Abstract The calcium-sensing receptor (CaSR) is a ubiquitously expressed multifunctional G protein-coupled receptor. Several studies reported that the CaSR plays an anti-inflammatory and anti-tumorigenic role in the intestine, and that it is down-regulated during colorectal carcinogenesis. We hypothesized that intestine-specific positive allosteric CaSR modulators (type II calcimimetics) could be used for the treatment of intestinal pathologies. Therefore, the aim of this study was to determine the effect of pharmacological stimulation of CaSR on gene expression in vitro and on tumor growth in vivo . We stably transduced two colon cancer cell lines (HT29 and Caco2) with lentiviral vectors containing either the CaSR fused to GFP or GFP only. Using RNA sequencing, RT-qPCR experiments and ELISA, we determined that CaSR over-expression itself had generally little effect on gene expression in these cells. However, treatment with 1μM of the calcimimetic NPS R-568 increased the expression of pro-inflammatory factors such as IL-23α and IL-8 and reduced the transcription of various differentiation markers in the cells over-expressing the CaSR. In vivo , neither the presence of the CaSR nor p.o . treatment of the animals with the calcimimetic cinacalcet affected tumor growth, tumor cell proliferation or tumor vascularization of murine HT29 xenografts. In summary, CaSR stimulation in CaSR over-expressing cells enhanced the expression of inflammatory markers in vitro , but was not able to repress colorectal cancer tumorigenicity in vivo . These findings suggest potential pro-inflammatory effects of the CaSR and type II calcimimetics in the intestine.

Calcimimetic

10.1101/2020.07.09.195255

Cite

Citations (1)

Cardiometabolic Phenotyping of Patients With Familial Hypocalcuric Hypercalcemia

The Journal of Clinical Endocrinology & Metabolism (2014)

Peter Wolf Martin Krššák Yvonne Winhofer Christian Anderwald Elisabeth Zwettler

Heterozygous inactivating mutations of the calcium-sensing receptor (CaSR) gene cause alterations in calcium metabolism [familial hypocalciuric hypercalcemia (FHH)]. In addition, calcium-sensing receptor is expressed in the myocardium and endocrine cells including pancreatic islets, enteroendocrine cells, and adipose tissue.To discern whether FHH is associated with cardiometabolic alterations of clinical significance, endocrine responses to systemic calcium stimulation and oral glucose tolerance tests were performed. Ectopic lipid deposition and heart function were assessed using magnetic resonance spectroscopy/imaging.Eight FHH patients and nine controls matched for anthropometric characteristics (age 45 ± 18 y; body mass index 29 ± 4 vs 29 ± 6 kg/m(2)) were studied to determine cardiac function, ectopic and visceral lipid content, and insulin sensitivity and secretion.Insulin sensitivity (clamp-like index: 4.5 ± 0.6 vs 4.3 ± 0.4 mg/kg · min), basal (insulin secretion rate: 266 ± 33 vs 218 ± 25 pmol/min), and glucose-stimulated β-cell function (adaptation index: 180.2 ± 12.2 vs 176.2 ± 17.4) as well as calcium-stimulated insulin secretion were comparable between FHH and controls, respectively. Ectopic lipid content in liver [3.75% (1.4%; 34%) vs 4.18% (0.9%; 28%)], soleus muscle (1.07% ± 0.38% vs 1.02% ± 0.56 %), and myocardium (0.39% ± 0.3% vs 0.32% ± 0.1 %), visceral and sc adipose tissue distribution (0.51 ± 0.16 vs 0.47 ± 0.17) as well as heart function (ejection fraction: 71.5% ± 8% vs 72.8% ± 8 %; E to A ratio: 1.4% ± 0.6% vs 1.3% ± 0.7%) were not different between the groups.Despite comprehensive cardiometabolic phenotyping, no alterations in myocardial function, lipid distribution, or glucose metabolism were observed in FHH. Thus, FHH might reflect a laboratory finding without any relevant cardiometabolic alterations.

10.1210/jc.2014-1541

Cite

Citations (20)

Maternal Diet Influences Human Milk Protein Concentration and Adipose Tissue Marker

Nutrients (2023)

Christoph Binder Sabina Baumgartner‐Parzer Liliana-Imi Gard Angelika Berger Alexandra Thajer

(1) Background: Adequate protein intake plays an essential role in growth and neurodevelopment, especially in preterm infants. We investigated the effects of maternal diet and body mass index (BMI) on human milk (HM) composition. (2) Methods: HM samples were obtained from 136 lactating mothers (BMI: 18.0−36.7 kg/m2), of which 93% gave birth to preterm infants. Macronutrient content in HM was measured by mid-infrared transmission spectroscopy. Leptin and adiponectin were analyzed using appropriate ELISAs. Maternal diet was determined by 24-h recall. (3) Results: Significant positive associations were found between protein, fat, carbohydrate and energy intake, and levels of corresponding macronutrients in HM, especially in protein concentrations (p < 0.001). An increased protein intake was positively correlated with adiponectin (p < 0.001) and leptin (p = 0.035) in HM. Maternal BMI was positively associated with a higher protein level in HM (p < 0.05), as well as with a higher dietary protein intake (p < 0.05). (4) Conclusions: Knowledge of maternal diet and BMI impacting HM composition is essential to optimize the feeding of newborn infants. This is especially relevant in the nutritional management of preterm infants; it can be utilized in approaches to improve growth rates and the appropriate development of infants and to prevent obesity.

10.3390/nu15020433

Cite

Citations (11)

A Rare Duplicated 21-Hydroxylase Haplotype and ade NovoMutation: A Family Analysis

The Journal of Clinical Endocrinology & Metabolism (2003)

Sabina Baumgartner‐Parzer P. Nowotny W Waldhäusl H. Vierhapper

21-Hydroxylase (21-OH) genotyping was performed in clinically unaffected family members of a congenital adrenal hyperplasia (CAH) index patient (Prader stage 3), who is a compound heterozygous carrier of the I172N (exon 4) and the intron2 splicing mutations. Whereas the latter mutation could be traced to the father, the exon 4 aberration represents a de novo mutation (accounting for 1% of CAH alleles) harbored on an unaffected allele, which was inherited from the mother. Although clinically and biochemically unaffected, the patient's brother was found to be compound heterozygous for intron2splice (paternal allele) and Q318X in exon 8 (maternal allele). As shown by PCR-based sequence and Southern blot analysis, the maternal haplotype, inherited by the brother, has a duplicated CYP21B (functional) gene, one of which carries a Q318X mutation. This duplicated Q318X-affected haplotype is the first of its kind among 800 alleles screened for 21-OH deficiency in our laboratory and has to date been reported only in three Swedish CAH patients, all of them bearing an intron2splice and a Q318X mutation. This family analysis highlights the complexity of the CYP21/CYP21P(pseudogene) loci and the difficulties of 21-OH genotyping.

Compound heterozygosity

Phenylalanine hydroxylase

10.1210/jc.2002-021589

Cite

Citations (16)

The role of GLI1 in pituitary tumor formation and pituitary cell survival

Endocrine Abstracts (2013)

Katharina Lampichler Patricio Ferrer Greisa Vila Anton Luger Engelbert Knosp

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

10.1530/endoabs.32.p826

Cite

Citations (1)

Early Diagnosis and Curative Therapy of Medullary Thyroid Carcinoma by Routine Measurement of Serum Calcitonin in Patients with Thyroid Disorders

Thyroid (2005)

H. Vierhapper Bruno Niederle Ch. Bieglmayer Klaus Kaserer Sabina Baumgartner‐Parzer

To identify patients with medullary thyroid carcinoma (MTC) at a potentially curable stage of the disease, serum concentrations of calcitonin (hCT) were determined in 14,000 patients (including 10,158 patients with thyroid nodules) referred to a thyroid outpatient clinic. Excluding patients in whom elevated basal hCT concentrations had already been known at the time of their referral, 507 patients with thyroid nodules presented basal concentrations of hCT of more than 10 pg/ml. Following stimulation by IV pentagastrin (0.5 microg/kg BW), hCT concentrations of more than 100 pg/ml were seen in 103 patients. This group included 32 new cases of MTC (29 patients with sporadic MTC and 3 new index cases of the familial form) and 43 patients with C cell hyperplasia (CCH). Among the 3,843 patients without thyroid nodules, 2 were found to harbor sporadic MTC while 4 had CCH. As compared to 1.1 cases of MTC per 1,000 patients with nodular thyroid diseases diagnosed in our institution before hCT screening was begun, 3.2 cases of MTC per 1,000 patients were identified when hCT was determined in all patients with thyroid nodules. The determination of hCT in all patients with thyroid nodular disease facilitates the timely diagnosis of MTC, thus providing the chance of curative surgery.

Thyroid Nodules

Pentagastrin

10.1089/thy.2005.15.1267

Cite

Citations (112)

Erratum

Hormone Research in Paediatrics (2016)

Judith Stoklasova Jana Kaprova Fotini-Eleni Karachaliou Elpis-Athina Vlachopapadopoulou Marina Vakaki

10.1159/000451075

Cite

Citations (0)

Leptin Increases Hepatic Triglyceride Export via a Vagal Mechanism in Humans

SSRN Electronic Journal (2022)

Matthäus Metz Marianna Beghini Peter Wolf Lorenz Pfleger Martina Häckl

Recombinant human leptin (metreleptin) reduces hepatic lipid content in patients with lipodystrophy and overweight non-alcoholic fatty liver disease patients with relative hypoleptinemia independent of its anorexic action. In rodents, CNS leptin signaling increases very-low density lipoprotein triglyceride (VLDL-TG) secretion and reduces hepatic lipid content via the vagus nerve. In this randomized, placebo-controlled, crossover trial we tested whether a comparable mechanism regulates hepatic lipid metabolism in humans. An acute metreleptin injection stimulated hepatic VLDL-TG secretion and reduced hepatic lipid content in fasted, lean men, but failed to do so in metabolically healthy liver transplant recipients, a model for hepatic denervation. In an independent cohort of lean men, vagal stimulation by modified sham feeding replicated the effects of metreleptin on VLDL-TG secretion. Therefore, we propose that leptin has anti-steatotic properties that are independent of food intake by stimulating hepatic VLDL-TG export via a brain-vagus-liver axis.

10.2139/ssrn.4078237

Cite

Citations (0)