Biology subjects

Templeman, N. M.

Publications and source records attributed to Templeman, N. M..

5 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

Lowering insulin mitigates female reproductive aging and diet-induced ovarian dysfunction

Hyperinsulinemia has consequences beyond metabolic dysfunction, including reproductive system effects. We found that hyperinsulinemia at age 46-47 was predictive of earlier menopause in the Study of Womens Health Across the Nation. To test causality between insulin levels and reproductive aging, we longitudinally evaluated chow- or high-fat, high-sucrose (HFHS)-fed Ins1-null female mice with full or partial Ins2 insulin gene expression. Ins1-/-;Ins2+/-mice had lower HFHS-induced hyperinsulinemia and less weight gain than their full-Ins2 littermates, despite comparable HFHS-induced glucose intolerance up to 9 months. By 15 months, Ins1-/-;Ins2+/+ ovaries showed multinucleated giant cell accumulation with HFHS, while Ins1-/-;Ins2+/- mice were protected against this response and maintained a higher reserve of follicles. Moreover, aged Ins1-/-;Ins2+/- mice were 9-fold more likely to conceive on HFHS than hyperinsulinemic Ins1-/-;Ins2+/+ mice. Elevated insulin is therefore a critical mechanistic link between metabolic dysfunction and reproductive aging, and curtailing insulin levels protects against subfertility and HFHS-induced ovarian decline.

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↗

bioRxiv2020

Adipocyte depot-specific up-regulation of uncoupling protein 1 or mitochondrial oxidative complex proteins are early consequences of genetic insulin reduction in mice

Hyperinsulinemia plays a causal role in adipose tissue expansion. Mice with reduced insulin have increased energy expenditure, but the mechanisms remained unclear. Here we investigated the effects of genetically reducing insulin production on uncoupling and oxidative mitochondrial proteins in liver, skeletal muscle, white adipose tissue (WAT), and brown adipose tissue (BAT). Male Ins1+/+ or Ins1+/- littermates were fed either a low-fat diet (LFD) or a high-fat diet (HFD) for 4 weeks, starting at 8 weeks of age. Replicating our previous observations, HFD increased fasting hyperinsulinemia, and Ins1+/- mice had significantly lower circulating insulin compared with Ins1+/+ littermates. Fasting glucose and body weight were not different between genotypes. We did not observe significant differences in liver in skeletal muscle. In mesenteric WAT, Ins1+/- mice had reduced Ndufb8 and Sdhb. Ucp1 was increased in the context of the HFD, and HFD alone had a dramatic inhibitory effect on Pparg abundance. In inguinal WAT, Ins1+/- mice exhibited significant increases in oxidative complex proteins, independent of diet, without affecting Ucp1, Pparg, or Prdm16:Pparg association. In BAT, lowered insulin increased Sdhb protein levels that had been reduced by HFD. Ucp1 protein, Prdm16:Pparg association, and Sirt3 abundance were all increased in the absence of diet-induced hyperinsulinemia. Our data show that reducing insulin upregulates oxidative proteins in inguinal WAT without affecting Ucp1, while in mesenteric WAT and BAT, reducing insulin upregulates Ucp1 in the context of HFD. Preventing hyperinsulinemia has early depot-specific effects on adipose tissue metabolism and help explain the increased energy expenditure previously reported in Ins1+/- mice.

physiology↗

bioRxiv2020

CREB non-autonomously regulates Reproductive Aging through Hedgehog/Patched Signalling

Evolutionarily conserved signaling pathways are crucial for adjusting growth, reproduction, and cell maintenance in response to altered environmental conditions or energy balance. However, we have an incomplete understanding of the signaling networks and mechanistic changes that coordinate physiological changes across tissues. We found that loss of the cAMP response element-binding protein (CREB) transcription factor significantly slows Caenorhabditis elegans reproductive decline, an early hallmark of aging in many animals. Our results indicate that CREB acts downstream of the transforming growth factor beta (TGF-{beta}) Sma/Mab pathway in the hypodermis to control reproductive aging, and that it does so by regulating a Hedgehog-related signaling factor, WRT-10. Overexpression of hypodermal wrt-10 is sufficient to delay reproductive decline and oocyte quality deterioration, potentially acting via Patched-related receptors in the germline. This TGF-{beta}/CREB/WRT-10 signaling axis allows a key metabolic tissue to communicate with the reproductive system to regulate oocyte quality and the rate of reproductive decline. HighlightsO_LIThe transcription factor CREB regulates oocyte quality and reproductive decline C_LIO_LIHypodermal CREB downstream of TGF-{beta} Sma/Mab signaling controls reproductive aging C_LIO_LICREB targets in the hypodermis include a Hedgehog-related signaling factor, wrt-10 C_LIO_LIWRT-10 regulates reproductive aging, potentially via germline Patched receptors C_LI eTOC BlurbTempleman et al. describe how CREB, a highly conserved transcription factor, is a central regulator of age-dependent reproductive decline. CREB acts downstream of the TGF-{beta} Sma/Mab pathway in the hypodermis, a key Caenorhabditis elegans metabolic tissue, to control oocyte quality maintenance and the rate of reproductive decline. Hypodermal CREB affects the expression of wrt-10, which encodes a Hedgehog-related signaling factor. The authors show that wrt-10 regulates reproductive aging, potentially via Patched-related receptors in the germline.

developmental biology↗