Nicotinic Cholinergic Signaling in Adipose Tissue and Pancreatic Islets Biology: Revisited Function and Therapeutic Perspectives

Nicotinic acetylcholine receptors (nAChRs) are membrane ligand-gated cation channels whose activation is triggered by the binding of the endogenous neurotransmitter acetylcholine or other biologic compounds including nicotine. Their roles in synaptic transmission in the central and peripheral nervous system as well as in the neuromuscular junction have been extensively studied. Recent implications of nAChRs in intracellular signaling and their detection in peripheral nonneural cells (including epithelial cells and immune cells) have renewed the interest for this class of ionotropic receptors. In the present review, we focus our attention on the potential use of nicotinic cholinergic signaling in the treatment of metabolic diseases (such as obesity and diabetes) in browsing functions of nAChRs in adipose tissue and pancreatic islet biology. In fact, different nAChR subunits can be detected in these metabolic tissues, as well as in immune cells interacting with them. Various rodent models of obesity and diabetes benefit from stimulation of the nicotinic cholinergic pathway, whereas mice deficient for some nAChRs, in particular the α7 nAChR subunit, harbor a worsened metabolic phenotype. In contrast to potential therapeutic applications in metabolic diseases, an overstimulation of this signaling pathway during the early stage of development (typically through nicotine exposure during fetal life) presents deleterious consequences on ontogeny and functionality of adipose tissue and the endocrine pancreas which persist throughout life

Prenatal nicotine exposure alters early pancreatic islet and adipose tissue development with consequences on the control of body weight and glucose metabolism later in life. Endocrinology 149

ABSTRACT Despite medical advice, 20% to 30% of female smokers continue to smoke during pregnancy. Epidemiological studies have associated maternal smoking with increased risk of obesity and type-2 diabetes in the offspring. In the present study, we investigated the impact of prenatal nicotine exposure (3mg/kg in Sprague-Dawley rats via osmotic Alzet minipumps) on the early endocrine pancreas and adipose tissue development in rat pups before weaning. Body weight, fat deposition, food intake and food efficiency, cold tolerance, spontaneous physical activity, glucose utilization and insulin sensitivity were also examined at adulthood. Prenatal nicotine exposure led to a decrease in endocrine pancreatic islet size and number at 7 days of life (PND7) which corroborates with a decrease in gene expression of specific transcription factors such as Pdx-1, Pax-6, Nkx6.1 and of hormones such as insulin and glucagon. The prenatal nicotine exposure also led to an increase in epididymal white adipose tissue (eWAT) weight at weaning (PND21), and marked hypertrophy of adipocytes, with increased gene expression of proadipogenic transcription factors such as C/EBP-α, PPAR-γ and SREBP-1C. These early tissue alterations led to significant metabolic consequences, as shown by increased body weight and fat deposition, increased food efficiency on high fat diet, cold intolerance, reduced physical activity, glucose intolerance combined with insulin resistance observed at adulthood. These results prove a direct association between fetal nicotine exposure and offspring metabolic syndrome with early signs of dysregulations of adipose tissue and pancreatic development

NFE2-Related transcription factor 2 coordinates antioxidant defense with thyroglobulin production and iodination in the thyroid gland

Background: The thyroid gland has a special relationship with oxidative stress. While generation of oxidative substances is part of normal iodide metabolism during thyroid hormone synthesis, the gland must also defend itself against excessive oxidation in order to maintain normal function. Antioxidant and detoxification enzymes aid thyroid cells to maintain homeostasis by ameliorating oxidative insults, including during exposure to excess iodide, but the factors that coordinate their expression with the cellular redox status are not known. The antioxidant response system comprising the ubiquitously expressed NFE2-related transcription factor 2 (Nrf2) and its redox-sensitive cytoplasmic inhibitor Kelch-like ECH-associated protein 1 (Keap1) defends tissues against oxidative stress, thereby protecting against pathologies that relate to DNA, protein, and/or lipid oxidative damage. Thus, it was hypothesized that Nrf2 should also have important roles in maintaining thyroid homeostasis. Methods: Ubiquitous and thyroid-specific male C57BL6J Nrf2 knockout (Nrf2-KO) mice were studied. Plasma and thyroids were harvested for evaluation of thyroid function tests by radioimmunoassays and of gene and protein expression by real-time polymerase chain reaction and immunoblotting, respectively. Nrf2-KO and Keap1-KO clones of the PCCL3 rat thyroid follicular cell line were generated using CRISPR/Cas9 technology and were used for gene and protein expression studies. Software-predicted Nrf2 binding sites on the thyroglobulin enhancer were validated by site-directed in vitro mutagenesis and chromatin immunoprecipitation. Results: The study shows that Nrf2 mediates antioxidant transcriptional responses in thyroid cells and protects the thyroid from oxidation induced by iodide overload. Surprisingly, it was also found that Nrf2 has a dramatic impact on both the basal abundance and the thyrotropin-inducible intrathyroidal abundance of thyroglobulin (Tg), the precursor protein of thyroid hormones. This effect is mediated by cell-autonomous regulation of Tg gene expression by Nrf2 via its direct binding to two evolutionarily conserved antioxidant response elements in an upstream enhancer. Yet, despite upregulating Tg levels, Nrf2 limits Tg iodination both under basal conditions and in response to excess iodide. Conclusions: Nrf2 exerts pleiotropic roles in the thyroid gland to couple cell stress defense mechanisms to iodide metabolism and the thyroid hormone synthesis machinery, both under basal conditions and in response to excess iodide.Fil: Ziros, Panos G. Lausanne University; SuizaFil: Habeos, Ioannis. Patras University; GreciaFil: Chartoumpekis, Dionysios V. University of Pittsburgh; Estados UnidosFil: Ntalampyra, Eleni. Universite de Lausanne; SuizaFil: Somm, Emmanuel. Universite de Lausanne; SuizaFil: Renaud, Cédric O.. Universite de Lausanne; SuizaFil: Bongiovanni, Massimo. Institute Of Pathology Locarno; SuizaFil: Trougakos, Ioannis P. Universidad Nacional y Kapodistríaca de Atenas; GreciaFil: Yamamoto, Masayuki. University Of Tohoku; JapónFil: Kensler, Thomas W.. University of Pittsburgh at Johnstown; Estados UnidosFil: Santisteban, Pilar. Universidad Autónoma de Madrid; EspañaFil: Carrasco, Nancy. University of Yale. School of Medicine; Estados UnidosFil: Ris Stalpers, Carrie. Academic Medical Center; Países BajosFil: Amendola, Elena. Universidad de Nápoles; ItaliaFil: Liao, Xiao-Hui. University of Chicago; Estados UnidosFil: Rossich, Luciano Esteban. Comisión Nacional de Energía Atómica de Argentina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Thomasz, Lisa. Comisión Nacional de Energía Atómica de Argentina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Juvenal, Guillermo Juan. Comisión Nacional de Energía Atómica de Argentina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Refetoff, Samuel. University of Chicago; Estados UnidosFil: Sykiotis, Gerasimos P.. Universite de Lausanne; Suiz

Perinatal Exposure to Bisphenol A Alters Early Adipogenesis in the Rat

BACKGROUND: The causes of the current obesity pandemic have not been fully elucidated. Implication of environmental endocrine disruptors such as bisphenol A (BPA) on adipose tissue development has been poorly investigated. OBJECTIVES: The aim of the present study was to evaluate the effects of perinatal exposure to BPA on early adipose storage at weaning. METHODS: Pregnant Sprague-Dawley rats had access to drinking water containing 1 mg/L BPA from day 6 of gestation through the end of lactation. Pups were weaned on postnatal day (PND) 21. At that time, we investigated perigonadal adipose tissue of pups (weight, histology, gene expression). For the remaining animals, we recorded body weight and food intake for animals on either standard chow or a high-fat diet. RESULTS: Gestational exposure to BPA did not alter the sex ratio or litter size at birth. On PND1, the weight of male and female BPA-exposed pups was increased. On PND21, body weight was increased only in females, in which parametrial white adipose tissue (pWAT) weight was increased about 3-fold. This excess of pWAT was associated with adipocyte hypertrophy and overexpression of lipogenic genes such as C/EBP-alpha (CAAT enhancer binding protein alpha), PPAR-gamma (peroxisome proliferator-activated receptor gamma), SREBP-1C (sterol regulatory element binding protein-1C), LPL (lipoprotein lipase), FAS (fatty acid synthase), and SCD-1 (stearoyl-CoA desaturase 1). In addition, gene expression of SREBP-1C, FAS, and ACC (acetyl-CoA carboxylase) was also increased in liver from BPA-exposed females at PND21, without a change in circulating lipids and glucose. After weaning, perinatal BPA exposure predisposed to overweight in a sex- and diet-dependent manner. We observed no change in food intake due to perinatal BPA exposure in rats on either standard chow or a high-fat diet. CONCLUSIONS: Perinatal exposure to a low dose of BPA increased adipogenesis in females at weaning. Adult body weight may be programmed during early life, leading to changes dependent on the sex and the nutritional status. Although further studies are required to understand the mechanisms of BPA action in early life, these results are particularly important with regard to the increasing prevalence of childhood obesity and the context-dependent action of endocrine disruptors

KLB , encoding β‐Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic form of isolated gonadotropin‐releasing hormone (GnRH) deficiency caused by mutations in > 30 genes. Fibroblast growth factor receptor 1 (FGFR1) is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH FGFR1 mutation (p.L342S) decreases signaling of the metabolic regulator FGF21 by impairing the association of FGFR1 with β‐Klotho (KLB), the obligate co‐receptor for FGF21. We thus hypothesized that the metabolic FGF21/KLB/FGFR1 pathway is involved in CHH. Genetic screening of 334 CHH patients identified seven heterozygous loss‐of‐function KLB mutations in 13 patients (4%). Most patients with KLB mutations (9/13) exhibited metabolic defects. In mice, lack of Klb led to delayed puberty, altered estrous cyclicity, and subfertility due to a hypothalamic defect associated with inability of GnRH neurons to release GnRH in response to FGF21. Peripheral FGF21 administration could indeed reach GnRH neurons through circumventricular organs in the hypothalamus. We conclude that FGF21/KLB/FGFR1 signaling plays an essential role in GnRH biology, potentially linking metabolism with reproduction

Fibroblast Growth Factor 15/19 - From Basic Functions to Therapeutic Perspectives

Discovered 20 years ago, Fibroblast Growth Factor (FGF) 19, and its mouse ortholog FGF15, were the first members of a new subfamily of FGFs able to act as hormones. During fetal life, FGF15/19 is involved in organogenesis, affecting the development of the ear, eye, heart and brain. At adulthood, FGF15/19 is mainly produced by the ileum, acting on the liver to repress hepatic bile acid synthesis and promote postprandial nutrient partitioning. In rodents, pharmacologic doses of FGF19 induce the same anti-obesity and anti-diabetic actions as FGF21, these metabolic effects being partly mediated by the brain. However, activation of hepatocyte proliferation by FGF19 has long been a challenge to its therapeutic use. Recently, genetic reengineering of the molecule has resolved this issue. Despite a global overlap in expression pattern and function, murine FGF15 and human FGF19 exhibit several differences in terms of regulation, molecular structure, signaling and biological properties. As most of the knowledge originates from the use of FGF19 in murine models, differences between mice and humans in the biology of FGF15/19 have to be considered for a successful translation from bench to bedside. This review summarizes the basic knowledge concerning FGF15/19 in mice and humans, with a special focus on regulation of production, morphogenic properties, hepatocyte growth, bile acid homeostasis, as well as actions on glucose, lipid and energy homeostasis. Moreover, implications and therapeutic perspectives concerning FGF19 in human diseases (including obesity, type 2 diabetes, hepatic steatosis, biliary disorders and cancer) are also discussed

Interleukin-18 in metabolism: from mice physiology to human diseases

Interleukin-18 (IL-18) is a classical member of the IL-1 superfamily of cytokines. As IL-1β, IL-18 precursor is processed by inflammasome/caspase-1 into a mature and biologically active form. IL-18 binds to its specific receptor composed of two chains (IL-18Rα and IL-18Rβ) to trigger a similar intracellular signaling pathway as IL-1, ultimately leading to activation of NF-κB and inflammatory processes. Independently of this IL-1-like signaling, IL-18 also specifically induces IFN-γ production, driving the Th1 immune response. In circulation, IL-18 binds to the IL-18 binding protein (IL-18BP) with high affinity, letting only a small fraction of free IL-18 able to trigger receptor-mediated signaling. In contrast to other IL-1 family members, IL-18 is produced constitutively by different cell types, suggesting implications in normal physiology. If the roles of IL-18 in inflammatory processes and infectious diseases are well described, recent experimental studies in mice have highlighted the action of IL-18 signaling in the control of energy homeostasis, pancreatic islet immunity and liver integrity during nutritional stress. At the same time, clinical observations implicate IL-18 in various metabolic diseases including obesity, type 1 and 2 diabetes and nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). In the present review, we summarize and discuss both the physiological actions of IL-18 in metabolism and its potential roles in pathophysiological mechanisms leading to the most common human metabolic disorders, such as obesity, diabetes and NAFLD/NASH

Effect of developmental dioxin exposure on methylation and expression of specific imprinted genes in mice

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an endocrine disruptor affecting the reproductive system in humans. The aim of this study was to evaluate the effects of TCDD administered to pregnant mice at two different doses (2-10 ng/kg/day), on imprinted genes in the male offspring. The degree of methylation and the mRNA expression of Snrpn, Peg3 and Igf2r were analyzed in the sperm, skeletal muscle and liver. TCDD administration (10 ng/kg/day) decreased the sperm count in the male offspring. It did not affect methylation but increased mRNA expression of Snrpn, Peg3, Igf2r and Air ncRNA. In muscle and liver, TCDD (10 ng/kg/day) induced increases in methylation and decreases in mRNA expression of Igf2r. These results show that the robust effects of TCDD on the mRNA expression of Snrpn, Peg3 and Igf2r genes in the sperm and of Igf2r in the muscle and liver are unrelated to changes in methylation in their respective genes

Prenatal exposure to ethanol: a specific effect on the H19 gene in sperm

Alcohol exposure during pregnancy induces a range of disorders in the offspring. Methylation changes in imprinted genes may play a role in the teratogenic effects of alcohol. We evaluated the possible effects of alcohol administration in pregnant mice on the methylation pattern of 5 imprinted genes (H19, Gtl2, Peg1, Snrpn and Peg3) in somatic and sperm cell DNAs of the male offspring. The effects observed were a 3% (p < 0.005) decrease in the number of methylated CpGs of H19 in the F1 offspring sperm, a 4% (p < 0.005) decrease in the number of methylated CpGs of H19 in the F2 offspring brain and a 26% (p < 0.05) decrease in the mean sperm concentration. CpGs 1 and 2 of the H19 CTCF-binding site 2 exhibited significant methylation percentage losses. H19 CTCF-binding sites are important for the regulation of Igf2 gene expression. The hypomethylation of H19 may contribute to the decreased spermatogenesis in the offspring