano , ARN Ribosómico 16S/genéticaRESUMEN
There is increasing evidence that calorie restriction without malnutrition can extend longevity and delay the onset of age-associated disorders. Identifying the biochemical perturbations associated with different dietary habits would provide valuable insights into associations between metabolism and longevity. To reveal the effects of long-term dietary interventions on metabolic perturbations, we investigated serum and urinary metabolic changes induced by interactive high/low fat diet in combination with/without reduced caloric intake over a life span in mice using NMR-based metabonomics. We found that the high calorie dietary regime disturbed lipid metabolism, suppressed glycolysis and TCA cycles, stimulated oxidative stress, promoted nucleotide metabolism and gluconeogenesis, and perturbed gut microbiota-host interactions. Such changes could be modified by long-term low calorie intake. Most importantly, we found that the calorie intake index exerts a dominant effect on metabolic perturbations irrespective of dietary regime. Our investigation provides a holistic view of the metabolic impact of long-term dietary interventions, which are important for detecting physiological changes and dietary effects on mammalian metabolism.
Asunto(s)
Ingestión de Energía/fisiología , Metabolómica/métodos , Animales , Restricción Calórica , Dieta Alta en Grasa/efectos adversos , Longevidad , Espectroscopía de Resonancia Magnética , Metabolismo/fisiología , Ratones , Suero/metabolismo , Orina/químicaRESUMEN
Clinical and epidemiological evidence suggests that lifestyle factors, including nutrition, may influence the chances of developing of Alzheimer's disease (AD), and also likely affect the aging process. Whereas it is clear that high-fat diets are increasing both body weight and the risk of developing Alzheimer's disease, to date, there have been very few studies comparing diets high with different sources of calories (i.e., high fat versus high protein versus high carbohydrates) to determine whether dietary composition has importance beyond the known effect of high caloric intake to increase body weight, AD pathology and cognitive deficits. In the current study we examined the effects that different diets high in carbohydrate, protein or fat content, but similar in caloric value, have on the development of cognitive impairment and brain pathology in wild-type and Tg AD model mice. The results demonstrate that long term feeding with balanced diets similar in caloric content but with significant changes in the source of calories, all negatively influence cognition compared to the control diet, and that this effect is more pronounced in Tg animals with AD pathology.