Influence of Neonatal Hypothyroidism on Hepatic Gene Expression and Lipid Metabolism in Adulthood

Thyroid hormones are required for normal growth and development in mammals. Congenital-neonatal hypothyroidism (CH) has a profound impact on physiology, but its specific influence in liver is less understood. Here, we studied how CH influences the liver gene expression program in adulthood. Pregnant rats were given the antithyroid drug methimazole (MMI) from GD12 until PND30 to induce CH in male offspring. Growth defects due to CH were evident as reductions in body weight and tail length from the second week of life. Once the MMI treatment was discontinued, the feed efficiency increased in CH, and this was accompanied by significant catch-up growth. On PND80, significant reductions in body mass, tail length, and circulating IGF-I levels remained in CH rats. Conversely, the mRNA levels of known GH target genes were significantly upregulated. The serum levels of thyroid hormones, cholesterol, and triglycerides showed no significant differences. In contrast, CH rats showed significant changes in the expression of hepatic genes involved in lipid metabolism, including an increased transcription of PPARα and a reduced expression of genes involved in fatty acid and cholesterol uptake, cellular sterol efflux, triglyceride assembly, bile acid synthesis, and lipogenesis. These changes were associated with a decrease of intrahepatic lipids. Finally, CH rats responded to the onset of hypothyroidism in adulthood with a reduction of serum fatty acids and hepatic cholesteryl esters and to T3 replacement with an enhanced activation of malic enzyme. In summary, we provide in vivo evidence that neonatal hypothyroidism influences the hepatic transcriptional program and tissue sensitivity to hormone treatment in adulthood. This highlights the critical role that a euthyroid state during development plays on normal liver physiology in adulthood

Systemic Toll-Like Receptor Stimulation Suppresses Experimental Allergic Asthma and Autoimmune Diabetes in NOD Mice

BackgroundInfections may be associated with exacerbation of allergic and autoimmune diseases. Paradoxically, epidemiological and experimental data have shown that some microorganisms can also prevent these pathologies. This observation is at the origin of the hygiene hypothesis according to which the decline of infections in western countries is at the origin of the increased incidence of both Th1-mediated autoimmune diseases and Th2-mediated allergic diseases over the last decades. We have tested whether Toll-like receptor (TLR) stimulation can recapitulate the protective effect of infectious agents on allergy and autoimmunity. Methods and Findings Here, we performed a systematic study of the disease-modifying effects of a set of natural or synthetic TLR agonists using two experimental models, ovalbumin (OVA)-induced asthma and spontaneous autoimmune diabetes, presenting the same genetic background of the non obese diabetic mouse (NOD) that is highly susceptible to both pathologies. In the same models, we also investigated the effect of probiotics. Additionally, we examined the effect of the genetic invalidation of MyD88 on the development of allergic asthma and spontaneous diabetes. We demonstrate that multiple TLR agonists prevent from both allergy and autoimmunity when administered parenterally. Probiotics which stimulate TLRs also protect from these two diseases. The physiological relevance of these findings is further suggested by the major acceleration of OVA-induced asthma in MyD88 invalidated mice. Our results strongly indicate that the TLR-mediated effects involve immunoregulatory cytokines such as interleukin (IL)-10 and transforming growth factor (TGF)-β and different subsets of regulatory T cells, notably CD4+CD25+FoxP3+ T cells for TLR4 agonists and NKT cells for TLR3 agonists. Conclusions/Significance These observations demonstrate that systemic administration of TLR ligands can suppress both allergic and autoimmune responses. They provide a plausible explanation for the hygiene hypothesis. They also open new therapeutic perspectives for the prevention of these pathologies

Focal Hyperinsulinism Due to 2 Novel Paternally Derived Mutations in SUR1 and Kir 6.2

Persistent hyperinsulinemic hypoglycaemia of infancy (PHHI) is heterogeneous condition often due to focal adenomatous hyperplasia of the pancreas. Secretion of insulin is unregulated, resulting in profound hypoglycemia. Mutations in the genes of both subunits of the betacell KATP channel, Kir6.2 (potassium channel) and SUR1 (sulfonylurea receptor) have been associated with the autosomal recessive form of this disorder. Patients harboring SUR1 mutations often do not respond well to diazoxide (D). Generally in focal forms two paternal alleles are present with subsequent alteration of insulin secretion. The lesions can be cured by selective resection, but these lesions are difficult to detect. The definitive diagnostic tool are pancreatic venous sampling (PVS) and 18Fluoro L-DOPA>positron emission tomography (PET-DOPA). Patient was born at term (BW 4.1 kg), soon after birth he developed hypoglycemia occasionally symptomatic with tremors and hypotonia, required increased glucose therapy (9mg/kg/min, i.v.) despite milk administration (75cc/kg/day). No response to glucagon (0.5mg/kgday i.v.) and D (20mg/kg/day, per os). Good response to octreotide injections (32.2 microgr/kg/day, s.c.). Pancreatic biopsy, genetic study and PETDOPA were performed. Pancreatic biopsy on our patient shows normal cell nuclei, no evidence of diffuse disease. Genetics demonstrated he has 2 paternally derived mutations in SUR1 and Kir 6.2, causing abnormal insulin secretion (which type of mutation?). The whole body examination with PETDOPA scan demonstrated a very intensive focus in the uppermost area of the corpus of the pancreas.In our patient, as suspected by no response to D, SUR1 mutation was demonstrated. Moreover, like our child, we suggest that all patients with PHHI D resistant should have PET-DOPA that represents a noninvasive method for the identification and localisation of focal PHHI. Focal forms of PHHI should be operated because complete cure without risk of diabetes