Association between obesity and bacterial vaginosis as assessed by Nugent score

Background Bacterial vaginosis is one of the most common vaginal conditions in the U.S. Recent studies have suggested obese women have an abnormal microbiota reminiscent of BV; however, few studies have investigated the prevalence of bacterial vaginosis in overweight and obese populations. Moreover, despite the increased prevalence of obesity and bacterial vaginosis in black women, it is not known whether racial disparities exist in the relationship between obesity and bacterial vaginosis. Objective The objective of this study was to examine the relationship between body mass index and bacterial vaginosis as determined by Nugent score and to determine the influence of race in this context. Study Design We performed a cross-sectional study using patient data and vaginal smears from 5,918 participants of the Contraceptive CHOICE Project. Gram stained vaginal smears were scored using the Nugent method and categorized as BV-negative (Nugent score 0-3), BV-intermediate (Nugent score 4-6), or BV-positive (Nugent score 7-10). Body mass index was determined using Centers for Disease Control and Prevention guidelines and obese individuals were categorized as Class I, II, or III obese based on NIH and World Health Organization body mass index parameters. Linear regression was used to model mean differences in Nugent scores and Poisson regression with robust error variance was used to model prevalence of bacterial vaginosis. Results In our cohort, 50.7% of participants were black, 41.5% were white, and 5.1% were of Hispanic ethnicity with an average age of 25.3 years old. Overall, 28.1% of participants were bacterial vaginosis-positive. Bacterial vaginosis was prevalent in 21.3% of lean, 30.4% of overweight, and 34.5% of obese women (p<0.001). The distribution of bacterial vaginosis-intermediate individuals was similar across all body mass index categories. Compared to lean women, Nugent scores were highest among overweight and obese Class I women (adjusted mean difference; overweight 0.33 [95% CI 0.14, 0.51] and Class I obese 0.51 [95% CI 0.29, 0.72]). Consistent with this, overweight and obese women had a higher frequency of bacterial vaginosis compared to lean women, even after adjusting for variables including race. Among white women, the prevalence of BV was higher for overweight and Class I and Class II/III obese white women compared to lean white women, a phenomenon not observed among black women, suggesting an effect modification. Conclusion Overweight and obese women have higher Nugent scores and a greater occurrence of bacterial vaginosis compared to lean women. Black women have a greater prevalence of bacterial vaginosis independent of their body mass index compared to white women

Site-1 protease inhibits mitochondrial respiration by controlling the TGF-β target gene Mss51

The mitochondrial response to changes in cellular energy demand is necessary for cellular adaptation and organ function. Many genes are essential in orchestrating this response, including the transforming growth factor (TGF)-β1 target gene Mss51, an inhibitor of skeletal muscle mitochondrial respiration. Although Mss51 is implicated in the pathophysiology of obesity and musculoskeletal disease, how Mss51 is regulated is not entirely understood. Site-1 protease (S1P) is a key activator of several transcription factors required for cellular adaptation. However, the role of S1P in muscle is unknown. Here, we identify S1P as a negative regulator of muscle mass and mitochondrial respiration. S1P disruption in mouse skeletal muscle reduces Mss51 expression and increases muscle mass and mitochondrial respiration. The effects of S1P deficiency on mitochondrial activity are counteracted by overexpressing Mss51, suggesting that one way S1P inhibits respiration is by regulating Mss51. These discoveries expand our understanding of TGF-β signaling and S1P function

Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutations

Lipin 1 is a bifunctional protein that is a transcriptional regulator and has phosphatidic acid (PA) phosphohydrolase activity, which dephosphorylates PA to generate diacylglycerol. Human lipin 1 mutations lead to episodic rhabdomyolysis, and some affected patients exhibit cardiac abnormalities, including exercise-induced cardiac dysfunction and cardiac triglyceride accumulation. Furthermore, lipin 1 expression is deactivated in failing heart, but the effects of lipin 1 deactivation in myocardium are incompletely understood. We generated mice with cardiac-specific lipin 1 KO (cs-Lpin1-/-) to examine the intrinsic effects of lipin 1 in the myocardium. Cs-Lpin1-/- mice had normal systolic cardiac function but mild cardiac hypertrophy. Compared with littermate control mice, PA content was higher in cs-Lpin1-/- hearts, which also had an unexpected increase in diacylglycerol and triglyceride content. Cs-Lpin1-/- mice exhibited diminished cardiac cardiolipin content and impaired mitochondrial respiration rates when provided with pyruvate or succinate as metabolic substrates. After transverse aortic constriction-induced pressure overload, loss of lipin 1 did not exacerbate cardiac hypertrophy or dysfunction. However, loss of lipin 1 dampened the cardiac ionotropic response to dobutamine and exercise endurance in association with reduced protein kinase A signaling. These data suggest that loss of lipin 1 impairs cardiac functional reserve, likely due to effects on glycerolipid homeostasis, mitochondrial function, and protein kinase A signaling

Effects of S1P Mutation on ER Stress and Cholesterol Synthesis Markers in Human Epithelial Cells

Site-1 Protease (S1P) is a Golgi-resident enzyme required for activation and subsequent nuclear localization of several major transcription factors. A 24-year-old female patient with a de novo single point mutation in S1P presented with a complex phenotype that includes gut hypomotility and abnormal optic nerves. Exomic sequencing revealed a heterozygous amino acid substitution of S1P. Previous research has shown that S1P plays an integral role in the activation of ATF6 and SREBP2, key transcription factors involved in the ER stress response and cholesterol biosynthetic pathway, respectively. The goal of this study was to characterize the mutant S1P protein by assessing protein activity and localization. Over-expression of mutant S1P in a lipid and cholesterol auxotrophic S1P-null cell line rescued the dependence on exogenous lipids and sterols similar to null cells expressing wild-type S1P. Furthermore, induction of ER stress with tunicamycin showed a heightened expression of ATF6 target genes in mutant S1P patient fibroblasts relative to control patient cells. A similar elevated response in SREBP2 target genes was also observed when the SREBP2 pathway was stimulated in the mutant fibroblasts. In addition, EndoH sensitivity assays showed that localization of mutant S1P to the Golgi was not impaired. This initial characterization demonstrated that the de novo mutation produces a gain-of function phenotype and that the mutation does not disrupt proper localization of the protein. This is the first known case of S1P mutation in humans and it is unknown how many harbor similar mutations of the S1P protein, critical for sterol homeostasis. Abstract updated November 7, 201