Follicle-stimulating hormone orchestrates glucose-stimulated insulin secretion of pancreatic islets.

Follicle-stimulating hormone (FSH) is involved in mammalian reproduction via binding to FSH receptor (FSHR). However, several studies have found that FSH and FSHR play important roles in extragonadal tissue. Here, we identified the expression of FSHR in human and mouse pancreatic islet ß-cells. Blocking FSH signaling by Fshr knock-out led to impaired glucose tolerance owing to decreased insulin secretion, while high FSH levels caused insufficient insulin secretion as well. In vitro, we found that FSH orchestrated glucose-stimulated insulin secretion (GSIS) in a bell curve manner. Mechanistically, FSH primarily activates Gαs via FSHR, promoting the cAMP/protein kinase A (PKA) and calcium pathways to stimulate GSIS, whereas high FSH levels could activate Gαi to inhibit the cAMP/PKA pathway and the amplified effect on GSIS. Our results reveal the role of FSH in regulating pancreatic islet insulin secretion and provide avenues for future clinical investigation and therapeutic strategies for postmenopausal diabetes.

The causal association between smoking initiation, alcohol and coffee consumption, and women's reproductive health: A two-sample Mendelian randomization analysis.

Objective: A number of epidemiological studies have demonstrated that smoking initiation and alcohol and coffee consumption were closely related to women's reproductive health. However, there was still insufficient evidence supporting their direct causality effect. Methods: We utilized two-sample Mendelian randomization (TSMR) analysis with summary datasets from genome-wide association study (GWAS) to investigate the causal relationship between smoking initiation, alcohol and coffee consumption, and women's reproductive health-related traits. Exposure genetic instruments were used as variants significantly related to traits. The inverse-variance weighted (IVW) method was used as the main analysis approach, and we also performed MR-PRESSO, MR-Egger, weighted median, and weighted mode to supplement the sensitivity test. Then, the horizontal pleiotropy was detected by using MRE intercept and MR-PRESSO methods, and the heterogeneity was assessed using Cochran's Q statistics. Results: We found evidence that smoking women showed a significant inverse causal association with the sex hormone-binding globulin (SHBG) levels (corrected ß = -0.033, p = 9.05E-06) and age at menopause (corrected ß = -0.477, p = 6.60E-09) and a potential positive correlation with the total testosterone (TT) levels (corrected ß = 0.033, p = 1.01E-02). In addition, there was suggestive evidence for the alcohol drinking effect on the elevated TT levels (corrected ß = 0.117, p = 5.93E-03) and earlier age at menopause (corrected ß = -0.502, p = 4.14E-02) among women, while coffee consumption might decrease the female SHBG levels (corrected ß = -0.034, p = 1.33E-03). Conclusion: Our findings suggested that smoking in women significantly decreased their SHBG concentration, promoted earlier menopause, and possibly reduced the TT levels. Alcohol drinking had a potential effect on female higher TT levels and earlier menopause, while coffee consumption might lead to lower female SHBG levels.

The Causal Evidence of Birth Weight and Female-Related Traits and Diseases: A Two-Sample Mendelian Randomization Analysis.

Objectives : A large meta-analysis indicated a more pronounced association between lower birth weight (BW) and diseases in women but less concern about the causality between BW and female-related phenotypes and diseases. Methods: Mendelian randomization (MR) analysis was used to estimate the causal relationship between two traits or diseases using summary datasets from genome-wide association studies. Exposure instrumental variables are variants that are strongly associated with traits and are tested using four different statistical methods, including the inverse variance weighting, MR-Egger, weighted median, and weighted mode in MR analysis. Next, sensitivity analysis and horizontal pleiotropy were assessed using leave-one-out and MR-PRESSO packages. Results: The body mass index (BMI) in adulthood was determined by BW (corrected ß = 0.071, p = 3.19E-03). Lower BW could decrease the adult sex hormone-binding globulin (SHBG) level (ß = -0.081, p = 2.08E-06), but it resulted in increased levels of bioavailable testosterone (bio-T) (ß = 0.105, p = 1.25E-05). A potential inverse effect was observed between BW and menarche (corrected ß = -0.048, p = 4.75E-03), and no causal association was confirmed between BW and the risk of endometriosis, leiomyoma, and polycystic ovary syndrome. Conclusion: Our results suggest that BW may play an important role and demonstrates a significant direct influence on female BMI, SHBG and bio-T levels, and menarche.

Paternal obesity impairs hepatic gluconeogenesis of offspring by altering Igf2/H19 DNA methylation.

Over the past four decades, the global prevalence of obesity has increased rapidly in all age ranges. Emerging evidence suggests that paternal lifestyle and environmental exposure have a crucial role in the health of offspring. Therefore, the current study investigated the impact of paternal obesity on the metabolic profile of offspring in a male mouse model of obesity. Female offspring of obese fathers fed a high-fat diet (HFD) (60% kcal fat) showed hyperglycemia because of enhanced gluconeogenesis and elevated expression of phosphoenolpyruvate carboxykinase (PEPCK), which is a key enzyme involved in the regulation of gluconeogenesis. Methylation of the Igf2/H19 imprinting control region (ICR) was dysregulated in the liver of offspring, and the sperm, of HFD fathers, suggesting that epigenetic changes in germ cells contribute to this father-offspring transmission. In addition, we explored whether H19 might regulate hepatic gluconeogenesis. Our results showed that overexpression of H19 in Hepa1-6 cells enhanced the expression of PEPCK and gluconeogenesis by promoting nuclear retention of forkhead box O1 (FOXO1), which is involved in the transcriptional regulation of Pepck. Thus, the current study suggests that paternal exposure to HFD impairs the gluconeogenesis of offspring via altered Igf2/H19 DNA methylation.