Porcupine inhibitors impair trabecular and cortical bone mass and strength in mice
WNT signaling is involved in the tumorigenesis of various cancers and regulates bone homeostasis. Palmitoleoylation of WNTs by Porcupine is required for WNT activity. Porcupine inhibitors are under development for cancer therapy. As the possible side effects of Porcupine inhibitors on bone health are unknown, we determined their effects on bone mass and strength. Twelve-week-old C57BL/6N female mice were treated by the Porcupine inhibitors LGK974 (low dose = 3 mg/kg/day; high dose = 6 mg/kg/day) or Wnt-C59 (10 mg/kg/day) or vehicle for 3 weeks. Bone parameters were assessed by serum biomarkers, dual-energy X-ray absorptiom...
Source: Journal of Endocrinology - May 31, 2018 Category: Endocrinology Authors: Funck-Brentano, T., Nilsson, K. H., Brommage, R., Henning, P., Lerner, U. H., Koskela, A., Tuukkanen, J., Cohen-Solal, M., Moverare-Skrtic, S., Ohlsson, C. Tags: Research Source Type: research
It's reticulated: the liver at the heart of atherosclerosis
Platelets play a critical role in both the initiation and progression of atherosclerosis, and even more so in the ensuing atherothrombotic complications. Low-dose aspirin remains the mainstay of antiplatelet therapy in high-risk patients by reducing the risk of myocardial ischemia, stroke or death due to cardiovascular disease. However, antiplatelet therapies lose their efficacy in people with diabetes mellitus, increasing the risk of future atherothrombotic events. The molecular mechanisms that promote platelet hyperactivity remain unclear but could be due to glycation-induced conformational changes of platelet membranes ...
Source: Journal of Endocrinology - May 29, 2018 Category: Endocrinology Authors: Nagareddy, P. R., Noothi, S. K., Flynn, M. C., Murphy, A. J. Tags: Review Source Type: research
Impacts of pre- and postnatal nutrition on glucagon regulation and hepatic signalling in sheep
In conclusion, prenatal undernutrition and postnatal overnutrition had similar long-term implications and reduced hepatic glucagon signalling. Glucagon secretory responses to propionate were, however, not related to the prenatal nutrition history, but negatively affected by the postnatal obesogenic diet. The pancreatic α-cell compared to β-cells may thus be less sensitive towards late gestation malnutrition, whereas hepatic glucagon signalling appears to be a target of prenatal programming. (Source: Journal of Endocrinology)
Source: Journal of Endocrinology - May 23, 2018 Category: Endocrinology Authors: Adhikari, B., Khanal, P., Nielsen, M. O. Tags: Research Source Type: research
Phenylmethimazole abrogates diet-induced inflammation, glucose intolerance and NAFLD
Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of both metabolic and inflammatory diseases and has become the leading chronic liver disease worldwide. High-fat (HF) diets promote an increased uptake and storage of free fatty acids (FFAs) and triglycerides (TGs) in hepatocytes, which initiates steatosis and induces lipotoxicity, inflammation and insulin resistance. Activation and signaling of Toll-like receptor 4 (TLR4) by FFAs induces inflammation evident in NAFLD and insulin resistance. Currently, there are no effective treatments to specifically target inflammation associated with this disease. We ...
Source: Journal of Endocrinology - May 14, 2018 Category: Endocrinology Authors: Patton, A., Church, T., Wilson, C., Thuma, J., Goetz, D. J., Berryman, D. E., List, E. O., Schwartz, F., McCall, K. D. Tags: Research Source Type: research
Estrogen receptor subtypes dictate the proliferative nature of the mammary gland
Estrogen induces proliferation of breast epithelial cells and is responsible for breast development at puberty. This tightly regulated control is lost in estrogen-receptor-positive (ER+) breast cancers, which comprise over 70% of all breast cancers. Currently, breast cancer diagnosis and treatment considers only the α isoform of ER; however, there is a second ER, ERβ. Whilst ERα mediates estrogen-driven proliferation of the normal breast in puberty and breast cancers, ERβ has been shown to exert an anti-proliferative effect on the normal breast. It is not known how the expression of each ER (alone or ...
Source: Journal of Endocrinology - May 14, 2018 Category: Endocrinology Authors: Dall, G. V., Hawthorne, S., Seyed-Razavi, Y., Vieusseux, J., Wu, W., Gustafsson, J.-A., Byrne, D., Murphy, L., Risbridger, G. P., Britt, K. L. Tags: Research Source Type: research
APP deficiency results in resistance to obesity but impairs glucose tolerance upon high fat feeding
The amyloid precursor protein (APP) generates a number of peptides when processed through different cleavage mechanisms, including the amyloid beta peptide that is implicated in the development of Alzheimer’s disease. It is well established that APP via its cleaved peptides regulates aspects of neuronal metabolism. Emerging evidence suggests that amyloidogenic processing of APP can lead to altered systemic metabolism, similar to that observed in metabolic disease states. In the present study, we investigated the effect of APP deficiency on obesity-induced alterations in systemic metabolism. Compared with WT littermat...
Source: Journal of Endocrinology - May 14, 2018 Category: Endocrinology Authors: Czeczor, J. K., Genders, A. J., Aston-Mourney, K., Connor, T., Hall, L. G., Hasebe, K., Ellis, M., De Jong, K. A., Henstridge, D. C., Meikle, P. J., Febbraio, M. A., Walder, K., McGee, S. L. Tags: Research Source Type: research
Chorionic somatomammotropin impacts early fetal growth and placental gene expression
Several developmental windows, including placentation, must be negotiated to establish and maintain pregnancy. Impaired placental function can lead to preeclampsia and/or intrauterine growth restriction (IUGR), resulting in increased infant mortality and morbidity. It has been hypothesized that chorionic somatomammotropin (CSH) plays a significant role in fetal development, potentially by modifying maternal and fetal metabolism. Recently, using lentiviral-mediated in vivo RNA interference in sheep, we demonstrated significant reductions in near-term (135 days of gestation; dGA) fetal and placental size, and altered fetal l...
Source: Journal of Endocrinology - May 14, 2018 Category: Endocrinology Authors: Jeckel, K. J., Boyarko, A. C., Bouma, G. J., Winger, Q. A., Anthony, R. V. Tags: Research Source Type: research
Soluble Klotho causes hypomineralization in Klotho-deficient mice
The type I transmembrane protein αKlotho (Klotho) serves as a coreceptor for the phosphaturic hormone fibroblast growth factor 23 (FGF23) in kidney, while a truncated form of Klotho (soluble Klotho, sKL) is thought to exhibit multiple activities, including acting as a hormone, but whose mode(s) of action in different organ systems remains to be fully elucidated. FGF23 is expressed primarily in osteoblasts/osteocytes and aberrantly high levels in the circulation acting via signaling through an FGF receptor (FGFR)-Klotho coreceptor complex cause renal phosphate wasting and osteomalacia. We assessed the effects of exoge...
Source: Journal of Endocrinology - May 14, 2018 Category: Endocrinology Authors: Minamizaki, T., Konishi, Y., Sakurai, K., Yoshioka, H., Aubin, J. E., Kozai, K., Yoshiko, Y. Tags: Research Source Type: research
Chronic AT1 blockade improves glucose homeostasis in obese OLETF rats
Obesity is associated with the inappropriate activation of the renin-angiotensin system (RAS), which increases arterial pressure, impairs insulin secretion and decreases peripheral tissue insulin sensitivity. RAS blockade reverses these detriments; however, it is not clear whether the disease state of the organism and treatment duration determine the beneficial effects of RAS inhibition on insulin secretion and insulin sensitivity. Therefore, the objective of this study was to compare the benefits of acute vs chronic angiotensin receptor type 1 (AT1) blockade started after the onset of obesity, hyperglycemia and hypertensi...
Source: Journal of Endocrinology - May 8, 2018 Category: Endocrinology Authors: Rodriguez, R., Minas, J. N., Vazquez-Medina, J. P., Nakano, D., Parkes, D. G., Nishiyama, A., Ortiz, R. M. Tags: Research Source Type: research
Bufalin suppresses endometriosis progression by inducing pyroptosis and apoptosis
The steroid receptor coactivator (SRC)-1 isoform/estrogen receptor (ER)-β axis has an essential role in endometriosis progression. In this context, therefore, bufalin was employed as a ‘tool compound’ to evaluate inhibitors of SRC in alternative endometriosis treatment. Bufalin effectively suppressed the growth of primary human endometrial stroma cells isolated from endometriosis patients compared to women without endometriosis and immortalized human endometrial epithelial and stromal cells expressing the SRC-1 isoform compared to their parental cells in vitro. In vivo, compared to the vehicle, bufalin tre...
Source: Journal of Endocrinology - May 8, 2018 Category: Endocrinology Authors: Cho, Y. J., Lee, J. E., Park, M. J., OMalley, B. W., Han, S. J. Tags: Research Source Type: research
Adipose and skeletal muscle thermogenesis: studies from large animals
The balance between energy intake and energy expenditure establishes and preserves a ‘set-point’ body weight. The latter is comprised of three major components including metabolic rate, physical activity and thermogenesis. Thermogenesis is defined as the cellular dissipation of energy via heat production. This process has been extensively characterised in brown adipose tissue (BAT), wherein uncoupling protein 1 (UCP1) creates a proton leak across the inner mitochondrial membrane, diverting protons away from ATP synthesis and resulting in heat dissipation. In beige adipocytes and skeletal muscle, thermogenesis c...
Source: Journal of Endocrinology - April 27, 2018 Category: Endocrinology Authors: Fuller-Jackson, J.-P., Henry, B. A. Tags: Review Source Type: research
Actions of pituitary hormones beyond traditional targets
Studies over the past decade have challenged the long-held belief that pituitary hormones have singular functions in regulating specific target tissues, including master hormone secretion. Our discovery of the action of thyroid-stimulating hormone (TSH) on bone provided the first glimpse into the non-traditional functions of pituitary hormones. Here we discuss evolving experimental and clinical evidence that growth hormone (GH), follicle-stimulating hormone (FSH), adrenocorticotrophic hormone (ACTH), prolactin, oxytocin and arginine vasopressin (AVP) regulate bone and other target tissues, such as fat. Notably, genetic and...
Source: Journal of Endocrinology - April 26, 2018 Category: Endocrinology Authors: Zaidi, M., New, M. I., Blair, H. C., Zallone, A., Baliram, R., Davies, T. F., Cardozo, C., Iqbal, J., Sun, L., Rosen, C. J., Yuen, T. Tags: Review Source Type: research
Low-protein diet in puberty impairs testosterone output and energy metabolism in male rats
We examined the long-term effects of protein restriction during puberty on the function of hypothalamic–pituitary–adrenal (HPA) and hypothalamic–pituitary–gonadal (HPG) axes in male rats. Male Wistar rats from the age of 30 to 60 days were fed a low-protein diet (4%, LP). A normal-protein diet (20.5%) was reintroduced to rats from the age of 60 to 120 days. Control rats were fed a normal-protein diet throughout life (NP). Rats of 60 or 120 days old were killed. Food consumption, body weight, visceral fat deposits, lipid profile, glycemia, insulinemia, corticosteronemia, adrenocorticotropic hormone (...
Source: Journal of Endocrinology - April 24, 2018 Category: Endocrinology Authors: de Oliveira, J. C., de Moura, E. G., Miranda, R. A., de Moraes, A. M. P., Barella, L. F., da Conceicao, E. P. S., Gomes, R. M., Ribeiro, T. A., Malta, A., Martins, I. P., Franco, C. C. d. S., Lisboa, P. C., Mathias, P. C. d. F. Tags: Research Source Type: research
Leptin stimulates aromatase in the growth plate: limiting catch-up growth efficiency
Catch-up growth (CUG) in childhood is defined as periods of growth acceleration, after the resolution of growth attenuation causes, bringing the children back to their original growth trajectory. Sometimes, however, CUG is incomplete, leading to permanent growth deficit and short stature. The aim of this study was to investigate the mechanisms that limit nutritional-CUG. Specifically, we focused on the crosstalk between leptin, increased by re-feeding, and sex hormones, which increase with age. In vivo studies were performed in young male Sprague Dawley rats fed ad libitum or subjected to 10/36 days of 40% food restriction...
Source: Journal of Endocrinology - April 24, 2018 Category: Endocrinology Authors: Masarwi, M., Shamir, R., Phillip, M., Gat-Yablonski, G. Tags: Research Source Type: research
Neuronostatin exerts actions on pituitary that are unique from its sibling peptide somatostatin
This study used baboon (Papio anubis) primary pituitary cell cultures, a species that closely models human physiology, to demonstrate that neuronostatin inhibits basal, but not ghrelin-/GnRH-stimulated, growth hormone (GH) and luteinizing hormone (LH) secretion in a dose- and time-dependent fashion, without affecting the secretion of other pituitary hormones (prolactin, ACTH, FSH, thyroid-stimulating hormone (TSH)) or changing mRNA levels. Actions of neuronostatin differs from somatostatin which in this study reduced GH/PRL/ACTH/LH/TSH secretion and GH/PRL/POMC/LH gene expression. Remarkably, we found that inhibitory actio...
Source: Journal of Endocrinology - April 24, 2018 Category: Endocrinology Authors: Luque, R. M., Kineman, R. D. Tags: Research Source Type: research
