Prolonged diet-induced obesity modifies DNA methylation and gene expression in the hippocampus

Velden, Jacob W Vander; Osborne, Danielle M.

doi:10.1016/j.neulet.2022.136656

Cited by 6 publications

(2 citation statements)

References 46 publications

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“…FLCN is a GTPase activating protein that modulates lysosomal activity in response to nutrient availability [39], it also directly interacts with AMPK, TFEB, and TFE3 [40], but it's role in the brain has yet to be studied. It's actions are directed by its interacting proteins, FNIP1 and FNIP2, of which FNIP2 we previously found to be differentially methylated and expressed in the hippocampus following 14 months of a high-fat and high-sugar diet [41]. Interestingly, in females, effects on FNIP2 (5C) were identical to TFE3 (5A), suggesting in the brain these proteins may be linked.…”

Section: Autophagy and Amino Acid Sensingmentioning

confidence: 84%

Sex differences in response to obesity and caloric restriction on cognition and hippocampal markers of autophagic-lysosomal pathway function

Baer

Dorn

Osborne

2023

Preprint

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Obesity rates in the U.S. continue to increase, with nearly 50% of the population being either obese or morbidly obese. Obesity, along with female sex, are leading risk factors for sporadic Alzheimer’s Disease (AD). Animal and clinical studies both indicate that autophagy-lysosomal pathway (ALP) dysfunction is among the earliest known cellular systems to become perturbed in AD, preceding cognitive decline, yet little is known about how obesity and sex affects these cellular functions in an AD susceptible brain region, like the hippocampus. We hypothesized that obesity would negatively affect key markers of ALP in the hippocampus, effects would vary based on sex, and that caloric restriction would counteract obesity effects. Female and male mice were placed on an obesogenic diet for 10 months, at which point half were switched to caloric restriction. Cognitive function in female mice responded differently to caloric restriction based on whether they were on a normal or obesogenic diet; male cognition was only mildly affected by obesity or caloric restriction. Significant male-specific changes occurred in cellular markers of autophagy, including pAkt, pRPS6, Slc38a9, Atg7, and Atg12. In contrast females experienced changes due to diet/caloric restriction predominately in lysosomal markers including TFE3, folliculin, folliculin interacting protein 2, and pAMPK. Results support that hippocampal ALP is a target of obesity and that sex shapes molecular responses to dietary manipulation, while supporting the need to pivot beyond late-stage pathological markers and focus on earlier etiological events of AD that begin decades prior to cognitive decline.

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Section: Autophagy and Amino Acid Sensingmentioning

confidence: 84%

Sex differences in response to obesity and caloric restriction on cognition and hippocampal markers of autophagic-lysosomal pathway function

Baer

Dorn

Osborne

2023

Preprint

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“…Obesity exerts detrimental effects on the brain, where the hippocampus is particularly susceptible [ 5 ]. We previously reported that long-term obesity changed hippocampal methylation and associated gene expression [ 6 ]. Obesity decreases brain derived neurotrophic factor and impairs synaptic plasticity [ 6 , 7 ], promotes neuroinflammation [ 8 ], impairs neurogenesis [ 7 ] and CA1 long-term potentiation [ 9 ], alters AMPA and NMDA receptor signaling [ 10 , 11 ], and impairs learning across a variety of hippocampal-dependent rodent tasks and humans [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Sex differences in response to obesity and caloric restriction on cognition and hippocampal measures of autophagic-lysosomal transcripts and signaling pathways

Baer,

Dorn,

Osborne

2024

BMC Neurosci

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Background Obesity rates in the U.S. continue to increase, with nearly 50% of the population being either obese or morbidly obese. Obesity, along with female sex, are leading risk factors for sporadic Alzheimer’s Disease (AD) necessitating the need to better understand how these variables impact cellular function independent of age or genetic mutations. Animal and clinical studies both indicate that autophagy-lysosomal pathway (ALP) dysfunction is among the earliest known cellular systems to become perturbed in AD, preceding cognitive decline, yet little is known about how obesity and sex affects these cellular functions in the hippocampus, a brain region uniquely susceptible to the negative effects of obesity. We hypothesized that obesity would negatively affect key markers of ALP in the hippocampus, effects would vary based on sex, and that caloric restriction would counteract obesity effects. Methods Female and male mice were placed on an obesogenic diet for 10 months, at which point half were switched to caloric restriction for three months, followed by cognitive testing in the Morris watermaze. Hippocampus was analyzed by western blot and qPCR. Results Cognitive function in female mice responded differently to caloric restriction based on whether they were on a normal or obesogenic diet; male cognition was only mildly affected by caloric restriction and not obesity. Significant male-specific changes occurred in cellular markers of autophagy, including obesity increasing pAkt, Slc38a9, and Atg12, while caloric restriction reduced pRPS6 and increased Atg7. In contrast females experienced changes due to diet/caloric restriction predominately in lysosomal markers including increased TFE3, FLCN, FNIP2, and pAMPK. Conclusions Results support that hippocampal ALP is a target of obesity and that sex shapes molecular responses, while providing insight into how dietary manipulations affect learning and memory based on sex.

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A Brief Introduction to Diet and DNA Methylation

Vaschetto

2024

Epigenetics and Human Health

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Prolonged diet-induced obesity modifies DNA methylation and gene expression in the hippocampus

Cited by 6 publications

References 46 publications

Sex differences in response to obesity and caloric restriction on cognition and hippocampal markers of autophagic-lysosomal pathway function

Sex differences in response to obesity and caloric restriction on cognition and hippocampal markers of autophagic-lysosomal pathway function

Sex differences in response to obesity and caloric restriction on cognition and hippocampal measures of autophagic-lysosomal transcripts and signaling pathways

A Brief Introduction to Diet and DNA Methylation

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