Search

Childhood obesity and diabetes are major threats to public health in the United States and abroad. In the United States, the prevalence of obesity among children and adolescents has almost [...]

Major depressive disorder and other neuropsychiatric disorders are often managed with long‐term use of antidepressant medication. Fluoxetine, an SSRI antidepressant, is widely used as a first‐line treatment for neuropsychiatric disorders. However, fluoxetine has also been shown to increase the risk of metabolic diseases such as non‐alcoholic fatty liver disease. Fluoxetine has been shown to increase hepatic lipid accumulation in vivo and in vitro. In addition, fluoxetine has been shown to alter the production of prostaglandins which have also been implicated in the development of non‐alcoholic fatty liver disease. The goal of this study was to assess the effect of fluoxetine exposure on the prostaglandin biosynthetic pathway and lipid accumulation in a hepatic cell line (H4‐II‐E‐C3 cells). Fluoxetine treatment increased mRNA expression of prostaglandin biosynthetic enzymes (Ptgs1, Ptgs2, and Ptgds), PPAR gamma (Pparg), and PPAR gamma downstream targets involved in fatty acid uptake (Cd36, Fatp2, and Fatp5) as well as production of 15‐deoxy‐Δ12,14PGJ2 a PPAR gamma ligand. The effects of fluoxetine to induce lipid accumulation were attenuated with a PTGS1 specific inhibitor (SC‐560), whereas inhibition of PTGS2 had no effect. Moreover, SC‐560 attenuated 15‐deoxy‐Δ12,14PGJ2 production and expression of PPAR gamma downstream target genes. Taken together these results suggest that fluoxetine‐induced lipid abnormalities appear to be mediated via PTGS1 and its downstream product 15d‐PGJ2 and suggest a novel therapeutic target to prevent some of the adverse effects of fluoxetine treatment. The use of SSRI antidepressants has been linked to adverse metabolic outcomes, including non‐alcoholic fatty liver disease. This study aimed to investigate mechanisms by which the SSRI fluoxetine contributes to elevated hepatic lipid accumulation. Fluoxetine treatment caused an increase in 15‐deoxy‐Δ12,14PGJ2 and mRNA expression of key components of the prostaglandin biosynthetic pathway. Fluoxetine‐induced lipid accumulation was blocked with the selective Ptgs1 inhibitor, SC‐560. Taken together these results suggest the altered prostaglandin production is a key mediator of fluoxetine‐induced lipid accumulation. [ABSTRACT FROM AUTHOR]

Urocortin: a mechanism for the sustained activation of the HPA axis in the late-gestation ovine fetus? Am J Physiol Endocrinol Metab 283: E165-E171, 2002. First published March 19, 2002; 10.1152/ajpendo.00497.2001.--We hypothesized that urocortin might be produced in the pituitary of the late-gestation ovine fetus in a manner that could contribute to the regulation of ACTH output. We used in situ hybridization and immunohistochemistry to identify urocortin mRNA and protein in late-gestation fetal pituitary tissue. Levels of urocortin mRNA rose during late gestation and were associated temporally with rising concentrations of pituitary proopiomelanocortin (POMC) mRNA. Urocortin was localized both to cells expressing ACTH and to non-ACTH cells by use of dual immunofluorescence histochemistry. Transfection of pituitary cultures with urocortin antisense probe reduced ACTH output, whereas added urocortin stimulated ACTH output from cultured pituitary cells. Cortisol infusion for 96 h in chronically catheterized late-gestation fetal sheep significantly stimulated levels of pituitary urocortin mRNA. We conclude that urocortin is expressed in the ovine fetal pituitary and localizes with, and can stimulate output of, ACTH. Regulation of urocortin by cortisol suggests a mechanism to override negative feedback and sustain feed-forward of fetal hypothalamic-pituitary-adrenal function, leading to birth. urocortin; adrenocorticotropic hormone; parturition; hypothalamic-pituitary-adrenal axis

Prenatal exposure to nicotine, tobacco's major addictive constituent, has been shown to reduce birth weight and increases apoptosis, oxidative stress, and mitochondrial dysfunction in the postnatal pancreas. Given that upregulated levels of the pro-oxidative adapter protein p66shc is observed in growth-restricted offspring and is linked to beta-cell apoptosis, the goal of this study was to investigate whether alterations in p66shc expression underlie the pancreatic deficits in nicotine-exposed offspring. Maternal administration of nicotine in rats increased p66shc expression in the neonatal pancreas. Similarly, nicotine treatment augmented p66shc expression in INS-1E pancreatic beta cells. Increased p66shc expression was also associated with decreased histone H3 lysine 9 methylation. Finally, nicotine increased the expression of Kdm4c, a key histone lysine demethylase, and decreased Suv39h1, a critical histone lysine methyltransferase. Collectively, these results suggest that upregulation of p66shc through posttranslational histone modifications may underlie the reported adverse outcomes of nicotine exposure on pancreatic function. [ABSTRACT FROM AUTHOR]

BACKGROUND: Diabetes and obesity are major threats to public health in the United States and abroad. Understanding the role that chemicals in our environment play in the development of these conditions is an emerging issue in environmental health, although identifying and prioritizing chemicals for testing beyond those already implicated in the literature is challenging. This review is intended to help researchers generate hypotheses about chemicals that may contribute to diabetes and to obesity-related health outcomes by summarizing relevant findings from the U.S. Environmental Protection Agency (EPA) ToxCast[TM] high-throughput screening (HTS) program. OBJECTIVES: Our aim was to develop new hypotheses around environmental chemicals of potential interest for diabetes--or obesity-related outcomes using high-throughput screening data. METHODS: We identified ToxCast[TM] assay targets relevant to several biological processes related to diabetes and obesity (insulin sensitivity in peripheral tissue, pancreatic islet and [beta] cell function, adipocyte differentiation, and feeding behavior) and presented chemical screening data against those assay targets to identify chemicals of potential interest. DISCUSSION: The results of this screening-level analysis suggest that the spectrum of environmental chemicals to consider in research related to diabetes and obesity is much broader than indicated by research papers and reviews published in the peer-reviewed literature. Testing hypotheses based on ToxCast[TM] data will also help assess the predictive utility of this HTS platform. CONCLUSIONS: More research is required to put these screening-level analyses into context, but the information presented in this review should facilitate the development of new hypotheses. http://dx.doi.org/10.1289/ehp.1510456, Introduction The rise in obesity and diabetes rates are major threats to public health in the United States and abroad [Centers for Disease Control and Prevention (CDC) 2011; Dahlquist et [...]

With the legalization of marijuana (Cannabis sativa) and increasing use during pregnancy, it is important to understand its impact on exposed offspring. Specifically, the effects of Δ-9-tetrahydrocannabinol (Δ9-THC), the major psychoactive component of cannabis, on fetal ovarian development and long-term reproductive health are not fully understood. The aim of this study was to assess the effect of prenatal exposure to Δ9-THC on ovarian health in adult rat offspring. At 6 months of age, Δ9-THC-exposed offspring had accelerated folliculogenesis with apparent follicular development arrest, but no persistent effects on circulating steroid levels. Ovaries from Δ9-THC-exposed offspring had reduced blood vessel density in association with decreased expression of the pro-angiogenic factor VEGF and its receptor VEGFR-2, as well as an increase in the anti-angiogenic factor thrombospondin 1 (TSP-1). Collectively, these data suggest that exposure to Δ9-THC during pregnancy alters follicular dynamics during postnatal life, which may have long-lasting detrimental effects on female reproductive health. [ABSTRACT FROM AUTHOR]