Effects of estradiol supplementation on the brain transcriptome of old rhesus macaques maintained on an obesogenic diet

Cervera-Juanes, Rita; Darakjian, Priscila; Ball, Megan; Kohama, Steven G.; Urbanski, Henryk F.

doi:10.1007/s11357-021-00453-8

Cited by 11 publications

(9 citation statements)

References 103 publications

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“…These include the voltage-gated potassium channel encoded by KCNG2 (proteasome, p=2.53x10 -2 ), the TATA-box binding protein associated factor (TAF1B, ribosome biogenesis, p=8.41x10 -6 ), the nuclear receptor corepressor 2 (NCOR2, NOTCH signaling, p=2.65x10 -2 ), the Ras-related protein 12 (RAB12, AMPK signaling, p=2.96x10 -2 ), and the kinesin associated protein 3 (KIFAP3, dopaminergic synapse, p=2.37x10 -6 ). Interestingly, KIFAP3 was downregulated in the PFC of Ov-HRT females under a chronic obesogenic diet [55]. In the current study, KIFAP3 was hypermethylated in the PFC with Ov as compared to OI, while the DNAm levels were similar to the group receiving HRT.…”

Section: Ov Is Associated With Dramatic Changes In Neural Signaling P...supporting

confidence: 51%

Modulation of neural gene networks by estradiol in old rhesus macaque females

Cervera-Juanes,

Zimmerman,

Wilhelm

et al. 2023

Preprint

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The postmenopausal decrease in circulating estradiol (E2) levels has been shown to contribute to several adverse physiological and psychiatric effects. To elucidate the molecular effects of E2 on the brain, we examined differential gene expression and DNA methylation (DNAm) patterns in the nonhuman primate brain following ovariectomy (Ov) and subsequent E2 treatment. We identified several dysregulated molecular networks, including MAPK signaling and dopaminergic synapse response, that are associated with ovariectomy and shared across two different brain areas, the occipital cortex (OC) and prefrontal cortex (PFC). The finding that hypomethylation (p=1.6×10-51) and upregulation (p=3.8×10-3) ofUBE2Macross both brain regions, provide strong evidence for molecular differences in the brain induced by E2 depletion. Additionally, differential expression (p=1.9×10-4; interactionp=3.5×10-2) ofLTBRin the PFC, provides further support for the role E2 plays in the brain, by demonstrating that the regulation of some genes that are altered by ovariectomy may also be modulated by Ov followed by hormone replacement therapy (HRT). These results present real opportunities to understand the specific biological mechanisms that are altered with depleted E2. Given E2’s potential role in cognitive decline and neuroinflammation, our findings could lead to the discovery of novel therapeutics to slow cognitive decline. Together, this work represents a major step towards understanding molecular changes in the brain that are caused by ovariectomy and how E2 treatment may revert or protect against the negative neuro-related consequences caused by a depletion in estrogen as women approach menopause.

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Section: Ov Is Associated With Dramatic Changes In Neural Signaling P...supporting

confidence: 51%

Modulation of neural gene networks by estradiol in old rhesus macaque females

Cervera-Juanes,

Zimmerman,

Wilhelm

et al. 2023

Preprint

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“…We modeled the expression of each gene as a function of diet (Western or Mediterranean) and RIN (to control for any effects of RNA quality on expression). Given that social status [62, 63] and estradiol [64] exert neurological effects in NHPs, we also included subject social status (relative dominance rank) and serum estradiol levels at time of necropsy as covariates. Genes were considered differentially expressed if they passed a Benjamini-Hochberg false discovery rate threshold of 0.05.…”

Section: Methodsmentioning

confidence: 99%

Mediterranean Diet Protects Against a Neuroinflammatory Cortical Transcriptome: Associations with Brain Volumetrics, Peripheral Inflammation, Social Isolation and Anxiety

Negrey,

Frye,

Johnson

et al. 2023

Preprint

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INTRODUCTIONMediterranean diets may be neuroprotective and prevent cognitive decline relative to Western diets, however the underlying biology is poorly understood.METHODSWe assessed the effects of Western vs. Mediterranean-like diets on RNAseq generated transcriptional profiles in temporal cortex and their relationships with changes in MRI neuroimaging phenotypes, circulating monocyte gene expression, and observations of social isolation and anxiety in 38 socially-housed, middle-aged female cynomolgus macaques.RESULTSDiet resulted in differential expression of seven transcripts (FDR<0.05). Cyclin dependent kinase 14 (CDK14), a proinflammatory regulator, was lower in the Mediterranean group. The remaining six transcripts [i.e., “lunatic fringe” (LFNG), mannose receptor C type 2 (MRC2), solute carrier family 3 member 2 (SLCA32), butyrophilin subfamily 2 member A1 (BTN2A1), katanin regulatory subunit B1 (KATNB1), and transmembrane protein 268 (TMEM268)] were higher in cortex of the Mediterranean group and generally associated with anti-inflammatory/neuroprotective pathways.KATNB1encodes a subcomponent of katanin, important in maintaining microtubule homeostasis.BTN2A1is involved in immunomodulation of γδ T-cells which have anti-neuroinflammatory and neuroprotective effects.CDK14,LFNG,MRC2,andSLCA32are associated with inflammatory pathways. The latter four differentially expressed cortex transcripts were associated with monocyte transcript levels, changes in AD-relevant brain volumes determined by MRI over the course of the study, and social isolation and anxiety.CDK14was positively correlated with monocyte inflammatory transcripts, changes in total brain, gray matter, cortical gray matter volumes, and time alone and anxious behavior, and negatively correlated with changes in total white matter and cerebrospinal fluid (CSF) volumes. In contrast,LFNG,MRC2, andSLCA32were negatively correlated with monocyte inflammatory transcripts and changes in total gray matter volume, and positively correlated with CSF volume changes, and SLCA32 was negatively correlated with time alone.DISCUSSIONCollectively, our results suggest that relative to Western diets, Mediterranean diets confer protection against peripheral and central inflammation which is reflected in preserved brain structure and behavior.

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“…Animal studies showed that hormone therapy significantly improved the pathological features of dementia in obese middle-aged female rhesus monkeys after surgical menopause ( Cervera-Juanes et al, 2022 ). Estrogen supplementation inhibited pathways associated with neuroinflammation, Aβ deposition, and tau tangles.…”

Section: Potential Association Between Fat Metabolism Disorder and Co...mentioning

confidence: 99%

“…A large number of studies showed that high-fat diet-induced neuroinflammation, oxidative stress, and mitochondrial damage in nerve cells significantly impair brain cognitive function ( Wang et al, 2018 ; Tan and Norhaizan, 2019 ; Maneechote et al, 2022 ). A study showed that middle-aged female rhesus monkeys on a high-fat diet after ovariectomy suffer significant brain damage, while estradiol supplementation protects against neuroinflammation, Aβ deposition and tau tangles ( Cervera-Juanes et al, 2022 ). Notably, in addition to estrogen, recent studies have shown that FSH is associated with fat metabolism disorders and cognitive impairment during MT, making it a promising target for the treatment of menopausal obesity and AD.…”

Section: Introductionmentioning

confidence: 99%

Effects of follicle-stimulating hormone on fat metabolism and cognitive impairment in women during menopause

et al. 2022

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Lipid metabolism disorder is a common pathological manifestation of menopausal women, and is also an important risk factor for many diseases at this stage of life. Epidemiological studies have shown that high levels of follicle-stimulating hormone (FSH) in menopausal women are closely associated with changes in body composition, central obesity, and cognitive decline. Exogenous FSH causes growth and proliferation of adipose, whereas blockage of the FSH signaling pathway leads to decline in adipose. Mechanistically, FSH, FSH receptor (FSHR), G protein coupling, gene mutation and other pathways are involved in adipogenesis and cognitive impairment. Here, we review the critical role and potential interactions of FSH in adipogenesis and cognitive impairment in menopausal women. Further understanding of the exact mechanisms of FSH aggravating obesity and cognitive impairment may provide a new perspective for promoting healthy aging in menopausal women.

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Effects of estradiol supplementation on the brain transcriptome of old rhesus macaques maintained on an obesogenic diet

Cited by 11 publications

References 103 publications

Modulation of neural gene networks by estradiol in old rhesus macaque females

Modulation of neural gene networks by estradiol in old rhesus macaque females

Mediterranean Diet Protects Against a Neuroinflammatory Cortical Transcriptome: Associations with Brain Volumetrics, Peripheral Inflammation, Social Isolation and Anxiety

Effects of follicle-stimulating hormone on fat metabolism and cognitive impairment in women during menopause

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