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ENDO 2021

The Role of Circadian Clocks in Reproduction

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The mechanisms that orchestrate the initiation of puberty are not well understood. DLK1 encodes a transmembrane protein that interacts with NOTCH1 receptor to negatively regulate NOTCH signaling. Loss-of-function mutations in DLK1 cause central precocious puberty, suggesting that DLK1 normally inhibits the reproductive axis centrally. The soluble form of DLK1, which is generated by proteolytic cleavage of the DLK1 extracellular domain, is measurable in human serum. We hypothesized that serum soluble DLK1 concentrations decline with age and that the decline, either in circulating levels or in tissue expression, contributes to the physiological mechanisms triggering pubertal initiation. Serum DLK1 was measured by immunoassay in 102 healthy subjects (age newborn - 26 yrs, 54 male). DLK1 concentrations did not differ by sex, BMI SDS, height, or status of fasting. DLK1 concentrations declined overall with age (R2=0.04, P<0.001). However, there was not a substantial decline in the peripubertal period (mean± SEM, at Tanner stage 1, 2, 3, 4, 5: 14.8 ± 1.9, 16.4 ± 1.2, 17.0 ± 5, 13.6 ± 3, 9.7 ± 0.9 ng/mL). Serum DLK1, measured in 12 subjects (2 male) with a previous history of idiopathic central precocious puberty, did not differ from healthy controls. We next hypothesized that declining expression of Dlk1 or increasing expression of competing canonical NOTCH ligands in hypothalamus contributes to pubertal onset. The preoptic area (POA) was microdissected from rat brains (age 4 d, 2 w, 6 w, and 8-16 w, n=5 each) and expression was measured by RT-PCR. Dlk1 expression increased with age in both female and male rats (P<0.001). Notch1 expression did not change with age. Expression of two ligands, Jag1 and Dll4, showed a peak at age 6 w, around the time of puberty, but only in males, and none of the other ligands (Jag1, Dll1, and Dll3) showed increasing expression at the age of puberty. In conclusion, we did not find evidence that declining serum soluble DLK1 concentrations in humans, declining DLK1 expression in rat preoptic area, or increasing NOTCH ligand expression in rat preoptic area contribute to pubertal onset.?? 

Exploring the Potential Role of DLK1 in Pubertal Initiation

Introduction: The influence of the immune system on follicular cell-derived thyroid cancer behavior has been suggested by various studies but this information has not been comprehensively translated into a prediction for thyroid cancer prognosis. We aimed to identify circulating immune cell profiles associated with thyroid cancer prognosis. This information would be a significant advance in the field of thyroid cancer management. Methods: We performed a single-center prospective cohort study of 32 follicular-cell derived thyroid cancer patients enrolled at the time of initial or subsequent surgery. We performed peripheral blood multi-parameter flow cytometry and collected relevant clinicopathologic, biochemical and radiologic data. We classified patients based on the AJCC TNM cancer stage, American Thyroid Association (ATA) initial risk of recurrence, and status of disease during follow-up. Results: On initial immunophenotyping, patients with aggressive/advanced thyroid cancer (ATA high risk vs. intermediate/low risk; AJCC stage 3/4 vs. 1/2; recurrence or distant metastases vs. no evidence of disease during follow-up) demonstrated increased circulating monocytes and granulocytes but decreased all lymphocytes, T cells (specifically CD4+ and gamma delta) and natural killer (NK) T-like cells. Further immunophenotyping revealed that aggressive/advanced thyroid cancer had increased circulating CD4+CD45+RO effector memory but decreased CD4+CD45+RA central memory T cells and increased regulatory T cells. Stage 3/4 thyroid cancer patients additionally had increased circulating CD33+HLADR- myeloid-derived suppressor cells (MDSCs) as compared to stage1/2. Conclusions: Aggressive thyroid cancer at presentation (AJCC stage, ATA risk category) or during follow-up (distant metastases) is characterized by a circulating immunophenotype comprising of increased immune suppressor cells (regulatory T cells, MDSCs, effector memory T cells) but decreased immune activator cells (CD4+ T cells, gamma delta T cells, NK T-like cells, central memory T cells) as compared to less aggressive thyroid cancer. This circulating immunophenotype may serve as a biomarker for cancer prognosis and guide the selection and development of novel immunotherapies for advanced thyroid cancer.?? 

Aggressive Thyroid Cancer is Associated with Suppressor Circulating Immunophenotype

A Novel Role of Nuclear and Membrane Receptor on Isoflavones-Induced Neuritogenesis and Synaptogenesis

Obesity-induced chronic adipose tissue inflammation is a significant risk factor for metabolic and cardiovascular disease (CVD), which affects 30.3 million adults in the United States. Interaction of adipocytes with hormonal, metabolic and immune systems play an integral role in the underlying pathophysiological mechanisms that leads to development of obesity-related complications. Despite this association, the mechanisms that coordinate the inflammatory mediators in causing adipose tissue inflammation are not well understood. Glucocorticoids (GC) are well known for their potent anti-inflammatory actions; however, the mechanism by which GC coordinate the inflammatory response of adipocytes are unknown. From our genome-wide microarray data derived from adipocyte-specific glucocorticoid receptor (GR) knockout (AdipoGRKO) mice, we found that GR inactivation leads to a significant increase in pro-inflammatory gene in white adipose tissue (WAT). Additionally, WAT isolated from AdipoGRKO mice showed significant increase in immune cell infiltration, which correlates with our gene expression data. Among the top up-regulated genes, we found the C-X-C Motif Chemokine Receptor 2 (Cxcr2), which is a powerful mediator of chemotaxis to the sites of inflammation. Although studies have shown the presence of Cxcr2 in adipocytes and suggested the contribution of Cxcr2 signaling in adipocyte development, its role in integrating adipose tissue inflammatory response is unknown. This led us to hypothesize that GR is critical to repress Cxcr2 gene expression and its pro inflammatory effects in adipocytes. Our in vitro studies using 3T3-L1 cells derived adipocytes showed that treatment with the synthetic glucocorticoid, Dexamethasone (Dex) led to a significant repression of Cxcr2 mRNA and protein levels. Furthermore, these effects are mediated by GR acting directly to repress Cxcr2 gene expression. Systemic administration of corticosterone significantly altered Cxcr2 expression in adipose tissue compared to untreated mice further supporting our results. Together our findings suggest that administration of glucocorticoids could inhibit adipose tissue inflammation and alleviate the comorbidities that arise from inflamed adipose tissue.?? 

Inhibition of Cxcr2 by Glucocorticoids in Adipose Tissue

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https://d3smihljt9218e.cloudfront.net/transcript/25871/subtitle/5bbe0479a346b3360bd35e0d13ef9790.vtt

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The Role of Circadian Clocks in Reproduction

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