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Glucocorticoid Production in the Nervous and Immune Systems: Evidence for a Local HPA Axis HomologThe hypothalamic-pituitary-adrenal (HPA) axis is a critical stress response system in vertebrates. The hypothalamus secretes corticotropin-releasing hormone (CRH), which binds its receptor (CRH-R1) in the anterior pituitary. The anterior pituitary then secretes adrenocorticotropic hormone (ACTH), which binds its receptor (MC2R) in the adrenal glands and stimulates secretion of glucocorticoids into the bloodstream. Glucocorticoids are critical modulators of neural and immune system development. During early development (postnatal day (PND) 2 to 12), mice show decreased adrenal glucocorticoid secretion at baseline and in response to stressors, termed the stress hyporesponsive period (SHRP) (1). Traditionally, glucocorticoids have been thought to be synthesized only in the adrenal glands. However, recent evidence demonstrates that glucocorticoids are also produced in extra-adrenal tissues, such as the brain and lymphoid organs (2). This may be of particular importance during the SHRP, as local production allows glucocorticoid modulation of specific tissues and cells, without general effects throughout the organism. Importantly, the factors that regulate local glucocorticoid production remain unknown. To study the regulation of local glucocorticoid production, we examined whether mediators of the HPA axis are locally expressed at baseline and in response to an immune stressor. We assessed systemic and local glucocorticoid levels in neonatal (PND5) C57BL/6J mice 4hr after an immune challenge with lipopolysaccharide (50µg/kg i.p.) or vehicle control. We examined blood, microdissected brain regions (prefrontal cortex, hippocampus, hypothalamus), and lymphoid organs (thymus, spleen, bone marrow). A panel of 7 steroids was measured via liquid chromatography tandem mass spectrometry (LC-MS/MS). Gene expression of Crh, Crh-R1, Pomc, and Mc2r was quantified via qPCR. Preliminary data indicate that corticosterone was 2-fold higher in tissues than in blood after an immune stressor. The thymus expressed all genes of interest, supporting the existence of a local HPA axis “homolog” in the thymus. Brain, spleen and bone marrow expressed a subset of the genes of interest. These exciting data demonstrate that all the mediators of the HPA axis are locally expressed within the thymus, likely to regulate thymocyte development and reactivity. Greater understanding of local glucocorticoid production will provide crucial insight into neural and immune development and function. Reference: (1) Sapolsky et al., Brain Res Rev. 1986 11(1):65-76. (2) Taves et al., Endocrinology. 2015 156(2):511-522.

ENDO 2020

Glucocorticoid Production in the Nervous and Immune Systems: Evidence for a Local HPA Axis Homolog

ENDO 2021

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Pparg is a nuclear receptor that regulates glucose and lipid metabolism. Thiazolidinediones (TZD) are PPARG agonists that may reduce hepatic steatosis through their effects in adipose tissue. However, some studies suggest that expression and activation of hepatocyte Pparg promotes steatosis. In this study, we have assessed the relevance of hepatocyte Pparg, and its TZD-mediated activation in the development and/or reduction of steatosis, with adult-onset hepatocyte-specific Pparg knockout (PpargΔHep) mice. We reported that a single iv injection of AAV8-TBG-Cre in Pparg-floxed mice, knocked out hepatocyte Pparg expression (PpargΔHep mice), and that prevented diet-induced steatosis. In this study, a group of 5 wk-old Pparg-floxed mice were fed a low fat (LF) or a high fat (HF) diet for 7 weeks before generating control and PpargΔHep mice. Then, half of the HF-fed mice in each group were switched to a HF diet supplemented with the TZD Rosiglitazone maleate, for 5 weeks. HF diet induced mild obesity (36.8 +/- 1.4 g of body weight [BW]), while TZD slightly increased BW (41.3 +/- 1.3 g) and insulin sensitivity. Liver weight was not altered in HF-fed mice with or without TZD, and we did not observe any effect induced by PpargΔHep. Due to the mild phenotype observed in this cohort, we generated a 2nd cohort adjusting for age and length of diet. Briefly, 10 wk-old Pparg-floxed mice were fed a LF or HF diet for 16 weeks before generating control and PpargΔHep mice. Then, half of the HF-fed mice in each group were switched to a HF diet supplemented with Rosiglitazone maleate for 7 weeks. In this group of mice, HF diet induced obesity (50.1 +/- 1.05 g BW), and increased liver weight independent of hepatic Pparg expression. TZD treatment exacerbated obesity (62.4 +/- 1.2g BW) and adiposity, but increased insulin sensitivity as compared to mice fed a HF diet without TZD. Interestingly, PpargΔHep mice fed a HF diet with TZD showed enlarged subcutaneous white and brown adipose tissue weight, and a dramatic reduction in liver weight and steatosis as compared to obese control mice treated with TZD. The expression of hepatic Cd36, Cidea, Cidec, and Fabp4 was increased by TZD in a Pparg-dependent manner in HF-fed mice. Altogether, this data suggest that hepatocyte Pparg expression may offset the antisteatogenic actions of TZD in mice with severe obesity. In obese and insulin resistant individuals, TZD-mediated activation of hepatocyte Pparg may exacerbate steatosis.

Hepatocyte Peroxisome Proliferator-Activated Receptor Gamma (PPARG) Offsets the Anti-Steatogenic Effects of Thiazolidinediones in Obese Male Mice

Glucocorticoids are required for metabolic adaptations during times of stress. However, chronic glucocorticoid exposure is associated with metabolic disorders such as insulin resistance. Glucocorticoids mainly convey their signals through an intracellular glucocorticoid receptor (GR). GR is a transcription factor that requires interactions with transcriptional coregulators to modulate the transcription of GR primary target genes, which in turn regulate specific aspects of physiology. Euchromatic Histone Methyltransferase 2 (Ehmt2) is a transcriptional coregulator for GR that can act as a corepressor or a coactivator. We found that glucocorticoid-induced insulin resistance was exacerbated when Ehmt2 levels were reduced in the liver. Intriguingly, this phenotype resulted from the transactivation function of Ehmt2. This is because a mutation at the lysine 182 automethylation site, which is required for the coactivation but not the corepression function of Ehmt2, results in similar exacerbated GC-induced insulin resistance. These results suggest that Ehmt2 coactivation dependent GR primary target genes restrict the extent of glucocorticoid-induced insulin resistance. Gene expression analysis identified Dusp4 (a.k.a. Mkp-2) as an Ehmt2 coactivation dependent GR-activated gene, which when overexpressed in liver, attenuated glucocorticoid-induced insulin resistance. Thus, we have identified a novel GR-Ehmt2-Dusp4 axis that plays a key role in controlling the extent of the development of insulin resistance. Notably, the classical view of how GC induce hepatic insulin resistance is that GR activates genes that inhibit insulin signaling and enhance hepatic gluconeogenesis. Our study, however, provides a revolutionary concept in which the extent of GC-induced insulin resistance is controlled by the balance of GR-activated genes that promote insulin sensitivity or insulin resistance.

The Transcriptional Coactivation Function of EHMT2 Restricts Chronic Glucocorticoid Exposure Induced Insulin Resistance

Humans and mice with Melanocortin 4 receptor (MC4R) deficiency remain protected from hyperglycemia despite chronic obesity and insulin resistance. We have observed that elevated glycosuria in MC4R deficient mice protects them from hyperglycemia. Moreover, our results indicate that circulating epinephrine may couple MC4R signaling with kidney glucose reabsorption. However, the direct role of epinephrine in regulating kidney glucose reabsorption remains unclear. We hypothesize that epinephrine is essential for maintaining glucose homeostasis via kidney glucose reabsorption. To test this hypothesis, we performed oral glucose tolerance tests (OGTTs) and intraperitoneal insulin tolerance tests (ITTs) in phenylethanolamine-N-methyltransferase (Pnmt) knockout (KO) mice that specifically lack epinephrine but have normal norepinephrine levels. Pnmt KO mice exhibited reduced insulin sensitivity compared to their Wild-Type (WT) littermates (Area under the curve for ITT: 9,700±256 vs. 8,482±417 mg/dL.min, p<0.05). Paradoxically, we observed improved rather than impaired glucose tolerance in Pnmt KO mice compared to their WT controls (Area under the curve for OGTT: 32,546±1,592 vs. 40,058±1,918 mg/dL.min, p<0.05). To ascertain if Pnmt KO mice, like MC4R deficient mice, show elevated glycosuria, we quantified their 24 urine glucose levels after oral glucose (250 mg) challenge. Indeed, Pnmt KO mice demonstrated elevated glycosuria compared to their WT littermates (Urine glucose: Baseline, 24.63±2.2 vs. 11.14±0.82 mg/dl; post glucose challenge: 67.83±5 vs. 16.09±1.13 mg/dl, p<0.001), again validating the phenotype similar to that of MC4R deficient mice. To determine the glucose transporters involved in mediating elevated glycosuria in the Pnmt KO mice, we measured the levels of different renal glucose transporters using western blot. We found that GLUT2 was decreased by ~26% in Pnmt KO mice compared to their WT littermates. Levels of other glucose transporters were not changed, indicating that suppression of renal GLUT2 mediates elevated glycosuria in the epinephrine deficient mice. We validated the direct effect of epinephrine on GLUT2 levels in vitro using mouse primary renal proximal tubule epithelial cells. Indeed, epinephrine selectively increased GLUT2, but did not affect other glucose transporters in the mouse kidney primary cells. Our findings establish the essential role of epinephrine in glucose reabsorption via the renal glucose transporter GLUT2. Therefore, modulating the renal adrenergic system, or, kidney-specific GLUT2 may afford alternative strategies to regulate glycosuria and ultimately mitigate diabetes.

Epinephrine Is Essential for Normal Renal Glucose Reabsorption via the Glucose Transporter GLUT2

If we knew then what we know now would we have approached the development of Endocrine therapies differently?

During development of the central nervous system, neural cells respond to several external cues that influence cell proliferation, differentiation, axonal growth and synaptogenesis. Thyroid hormone plays a critical role in each of these processes. Previously, we showed that Krüppel-like factor 9 (KLF9), a zinc finger transcription factor, is strongly and directly induced by liganded thyroid hormone receptors, and it mediates the actions of thyroid hormone on neuronal differentiation during late fetal development. Here we analyzed the molecular mechanisms by which KLF9 maintains neuronal structure, and inhibits regeneration in juvenile and adult neuronal cells. We also investigated the actions of the closely related transcription factor KLF13, which is paralogous to KLF9. We engineered the adult mouse hippocampus-derived cell line HT22 to control Klf9 or Klf13 expression by addition of doxycycline. We also used CRISPR/Cas9 genome editing to generate Klf9 or Klf13 knock out (KO), and Klf9+Klf13 double KO HT22 cell lines. To induce neurite outgrowth, we treated cells with forskolin (FK)+IBMX, which increases intracellular cAMP; elevated cAMP is a hallmark of regenerative responses of neurons to injury. Our results show that FK+IBMX increased neurite length in the parent HT22 cell line, and this action was enhanced in Klf9 and Klf13 single KO cells, and was even greater in double KO cells. By contrast, the stimulatory effect of FK+IBMX on neurite outgrowth was blocked by simultaneous forced expression of Klf9 or Klf13 in parent HT22 cells. This effect on neurite outgrowth was confirmed in primary mouse hippocampal neurons, where electroporation of expression plasmids for Klf9 or Klf13 suppressed FK+IBMX-induced neurite extension compared with empty vector-transfected cells. Analysis of RNA-seq data obtained from HT22 cells following 8 hr of induced Klf9 or Klf13 expression showed that both proteins impact the cAMP signaling pathway. Using transfection-reporter assays and chromatin immunoprecipitation, we confirmed that several genes in this pathway are direct targets of both KLFs. Our findings suggest that KLF9 and KLF13 may cooperate to maintain the differentiated state of mammalian neurons and thereby block regeneration, in part, by repressing the cAMP signaling pathway.

Kruppel-Like Factors 9 and 13 Cooperate to Maintain Mammalian Neuronal Differentiation

Background Genetic mutations and histological appearances suggest that APCCs are precursors to some aldosterone producing adenomas (APA). They are hypothesised to contribute to post-operative non-cure and recurrence of primary aldosteronism (PA) but are currently undetectable pre-operatively. SLC35F1 is a possible nucleotide sugar transporter. On microarray it is highly expressed in APCCs, but not in the rest of the adrenal cortex (1). Our aim was to investigate the role of SLC35F1 in APCCs, determine its subcellular localisation and establish whether expression is consistent with pathological APCC subtypes (as suggested by recent evidence from in situ metabolomic studies (2)). Methods Comparative bioinformatic analysis of the SLC35F1 amino acid sequence was carried out. Ex vivo 4uM adrenal sections, from 6 PA patients in the MATCH study, were stained on serial sections with anti-CYP11B2 (Gomez-Sanchez) or anti-SLC35F1 (Novus NBP1-86755). In vitro, H295R cells were transfected with SLC35F1 cDNA. Subcellular localisation of SLC35F1-GFP was studied by comparison to organelle markers (golgin 97, RAB11, wheat germ agglutinin, calnexin and Tom20) using confocal microscopy. Overexpression and siRNA knock-down in H295R cells was correlated to aldosterone production. Results SLC35F1 is a decamembrane-spanning transporter molecule predicted to have a negatively charged pocket in the substrate binding site, implying a transport substrate with a positive charge. Strong staining of CYP11B2 in clusters of cells in adrenal cortex, consistent with APCCs, were present in all six adrenal glands (25 APCCs). Serial sections showed specific SLC35F1 staining of APCCs, in cytoplasm and plasma membrane. SLC35F1 staining was absent from normal cortex. 12 APCCs (48%) were SLC35F1-negative. Visualisation of transiently expressed SLC35F1 demonstrated localisation to the endoplasmic reticulum in H295R cells (Pearson’s coefficient r=0.758) with no plasma membrane localisation (r=-0.07). Preliminary transfection data suggest direct involvement in aldosterone production. Conclusions Expression of SLC35F1 in the plasma membrane and cytosol of APCC cells supports a role in pathological aldosterone production by APCCs. The inferred transport substrate of SLC35F1 is the NAD(P)(H) precursor, nicotinamide riboside, a positively-charged nucleotide sugar. If confirmed, the essential requirement for NAD(P)H in steroidogenesis, and heterogeneity of SLC35F1-staining in APCCs, is consistent with a metabolically active, possibly pathological, subtype of APCCs. Detection of SLC35F1 in vivo may therefore facilitate sub-classification of PA patients.1). Nishimoto et. al. PNAS. 2015 Aug 18;112(33):E4591-9. 2). Murakami et. al. 2019 Hypertension. In press.

Expression of SLC35F1 in the Plasma Membrane of Cells of Aldosterone Producing Cell Clusters (APCCs) and Its Possible Role in Aldosterone Synthesis

NAFLD (Non Alcoholic Fatty Liver Disease) has become the most common cause of chronic liver disease in many developed countries worldwide and represents a major health concern. The prevalence of NAFLD is sexually dimorphic with men suspected to be more susceptible to the development of hepatic steatosis than women. Women are mostly protected until hormonal imbalance induced by menopause. Nuclear receptor CAR (Constitutive Androstan Receptor) is at the crossroads between endocrine and metabolic regulations and could therefore represent an interesting therapeutic target. It is primarily expressed in the liver and involved in the catabolism of hormones such as thyroid hormones, corticosteroids and estrogens. In addition, several studies reveal a metabolic role of CAR through regulation of major hepatic pathways such as neoglucogenesis, beta-oxidation and de novo lipogenesis. Our research is aimed at better understanding the role of CAR using a mouse model genetically deficient for CAR. To explore the metabolic functions of CAR, knock-out male and female mice were subjected to a high fat diet (HFD) for 16 weeks. Concomitant CAR deletion and high fat diet induces sexually dimorphic metabolic disorders. Knock-out of CAR in males exacerbates HFD-induced fasted hyperglycemia whereas in females, it aggravates body weight gain and adipose tissue accumulation. In accordance with epidemiological studies revealing a protection of women from the development of hepatic steatosis, HFD-fed WT female mice present less important hepatic steatosis than HFD-fed WT male mice. However, following CAR deletion, HFD-fed female mice develop a severe steatosis along with important hepatic injury. Ongoing studies aim to understand the transcriptomic and endocrine dysregulations that may explain these phenotypes. These results reveal a previously unrecognized dimorphic role of CAR in energy homeostasis and highlights its involvement in the protection of female mice towards the development of hepatic steatosis. Overall, this research provides further insights in the pathogenesis of NAFLD and its dimorphic prevalence.

Nuclear Receptor CAR Protects Female Mice from the Development of Diet-Induced Nonalcoholic Fatty Liver Disease

Adrenal corticosteroids, such as glucocorticoids and mineralocorticoids, are indispensable for mediating response to stress, development, limiting inflammation, and maintaining energy and fluid homeostasis. These hormones exert their actions via binding to two closely related nuclear receptors, the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). The GR has low affinity for corticosteroids, but is expressed in nearly every cell. In contrast, the MR shows a higher affinity for corticosteroids and its expression is largely confined to those tissues where electrolyte exchange and fluid balance are required. GR and MR act as ligand-activated transcription factors which, following interaction with co-regulators and DNA responsive elements, either promote or repress gene transcription. The affinity for the same ligands, structural homology, and binding to the same DNA regions suggest GR and MR can compensate for each other’s actions. Yet, there are specific glucocorticoid and mineralocorticoid-mediated responses indicating GR-MR functional diversity. To investigate this interplay, we developed U-2 OS (human osteosarcoma) cell lines stably expressing GR, MR, and both GR and MR (GRMR). Immunofluorescence analysis showed that treatment of these cell lines with 1 nM of the synthetic glucocorticoid dexamethasone (Dex) induced nuclear traslocation of GR and MR. Conversely, treatment with 1 nM of aldosterone (Aldo) promoted nuclear translocation of the MR only. Moreover, Proximity Ligation Assay revealed that, in the absence of ligand, GR associated with MR in the cytoplasm and, upon 1 nM Dex exposure, GR-MR dimers were detected in the nucleus of GRMR cells. Surprisingly, nuclear GR-MR dimers were also detected in the presence of Aldo, suggesting that it is necessary to activate at least one receptor to induce nuclear traslocation of the heterocomplex. To decipher the functional contribution of GR-MR dimers in the transcriptional response of GR to Dex and MR to Aldo, we performed RNA-seq in GR, MR, and GRMR cells treated with 1 nM of Dex or Aldo. Transcriptome analysis revealed that Dex-activated GR regulated the transcription of 6180 genes. Co-expression of MR resulted in a blunted Dex-mediated gene response which affected only 1608 genes, suggesting a functional antagonism of MR. Aldo-activated MR regulated the transcription of 1660 genes. However, co-expression of GR expanded the Aldo-mediated gene response to 3150 genes. Strikingly, 74% of these genes were also regulated by Dex via GR, suggesting that GR-MR dimers in the presence of aldosterone are able to mimic the glucocorticod transcriptional response. Our data suggest that the role of distinct GR and MR homo- and hetero-dimers is relevant for regulating gene expression. Dissecting the mechanism and investigating the cross-talk between GR and MR may be useful to understanding these two receptors in heath and disease.

When the Glucocorticoid Receptor Meets the Mineralocorticoid Receptor in the Nucleus of Human Cells

The transcription factor OTX2 is implicated in pituitary, ocular and craniofacial development. Mutations have been described in patients with variable congenital hypopituitarism (CH) ranging from isolated growth hormone deficiency (IGHD) to combined pituitary hormone deficiency (CPHD) with/without an ectopic posterior pituitary (EPP).We aimed (i) to establish the contribution of OTX2 mutations in the etiology of CH in a sub-cohort of patients and to study their functional consequences and (ii) establish a detailed human OTX2 expression profile in a hypothalamo-pituitary (HP) context. We screened 127 patients from national (n=103) and international centers (n=24) on the septo-optic dysplasia (SOD) spectrum with variable eye abnormalities. Eye abnormalities included micro/anophthalmia, retinal dystrophy and/or coloboma in 29 of these patients, with the rest having optic nerve hypoplasia (ONH). An EPP was reported on MRI in 35 patients. The cohort previously tested negative for mutations in HESX1, SOX2, SOX3, PROKR2 and GH1. Transactivation assays involved a dual-luciferase reporter in murine hypothalamic GT1-7 neurons transiently transfected with OTX2 constructs. In situ hybridization was performed to analyze human brain OTX2 expression during embryogenesis. Seven heterozygous OTX2 changes were identified: two chromosomal deletions spanning OTX2 in patients with micro/anophthalmia, GHD and an EPP, with one patient having cerebellar hypoplasia. Three missense substitutions resulting in truncated proteins: (i) the previously reported p.S138* and (ii) p.C170*, in two patients with retinal dystrophy, EPP and IGHD respectively, and (iii) the novel p.E79* in a patient with micro/anophthalmia, EPP and CPHD. A novel insertion-deletion resulting in a truncated protein p.S167* in a patient with microphthalmia, GHD, ONH, EPP and an enlarged abnormal pituitary, and a novel deletion resulting in a frameshift p.Val139Aspfs*39 in a patient with microcephaly, microphthalmia, ONH and an EPP were also identified. The human OTX2 variants caused a significant reduction in transactivation compared to wild type. Our gene expression data identified human OTX2 transcripts in the posterior pituitary, retina, ear, thalamus, choroid plexus, and in the hypothalamus during embryogenesis, but not in RP. To conclude, we identified OTX2 variants in 7 unrelated CH patients with eye abnormalities including 3 with retinal dystrophy and one with a cerebellar abnormality. As OTX2 is involved at multiple levels during HP development, these patients should be monitored for evolving endocrinopathies. Human OTX2 is expressed in the posterior pituitary, the retina and the ear at CS19 and 20 (between 6-7 weeks gestation), and in areas of the hindbrain at CS23, but not in RP at any stage analyzed in this study. The endocrine phenotypes in patients with OTX2 mutations are most likely of hypothalamic origin.

OTX2 Mutations in Congenital Hypopituitarism Patients

We implemented single-cell RNA sequencing (scRNAseq) technology as a discovery tool to identify factors enriched in differentiated thyrotropes. Thyroid-stimulating hormone (TSH) is produced in the pars distalis of the anterior pituitary (AP) and primarily acts on the thyroid gland to regulate metabolism through T3/T4. However, TSH is also produced by cells in the pars tuberalis (PT), which is comprised of a thin layer of cells that extends rostrally from the pars distalis along the pituitary stalk to the median eminence in the hypothalamus. TSH produced by PT thyrotropes acts on hypothalamic tanycytes to regulate seasonal reproduction. PT thyrotropes likely descend from rostral tip thyrotropes that arise at e12.5 of mouse development, which transcribe the TSH beta subunit (Tshb) without detectable expression of the transcription factor POU1F1. POU1F1 is required for Tshb transcription in thyrotropes of the adenohypophysis, and it acts synergistically with GATA2 to drive cell fate. The molecular mechanisms driving Tshb expression independently of Pou1f1 in PT thyrotropes are unclear.Thyrotropes are the least abundant endocrine cell-type in the pituitary gland. We used genetic labeling and fluorescence-activated cell sorting (FACS) to enrich for thyrotropes for single-cell sequencing. We performed scRNAseq on 7-day-old GFP-positive pituitary cells from Tshb-Cre; R26-LSL-eYFP and intact whole pituitaries, recovering more than 15,000 cells altogether. We observe two distinct populations of cells expressing Tshb. The larger thyrotrope population has approximately twenty fold higher levels of Tshb and five fold higher Cga transcripts than the smaller population, and they are also distinguished by expression of Pou1f1, TSH-releasing hormone receptor (Trhr), and deiodinase 2 (Dio2), consistent with expectations for AP thyrotropes. The smaller thyrotrope population does not express Pou1f1, but those cells are characterized by expression of TSH receptor (Tshr) and melatonin receptor 1A (Mtnr1a), consistent with expectations for PT thyrotropes. They express mildly increased levels of Eya3 and Six1, although these genes are expressed in other cell-types including AP thyrotropes, stem cells, and gonadotropes. They have two-fold higher levels of Gata2 transcripts and uniquely express the transcription factor Sox14. SOX14 is a SoxB2 family transcription factor that counteracts the transcriptional activity of SoxB1 family members, such as Sox2. In conclusion, our scRNAseq has identified novel markers of PT thyrotropes and unveils novel insights into the similarities and differences in the development and function of pituitary thyrotrope subpopulations.

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Glucocorticoid Production in the Nervous and Immune Systems: Evidence for a Local HPA Axis Homolog

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