Biology subjects

Jewett, E.

Publications and source records attributed to Jewett, E..

3 recordsLinked to original sources

bioRxiv2026

Altered metabolic health during pregnancy in mice with lean polycystic ovary syndrome-like traits from high prenatal AMH

Polycystic ovary syndrome (PCOS) is a heterogenous reproductive disorder that is often associated with metabolic dysfunction, as well as comorbidities such as pregnancy complications. Although metabolic traits like hyperinsulinemia (i.e., elevated insulin without hypoglycemia) likely exacerbate the reproductive and metabolic features of PCOS, the precise impacts of specific metabolic traits on PCOS pathogenesis, symptom severity, and comorbidity incidence are not known. The aim of our study was to investigate the relationships between insulin levels, PCOS-like traits, and pregnancy complications by limiting endogenous insulin production in a mouse model of PCOS. Using Ins1-null mice with modulated Ins2 gene dosage (Ins1-/-:Ins2+/- versus Ins1-/-:Ins2+/+ littermates), we longitudinally assessed metabolic and reproductive phenotypes in PCOS-like mice generated via prenatal anti-Mullerian hormone (PAMH) exposure. We observed mild reproductive characteristics of PCOS in PAMH mice of both genotypes, including increased anogenital distances, delayed puberty, and disrupted estrous cycling, but did not detect robust PAMH-induced metabolic changes across six months. In the absence of PAMH-aggravated metabolic dysfunction or hyperinsulinemia--even in mice fed a high-fat, high-sucrose diet--reducing Ins2 gene dosage did not notably change most measured traits. However, high-fat, high-sucrose-fed PAMH pregnant dams exhibited a diminished pregnancy-induced insulinogenic response and a trend for reduced {beta}-cell mass compared to control mice, together with superior blood glucose homeostasis despite the physiological challenges of pregnancy. Therefore, while Ins1-null PAMH mice did not manifest pronounced PCOS-like metabolic features, prenatal AMH exposure can cause shifts in metabolic homeostasis during pregnancy.

physiology↗

bioRxiv2025

Glucose enrichment accelerates C. elegans reproductive aging via non-autonomous DAF-2/insulin-like receptor signaling in somatic tissues

Detrimental effects of chronic high-sugar overconsumption can extend from molecular and cellular responses to systemic changes. Reproductive systems are particularly sensitive to diet and energetic state, yet the long-term reproductive consequences of overnutrition are poorly defined. Here, we used Caenorhabditis elegans to study the impacts of glucose excess on reproductive aging. Glucose supplementation shortens C. elegans lifespan, and we found that it also hastens age-related reproductive decline, evidenced by a greater deterioration in oocyte quality and lower fertility with age. We next evaluated insulin-like signaling contributions, as this glucose-responsive pathway is well known to regulate both somatic aging and reproductive aging. Intriguingly, while 20 mM glucose enrichment still shortens the lifespan of daf-2(e1370) mutants, we found that it had no detrimental impact on their reproductive aging phenotypes. Using auxin-induced tissue-selective degradation, we discovered that DAF-2/insulin-like receptor signaling in C. elegans intestine and body wall musculature is required for glucose enrichment to exert damaging impacts on the reproductive system. However, suppressing insulin-like signaling in either of these tissues is sufficient to protect C. elegans against glucose-induced reproductive aging. These findings suggest that insulin-like signalling in metabolically active somatic tissues may represent a key link between overnutrition and reproductive aging.

physiology↗

bioRxiv2024

Evidence for direct control of neurovascular function by circulating platelets in healthy older adults

Platelets play a vital role in preventing haemorrhage through haemostasis, but complications arise when platelets become overly reactive, leading to pathophysiology such as athero-thrombosis. Elevated haemostatic markers are linked to dementia and predict its onset in long-term studies. Despite epidemiological evidence, the mechanism linking haemostasis with early brain pathophysiology remains unclear. Here, we aimed to determine whether a mechanistic association exists between platelet function and neurovascular function in 52 healthy mid- to older-age adults. To do this we combined, for the first time, magnetic resonance imaging (MRI) of neurovascular function, peripheral vascular physiology, and in vitro platelet assaying. We show a direct association between platelet reactivity and neurovascular function that is both independent of vascular reactivity and mechanistically specific: Distinct platelet signalling mechanisms (Adenosine 5-diphosphate, Collagen-Related Peptide, Thrombin Receptor Activator Peptide 6) were directly associated with different physiological components of the haemodynamic response to neural (visual) stimulation (full-width half-maximum, time to peak, area under the curve), an association that was not mediated by peripheral vascular effects. This finding challenges the previous belief that systemic vascular health determines the vascular component of neurovascular function, highlighting a specific link between circulating platelets and the neurovascular unit. Since altered neurovascular function marks the initial stages of neurodegenerative pathophysiology, understanding this novel association becomes now imperative, with the potential to lead to a significant advancement in our comprehension of early dementia pathophysiology. Key points summaryO_LIHaemostasis (platelet function) has been linked to the early stages of dementia, but the precise mechanisms are not well understood. C_LIO_LIThis study asks whether a causal mechanism exists through athero-thrombotic effects on the vasculature which can in turn affect brain health, or through direct platelet effects on brain physiology. C_LIO_LIHere we show that elevated platelet reactivity is associated with blunted (delayed, shorter, and smaller) blood flow responses to neural activation in healthy middle-aged and older adults. C_LIO_LIHowever, the association between platelet reactivity and neurovascular function was not mediated by systemic vascular reactivity. C_LIO_LIThis finding challenges the previous belief that systemic vascular health determines the vascular component of neurovascular function, highlighting a specific link between circulating platelets and the neurovascular unit in early dementia pathophysiology. C_LI

neuroscience↗