Pub Date : 2024-02-21DOI: 10.1038/s44324-024-00004-7
Eliana D. Weisz, Adam R. Fenton, Thomas A. Jongens
Fragile X Syndrome (FXS) is the most prevalent monogenetic form of intellectual disability and autism. Recently, dysregulation of insulin signaling (IS) and aberrations in mitochondrial function have emerged as robust, evolutionarily conserved components of FXS pathophysiology. However, the mechanisms by which altered IS and mitochondrial dysfunction impact behavior in the context of FXS remain elusive. Here, we show that normalization of IS improves mitochondrial volume and function in flies that lack expression of dfmr1, the Drosophila homolog of the causal gene of FXS in humans. Further, we demonstrate that dysregulation of IS underlies diminished expression of the mitochondrial master regulator PGC-1α/Spargel in dfmr1 mutant flies. These results are behaviorally relevant, as we show that pan-neuronal augmentation of PGC-1α/Spargel improves circadian behavior in dfmr1 mutants. Notably, we also show that modulation of PGC-1α/Spargel expression in wild-type flies phenocopies the dfmr1 mutant circadian defect. Taken together, the results presented herein provide a mechanistic link between mitochondrial function and circadian behavior both in FXS pathogenesis as well as more broadly at the interface between metabolism and behavioral output.
{"title":"PGC-1α integrates insulin signaling with mitochondrial physiology and behavior in a Drosophila model of Fragile X Syndrome","authors":"Eliana D. Weisz, Adam R. Fenton, Thomas A. Jongens","doi":"10.1038/s44324-024-00004-7","DOIUrl":"10.1038/s44324-024-00004-7","url":null,"abstract":"Fragile X Syndrome (FXS) is the most prevalent monogenetic form of intellectual disability and autism. Recently, dysregulation of insulin signaling (IS) and aberrations in mitochondrial function have emerged as robust, evolutionarily conserved components of FXS pathophysiology. However, the mechanisms by which altered IS and mitochondrial dysfunction impact behavior in the context of FXS remain elusive. Here, we show that normalization of IS improves mitochondrial volume and function in flies that lack expression of dfmr1, the Drosophila homolog of the causal gene of FXS in humans. Further, we demonstrate that dysregulation of IS underlies diminished expression of the mitochondrial master regulator PGC-1α/Spargel in dfmr1 mutant flies. These results are behaviorally relevant, as we show that pan-neuronal augmentation of PGC-1α/Spargel improves circadian behavior in dfmr1 mutants. Notably, we also show that modulation of PGC-1α/Spargel expression in wild-type flies phenocopies the dfmr1 mutant circadian defect. Taken together, the results presented herein provide a mechanistic link between mitochondrial function and circadian behavior both in FXS pathogenesis as well as more broadly at the interface between metabolism and behavioral output.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-12"},"PeriodicalIF":0.0,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-024-00004-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139915802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-29DOI: 10.1038/s44324-023-00003-0
Verena Preinfalk, Kerstin Schweiger, Leonie Hüller, Andreas Dunkel, Isabella Kimmeswenger, Corinna M. Deck, Petra Rust, Veronika Somoza, Gerhard E. Krammer, Jakob P. Ley, Barbara Lieder
Several studies proposed a role for the sweet taste receptor in energy intake and blood glucose regulation, but little is yet known about the impact of the individual sweet taste perception. Here, we found in a cross-over human intervention study with 29 male participants that modulating the sweetness of an isocaloric sucrose solution did not influence postprandial plasma concentrations of blood glucose and associated hormones over 120 min and 2 h post-load energy intake. Independent of the sweetness of the test solution, tests persons with a higher sucrose detection threshold had an average of 402 ± 78.8 kcal (39 ± 21%) higher energy intake and a higher glucose/insulin ratio, combined with a higher liking for sweet tasting food, than the test persons of the low threshold group. The body composition suggested a higher fat-free mass in the high threshold group that may have influenced energy intake and post-prandial glucose responses.
{"title":"A high sucrose detection threshold is associated with increased energy intake and improved post-prandial glucose response independent of the sweetness intensity of isocaloric sucrose solutions","authors":"Verena Preinfalk, Kerstin Schweiger, Leonie Hüller, Andreas Dunkel, Isabella Kimmeswenger, Corinna M. Deck, Petra Rust, Veronika Somoza, Gerhard E. Krammer, Jakob P. Ley, Barbara Lieder","doi":"10.1038/s44324-023-00003-0","DOIUrl":"10.1038/s44324-023-00003-0","url":null,"abstract":"Several studies proposed a role for the sweet taste receptor in energy intake and blood glucose regulation, but little is yet known about the impact of the individual sweet taste perception. Here, we found in a cross-over human intervention study with 29 male participants that modulating the sweetness of an isocaloric sucrose solution did not influence postprandial plasma concentrations of blood glucose and associated hormones over 120 min and 2 h post-load energy intake. Independent of the sweetness of the test solution, tests persons with a higher sucrose detection threshold had an average of 402 ± 78.8 kcal (39 ± 21%) higher energy intake and a higher glucose/insulin ratio, combined with a higher liking for sweet tasting food, than the test persons of the low threshold group. The body composition suggested a higher fat-free mass in the high threshold group that may have influenced energy intake and post-prandial glucose responses.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-11"},"PeriodicalIF":0.0,"publicationDate":"2024-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-023-00003-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139643958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-13DOI: 10.1038/s44324-023-00002-1
Amrendra Mishra, Maura Fanti, Xinzhou Ge, Don Vaughn, Sebastian Brandhorst, Min Wei, Kurt M. Hong, Matteo Pellegrini, Hanno Pijl, Mark C. Houston, Valter D. Longo
Abnormalities in the vascular endothelium such as impaired vasodilation can contribute to atherosclerosis and hypertension. Here we have performed a single-center randomized clinical trial to evaluate the efficacy of 4 months of a continuous Mediterranean diet (MD) regimen as compared to 4 cycles of fasting mimicking diet (FMD) administered for only 5 days/month on endothelial function, measured as reactive hyperemia index (RHI) and large/small-resistance artery compliance (AC1/AC2), and on other cardiometabolic risk factors, in hypertensive patients with obesity/excess weight [both sexes, body mass index (BMI) ≥ 28, RHI ≤ 2.0, and/or small-resistance artery compliance (AC2) ≤ 5.0]. At the end of the intervention period, FMD but not MD decreased RHI (p = 0.0023) compared to baseline with no increase in the portion of patients with abnormal RHI. Both FMD and MD improved PULS cardiac test score; evaluating the risk of cardiovascular events. FMD and MD did not show any significant change in either AC1 or AC2 compared to baseline. Both FMD and MD led to comparable decreases in weight, waist circumference, BMI, body fat mass and % body fat, total cholesterol, and leptin. FMD decreased HbA1c (p = 0.0059) and IGF-1 (p = 0.0427), while MD decreased glucose (p = 0.0488), HOMA-IR (p = 0.0476), and HDL-C (p = 0.0419). None of the parameters were significantly different between the FMD vs. MD group at the end of the intervention period. During the 3-month follow-up period, the FMD and MD groups continued to display weight and BMI reduction; however, the MD group also lost fat free mass (FMD vs. MD, p = 0.0498). In summary, both MD and FMD reduced a range of cardiometabolic risk factors, but FMD also decreased RHI, a change associated with either impaired functional integrity of vascular endothelial cells but also with vascular rejuvenation, with the latter being more likely considering the improved cardiometabolic profile, reduced PULS cardiac score and calculated heart age, and unaltered arterial compliance in the FMD group. MD but not FMD cycles caused loss of lean body mass.
{"title":"Fasting mimicking diet cycles versus a Mediterranean diet and cardiometabolic risk in overweight and obese hypertensive subjects: a randomized clinical trial","authors":"Amrendra Mishra, Maura Fanti, Xinzhou Ge, Don Vaughn, Sebastian Brandhorst, Min Wei, Kurt M. Hong, Matteo Pellegrini, Hanno Pijl, Mark C. Houston, Valter D. Longo","doi":"10.1038/s44324-023-00002-1","DOIUrl":"10.1038/s44324-023-00002-1","url":null,"abstract":"Abnormalities in the vascular endothelium such as impaired vasodilation can contribute to atherosclerosis and hypertension. Here we have performed a single-center randomized clinical trial to evaluate the efficacy of 4 months of a continuous Mediterranean diet (MD) regimen as compared to 4 cycles of fasting mimicking diet (FMD) administered for only 5 days/month on endothelial function, measured as reactive hyperemia index (RHI) and large/small-resistance artery compliance (AC1/AC2), and on other cardiometabolic risk factors, in hypertensive patients with obesity/excess weight [both sexes, body mass index (BMI) ≥ 28, RHI ≤ 2.0, and/or small-resistance artery compliance (AC2) ≤ 5.0]. At the end of the intervention period, FMD but not MD decreased RHI (p = 0.0023) compared to baseline with no increase in the portion of patients with abnormal RHI. Both FMD and MD improved PULS cardiac test score; evaluating the risk of cardiovascular events. FMD and MD did not show any significant change in either AC1 or AC2 compared to baseline. Both FMD and MD led to comparable decreases in weight, waist circumference, BMI, body fat mass and % body fat, total cholesterol, and leptin. FMD decreased HbA1c (p = 0.0059) and IGF-1 (p = 0.0427), while MD decreased glucose (p = 0.0488), HOMA-IR (p = 0.0476), and HDL-C (p = 0.0419). None of the parameters were significantly different between the FMD vs. MD group at the end of the intervention period. During the 3-month follow-up period, the FMD and MD groups continued to display weight and BMI reduction; however, the MD group also lost fat free mass (FMD vs. MD, p = 0.0498). In summary, both MD and FMD reduced a range of cardiometabolic risk factors, but FMD also decreased RHI, a change associated with either impaired functional integrity of vascular endothelial cells but also with vascular rejuvenation, with the latter being more likely considering the improved cardiometabolic profile, reduced PULS cardiac score and calculated heart age, and unaltered arterial compliance in the FMD group. MD but not FMD cycles caused loss of lean body mass.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-10"},"PeriodicalIF":0.0,"publicationDate":"2023-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-023-00002-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138864981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-13DOI: 10.1038/s44324-023-00001-2
Bridget Chalifour, Elizabeth A. Holzhausen, Joseph J. Lim, Emily N. Yeo, Natalie Shen, Dean P. Jones, Bradley S. Peterson, Michael I. Goran, Donghai Liang, Tanya L. Alderete
Infant fecal metabolomics can provide valuable insights into the associations of nutrition, dietary patterns, and health outcomes in early life. Breastmilk is typically classified as the best source of nutrition for nearly all infants. However, exclusive breastfeeding may not always be possible for all infants. This study aimed to characterize associations between levels of mixed breastfeeding and formula feeding, along with solid food consumption and the infant fecal metabolome at 1- and 6-months of age. As a secondary aim, we examined how feeding-associated metabolites may be associated with early life neurodevelopmental outcomes. Fecal samples were collected at 1- and 6-months, and metabolic features were assessed via untargeted liquid chromatography/high-resolution mass spectrometry. Feeding groups were defined at 1-month as 1) exclusively breastfed, 2) breastfed >50% of feedings, or 3) formula fed ≥50% of feedings. Six-month groups were defined as majority breastmilk (>50%) or majority formula fed (≥50%) complemented by solid foods. Neurodevelopmental outcomes were assessed using the Bayley Scales of Infant Development at 2 years. Changes in the infant fecal metabolome were associated with feeding patterns at 1- and 6-months. Feeding patterns were associated with the intensities of a total of 57 fecal metabolites at 1-month and 25 metabolites at 6-months, which were either associated with increased breastmilk or increased formula feeding. Most breastmilk-associated metabolites, which are involved in lipid metabolism and cellular processes like cell signaling, were associated with higher neurodevelopmental scores, while formula-associated metabolites were associated with lower neurodevelopmental scores. These findings offer preliminary evidence that feeding patterns are associated with altered infant fecal metabolomes, which may be associated with cognitive development later in life.
{"title":"The potential role of early life feeding patterns in shaping the infant fecal metabolome: implications for neurodevelopmental outcomes","authors":"Bridget Chalifour, Elizabeth A. Holzhausen, Joseph J. Lim, Emily N. Yeo, Natalie Shen, Dean P. Jones, Bradley S. Peterson, Michael I. Goran, Donghai Liang, Tanya L. Alderete","doi":"10.1038/s44324-023-00001-2","DOIUrl":"10.1038/s44324-023-00001-2","url":null,"abstract":"Infant fecal metabolomics can provide valuable insights into the associations of nutrition, dietary patterns, and health outcomes in early life. Breastmilk is typically classified as the best source of nutrition for nearly all infants. However, exclusive breastfeeding may not always be possible for all infants. This study aimed to characterize associations between levels of mixed breastfeeding and formula feeding, along with solid food consumption and the infant fecal metabolome at 1- and 6-months of age. As a secondary aim, we examined how feeding-associated metabolites may be associated with early life neurodevelopmental outcomes. Fecal samples were collected at 1- and 6-months, and metabolic features were assessed via untargeted liquid chromatography/high-resolution mass spectrometry. Feeding groups were defined at 1-month as 1) exclusively breastfed, 2) breastfed >50% of feedings, or 3) formula fed ≥50% of feedings. Six-month groups were defined as majority breastmilk (>50%) or majority formula fed (≥50%) complemented by solid foods. Neurodevelopmental outcomes were assessed using the Bayley Scales of Infant Development at 2 years. Changes in the infant fecal metabolome were associated with feeding patterns at 1- and 6-months. Feeding patterns were associated with the intensities of a total of 57 fecal metabolites at 1-month and 25 metabolites at 6-months, which were either associated with increased breastmilk or increased formula feeding. Most breastmilk-associated metabolites, which are involved in lipid metabolism and cellular processes like cell signaling, were associated with higher neurodevelopmental scores, while formula-associated metabolites were associated with lower neurodevelopmental scores. These findings offer preliminary evidence that feeding patterns are associated with altered infant fecal metabolomes, which may be associated with cognitive development later in life.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-13"},"PeriodicalIF":0.0,"publicationDate":"2023-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-023-00001-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138864980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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