Dioxin Disrupts Thyroid Hormone and Glucocorticoid Induction of klf9, a Master Regulator of Frog Metamorphosis

Frog metamorphosis, the development of an air-breathing froglet from an aquatic tadpole, is under endocrine control by thyroid hormone (TH) and glucocorticoids (GC). Metamorphosis is susceptible to disruption by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an aryl hydrocarbon receptor (AHR) agonist. Krüppel-Like Factor 9 (klf9), an immediate early gene in the endocrine-controlled cascade of expression changes that govern metamorphosis, can be synergistically induced by both hormones. This process is mediated by an upstream enhancer cluster, the klf9 synergy module (KSM). klf9 is also a target of the AHR. We measured klf9 mRNA expression following combined exposures to triiodothyronine (T3), corticosterone (CORT), and TCDD in the Xenopus laevis cell line XLK-WG. klf9 was induced 6-fold by 50 nM T3, 4-fold by 100 nM CORT, and 3-fold by 175 nM TCDD. Co-treatments of CORT and TCDD or T3 and TCDD induced klf9 mRNA 7- and 11-fold, respectively, while treatment with all 3 agents induced a 15-fold increase. Transactivation assays examined regulatory sequences from the Xenopus tropicalisklf9 upstream region. KSM-containing segments mediated a strong T3 response and a larger T3/CORT response, while induction by TCDD was mediated by a region ~1 kb farther upstream containing 5 AHR response elements. Unexpectedly, this region also supported a CORT response in the absence of readily- identifiable glucocorticoid responsive elements, suggesting mediation by protein-protein interactions. A similar AHRE cluster is positionally conserved in the human genome, and klf9 was induced by TCDD and TH in HepG2 cells. These results indicate that AHR binding to an upstream AHRE cluster represents an initiating event in TCDD disruption of klf9 expression and metamorphosis.

Evaluation of surgery and radiosurgery for acromegaly: A review of efficacy, complications, and follow-up

Background: Acromegaly is a rare disease caused by an over-increase in growth hormone (GH) and insulin-like growth factors. If left untreated, acromegaly is associated with many complications and increased mortality. The three modalities of treatment for this disease are surgery, pharmacotherapy, and radiotherapy. Another treatment option is stereotactic radiosurgery (SRS), which is used as an adjunct and alternative treatment in patients with acromegaly who are not suitable options for surgery. Methods: The present study is a review study conducted by searching the databases of Elsevier, PubMed, Springer, and Wiley, and using the keywords of acromegaly, treatment, transsphenoidal surgery, and radiosurgery. Fifteen studies, which had been performed between 2010 and 2021, were selected for review. Results: The results of these studies indicated that the use of SRS (LINAC SRS and GKRS) after surgery and medical treatment, before surgery and during radiotherapy improve biochemical and endocrine control and the quality of life of patients. However, due to some side effects of these treatments, it is necessary to conduct further studies in this field. Conclusion: All three modalities of treatment would be effective in acromegaly if used with appropriate indication in right sequence. Keywords: Pituitary Neoplasms, Pituitary Gland, Radiotherapy, Radiosurgery, Acromegaly

Orphan Nuclear Receptor ERRγ Is a Transcriptional Regulator of CB1 Receptor-Mediated TFR2 Gene Expression in Hepatocytes

Orphan nuclear receptor estrogen-related receptor γ (ERRγ) is an important transcription factor modulating gene transcription involved in endocrine control of liver metabolism. Transferrin receptor 2 (TFR2), a carrier protein for transferrin, is involved in hepatic iron overload in alcoholic liver disease (ALD). However, TFR2 gene transcriptional regulation in hepatocytes remains largely unknown. In this study, we described a detailed molecular mechanism of hepatic TFR2 gene expression involving ERRγ in response to an endocannabinoid 2-arachidonoylglycerol (2-AG). Treatment with 2-AG and arachidonyl-2′-chloroethylamide, a selective cannabinoid receptor type 1 (CB1) receptor agonist, increased ERRγ and TFR2 expression in hepatocytes. Overexpression of ERRγ was sufficient to induce TFR2 expression in both human and mouse hepatocytes. In addition, ERRγ knockdown significantly decreased 2-AG or alcohol-mediated TFR2 gene expression in cultured hepatocytes and mouse livers. Finally, deletion and mutation analysis of the TFR2 gene promoter demonstrated that ERRγ directly modulated TFR2 gene transcription via binding to an ERR-response element. This was further confirmed by chromatin immunoprecipitation assay. Taken together, these results reveal a previously unrecognized role of ERRγ in the transcriptional regulation of TFR2 gene expression in response to alcohol.

Micronutrients impact the gut microbiota and blood glucose

Micronutrients influence hormone action and host metabolism. Dietary minerals, trace elements and vitamins can alter blood glucose and cellular glucose metabolism and several micronutrients are associated with risk and progression of type 2 diabetes. Dietary components, microbes and host immune, endocrine, and metabolic responses all interact in the intestine. There has been a focus on macronutrients modifying the host-microbe relationship in metabolic disease. Micronutrients are positioned to alter host-microbe symbiosis that participates in host endocrine control of glucose metabolism. Minerals and trace elements can alter the composition of the intestinal microbiota, gut barrier function, compartmentalized metabolic inflammation, cellular glucose transport and endocrine control of glucose metabolism, including insulin and thyroid hormones. Dietary vitamins also influence the composition of the intestinal microbiota and vitamins can be biotransformed by gut microbes. Host-microbe regulation of vitamins can alter immunity, lipid and glucose metabolism, and cell fate and function of pancreatic beta cells. Causal effects of micronutrients in host-microbe metabolism are still emerging and the mechanisms linking dietary excess or deficiency of specific micronutrients to changes in gut microbes directly linked to metabolic disease risk are not yet clear. Dietary fiber, fat, protein, and carbohydrates are key dietary factors that impact how microbes participate in host glucose metabolism. It is possible that micronutrient and microbiota-derived factors also participate in host-microbe responses that tip the balance in endocrine control of host glucose metabolism. Dietary micronutrients should be considered, tested, and controlled in preclinical and clinical studies investigating host-microbe factors in metabolic diseases.

Endocrinology, Vitamin D and the UK’s Covid-19 Disaster

The formation of cholecalciferol (Vitamin D3) in skin depends on solar UVB to break the B ring of 7-dehydrocholesterol. Its discovery more than a century ago resulted from the identification of rickets as due to deficient sunshine in latitudes far from the equator, exacerbated by the air pollution, factory work and indoor living. Rickets resulted from defective endocrine control of blood calcium, and was accompanied by epidemic tuberculosis from failure of the D3-dependent first-line immune system. The influenza pandemic of 2018 revealed the need for D3 to fight viruses. Half a century later the systemic hormone role of 1,25(OH)D3 of renal origin, under control of PTH, was a major stimulus to understanding the mechanism of action via the VDR-RXR heterodimer. It was soon realised that 1,25(OH)D3 is also produced and acts locally in many organs and tissues provided that there are adequate reserves of the (protein-bound) blood storage form, 25(OH)D. This is the common pool for 1-hydroxylation by any cells that need local activation of VDR for induction of specific genes. In the case of the immune system, the trigger is foreign proteins recognised as ‘non-self’. Local production and action of 1,25(OH)D, and then its local destruction by 24-hydroxylation must all occur below the ‘endocrine radar’, so as not to interfere with systemic calcium control. Coronaviruses through their ‘spike’ protein are internalised by interacting with the ACE-2 receptor, which in turn is down-regulated by Vitamin D. In the process, 25(OH)D is hydroxylated to the active 1,25(OH)D, which must later be degraded to 1,24,25(OH)D. So it is to be expected that when 25(OH)D reserves are low at the onset of infection, they will fall further, allowing virus to enter the cells and trigger a cytokine storm and other damage. Blood PTH will rise to claim any residual 25(OH)D for the dominating systemic role in calcium homeostasis. It follows that intake of vitamin D3 should always be much more than the minimum claimed by the globally-active endocrine system. Unfortunately, the UK’s Specialised Advisory Committee on Nutrition (SACN), does not recognise this. It is dominated by nutritionists, even though food sources of D3 are for most non-existent, and of D2, the vegetable substitute, highly variable. The 400IU of D3 reluctantly recommended for those ‘at risk’, based on endocrinology alone, is grossly inadequate; 4,000IU daily is needed to maintain a blood 25(OH)D at more than 30 ng/ml (75 nmol/l), and provide sufficient reserve for its many autocrine and paracrine functions. The dangers of letting the dominant endocrine function of 1,25(OH)D in ionic calcium control dictate the level of D3 supplements, have once again been underlined by the Covid-19 disaster.