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- Adipose tissue biology in 2014: Advances in our understanding of adipose tissue homeostasis. [JOURNAL ARTICLE]
- Nat Rev Endocrinol 2014 Dec 16.
- Genetics of adrenal diseases in 2014: Genetics improves understanding of adrenocortical tumours. [JOURNAL ARTICLE]
- Nat Rev Endocrinol 2014 Dec 16.
- Social cues regulate reciprocal switching of hypothalamic Dio2/Dio3 and the transition into final follicle maturation in European starlings (Sturnus vulgaris). [JOURNAL ARTICLE]
- Endocrinology 2014 Dec 9.:en20141450.
With final maturation of ovarian follicles, birds are committed to a major energetic investment: egg-laying. Follicles develop in a two-step process 1) initial development of regressed follicles stimulated by long days and 2) yolk incorporation into hierarchical follicles, ovulation and oviposition. We know little about how females transduce environmental cues into neuroendocrine signals regulating the second step. The present study measures gene expression in tissues within the hypothalamo-pituitary gonadal (HPG) axis. Females were housed in semi-natural enclosures experiencing natural changes in photoperiod and environmental cues (e.g. temperature, rainfall, etc.), without males or with constant access to males (January to April). By April, females with males had begun to lay eggs, whereas those without males had not. In a second study, females without males for 3.5 months were then given access to males for seven days. Restricting male access completely inhibited final follicle maturation, whereas seven-day male access stimulated full vitellogenesis and follicle maturation. Few gene expression changes were attributable to constant male access (January to March), but naïve females given seven-day male access had increased DIO2 and decreased DIO3 synthesis in the hypothalamus, potentially influencing local thyroid hormone metabolism, increased expression of LH receptor and aromatase in follicles and vitellogenin in liver. Our data suggest initial follicle development may be more heavily influenced by photoperiod, but the second step (final maturation) is sensitive to other cues such as social interactions. This is the first demonstration of a social effect on the Dio2/Dio3 system - previously thought only responsive to photoperiod cues.
- Soy Protein Isolate Inhibits High Fat Diet-Induced Senescence Pathways in Osteoblasts to Maintain Bone Acquisition in Male Rats. [JOURNAL ARTICLE]
- Endocrinology 2014 Dec 9.:en20141427.
Chronic consumption by experimental animals of a typical Western diet high in saturated fats and cholesterol during postnatal life has been demonstrated to impair skeletal development. However, underlying mechanism by which high fat, energy dense diets affect bone forming cell phenotypes is poorly understood. Here, we show that male weanling rats fed a diet containing 45% fat and 0.5% cholesterol made with casein (HF-Cas) for 6 weeks displayed lower bone mineral density and strength compared to AIN-93G-fed dietary controls. Substitution of casein with soy protein isolate (SPI) in the high fat diet (HF-SPI) prevented these effects. The bone sparing effects of SPI were associated with prevention of HF-Cas-induced osteoblast senescence pathways through suppression of p53/p21 signaling pathways. HF-Cas-fed rats had increased caveolin-1 and down-regulated Sirt1 leading to activations of PPARγ and p53/p21; whereas, rats fed HF-SPI suppressed caveolin-1and activated Sirt1 to de-acetylate PPARγ and p53 in bone. Treatment of osteoblastic cells with non-esterified free fatty acid (NEFA) increased cell senescence signaling pathways. Isoflavones significantly blocked activations of senescence-associated β-galactosidase and PPARγ/p53/p21 by NEFA. Finally, replicative senescent osteoblastic cells and bone marrow mesenchymal ST2 cells exhibited similar behavior to cells treated with NEFA and in vivo bone cells in rats fed HF-Cas diet. These results suggest that: 1) high concentrations of NEFA occurring with HF intake are mediators of osteoblast cell senescence leading to impairment of bone development and acquisition; 2) the molecular mechanisms underlying the SPI-protective effects involve isoflavone-induced inhibition of osteoblastic cell senescence to prevent HF-induced bone impairments.
- Absence of TRH-receptor 1 in male mice affects gastric ghrelin production. [JOURNAL ARTICLE]
- Endocrinology 2014 Dec 9.:en20141395.
TRH not only functions as a thyrotropin-releasing hormone but also acts as a neuropeptide in central circuits regulating food intake and energy expenditure. As one suggested mode of action, TRH expressed in the caudal brainstem influences vagal activity by activating TRH-receptor 1 (TRH-R1). In order to evaluate the impact of a diminished medullary TRH signaling on ghrelin metabolism, we analyzed metabolic changes of TRH-R1 knock-out (ko) mice in response to 24 hours of food deprivation. Since TRH-R1 ko mice are hypothyroid, we also studied eu- and hypothyroid wild-type animals and TRH-R1 ko mice rendered euthyroid by thyroid hormone (TH) treatment. Independent of their thyroidal state, TRH-R1 ko mice displayed a higher body weight loss than wild-type animals, and a delayed reduction in locomotor activity upon fasting. Ghrelin transcript levels in the stomach as well as total ghrelin levels in the circulation were equally high in fasted wild-type and TRH-R1 ko mice. In contrast, only wild-type mice responded to fasting with a rise in ghrelin-O-acyltransferase (GOAT) mRNA expression and consequently an increase in serum levels of acylated ghrelin. Together, our data suggest that an up-regulation of medullary TRH expression and subsequently enhanced activation of TRH-R1 in the vagal system represents a critical step in the stimulation of GOAT expression upon starvation that in turn is important for adjusting the circulating levels of acylated ghrelin to the fasting condition.
- DYRK1A BAC transgenic mouse: a new model of thyroid dysgenesis in Down Syndrome. [JOURNAL ARTICLE]
- Endocrinology 2014 Dec 9.:en20141329.
The most common thyroid abnormality among Down Syndrome (DS) children corresponds to a mildly elevated TSH, with T4 decreased or in the normal range and thyroid hypoplasia, from the neonatal period onwards, which aggravate their mental impairment. Transgenic Dyrk1A mice, obtained by Bacterial Artificial Chromosome engineering (mBACTgDyrk1A), have three copies of the Dyrk1A gene. The objective is to determine if this transgenic Dyrk1A (Dyrk1A+/++) mouse is an adequate murine model for study of thyroid dysgenesis in DS. Embryonic thyroid development from E13.5 to E17.5 was analysed in wild type (wt) and Dyrk1A+/++ mice by immunofluorescence with anti-Nkx2-1, anti-Thyroglobulin and anti-T4 antibodies, markers of early thyroid development, hormonogenesis and final differentiation respectively. The expression of transcription factors Nkx2-1, Pax8 and Foxe1 involved in thyroidogenesis were studied by qRT-PCR at the same embryonic stages. We then compared the adult phenotype at 8-12 weeks in Dyrk1A+/++ and wt mice for T4 and TSH levels, thyroidal weight and histological analysis. Regarding thyroidal development, at E15.5 Dyrk1A+/++ thyroid lobes are double the size of wt thyroids (p= 0.01) but the Thyroglobulin stained surface in Dyrk1A+/++ thyroids is less than a third as large at E17.5 (p=0.04) and their differentiated follicular surface half the size (p= 0.004). We also observed a significant increase in Nkx2-1, Foxe1 and Pax8 RNA levels in E13.5 and E17.5 Dyrk1A+/++ embryonic thyroids. Dyrk1A+/++ young adult mice have significantly lower plasma T4 (2.4 ng/mL versus wt: 3.7 ng/mL; p = 0.019) and non-significant higher plasma TSH (114mUI/L versus wt: 73mUI/L; p=0.09). In addition, their thyroids are significantly heavier (p=0.04) and exhibit large disorganised regions. Dyrk1A overexpression directly leads to thyroidal embryogenetic, functional and morphological impairment. The young adult thyroid phenotype is probably a result of embryogenetic impairment. The Dyrk1A+/++ mouse can be considered a suitable study model for thyroid dysgenesis in DS.
- Glucose intolerance in aging male IGFBP-3 transgenic mice: differential effects of human IGFBP-3 and its mutant IGFBP-3 devoid of IGF binding ability. [JOURNAL ARTICLE]
- Endocrinology 2014 Dec 9.:en20141271.
We have reported a reduction of insulin secretion and glucose intolerance in young mice overexpressing human IGFBP-3 [phosphoglycerate kinase (PGK)BP3] or its mutant Gly56/Gly80/Gly81-IGFBP-3 (PGKmutBP3) under the PGK promoter. Here, we investigated changes in glucose and lipid homeostasis with age in PGKBP3 and PGKmutBP3 mice compared with wild-type mice. Body weight, glucose tolerance, insulin tolerance, visceral fat, interscapular brown adipose tissue (BAT), serum lipids, and pancreas histology were examined at age 3, 6, and 12 months. Murine IGFBP-3 was similar in all mouse genotypes and decreased with age in parallel with total IGF-I. Visceral fat and BAT masses increased in PGKmutBP3 mice, but not in PGKBP3 mice. Glucose tolerance was impaired in both PGKBP3 and PGKmutBP3 mice. However, PGKBP3 mice had increased expression of uncoupling protein-1 in BAT and reduced adiposity, and continued to have smaller pancreatic β-cell mass and reduced insulin secretion through age 12 months. In contrast, PGKmutBP3 mice developed insulin resistance with age in association with pancreatic β-cell hyperplasia, impaired expression of uncoupling protein-1 in BAT, and increased adiposity. In addition, both PGKBP3 and PGKmutBP3 mice had elevated glycerol in the circulation, but only PGKBP3 mice had elevated free fatty acids and only PGKmutBP3 mice had elevated triglycerides. Estimated free IGF-I did not increase with age in transgenic mice, as it did in wild-type mice. Thus, overexpression of human IGFBP-3 or its mutant devoid of IGF-binding ability leads to glucose intolerance with, however, different effects on insulin secretion, insulin sensitivity, and lipid homeostasis in aging mice.
- Effects and interactions of tachykinins and dynorphin on FSH and LH secretion in developing and adult rats. [JOURNAL ARTICLE]
- Endocrinology 2014 Dec 9.:en20141026.
KNDy neurons, which co-express kisspeptins (Kp), neurokinin B (NKB) and dynorphin (Dyn), regulate gonadotropin secretion. The KNDy model proposes that NKB (stimulator, through NK3R) and Dyn (inhibitor, through KOR) shape Kp secretion onto GnRH neurons. However, some aspects of this paradigm remain ill-defined. Here, we aimed to characterize (1) the effects of NKB signaling on FSH secretion, and (2) the role of Dyn in gonadotropin secretion after NK3R activation. Additionally, we explored (3) the roles of other tachykinin receptors, NK1R and NK2R, on gonadotropin release. Thus, the effects of NK3R agonist, senktide, on FSH release were explored across postnatal development in male and female rats; gonadotropin responses to agonists of NK1R (substance P; SP) and NK2R (neurokinin A, NKA) were also monitored. Moreover, the effects of senktide on gonadotropin secretion were assessed after antagonizing Dyn actions by nor-BNI. Before puberty, rats of both sexes showed increased FSH secretion to senktide (and Kp-10). Conversely, adult female rats were irresponsive to senktide in terms of FSH, despite proven LH responses, while adult males did not display FSH or LH responses to senktide, even at high doses. In turn, SP and NKA stimulated gonadotropin secretion in pre-pubertal rats, while in adults modest gonadotropin responses to NKA were detected. By pre-treatment with Dyn antagonist, adult males became responsive to senktide in terms of LH secretion, and displayed elevated basal LH and FSH levels; nor-BNI treatment uncovered FSH responses to senktide in adult females. Furthermore, expression of Pdyn and Opkr1 (encoding Dyn and KOR, respectively) in the mediobasal hypothalamus was greater in males than in females at pre-pubertal ages. Overall, our data contribute to refine our understanding on how the elements of the KNDy node and related factors (i.e., other tachykinins) differentially participate in the control of gonadotropins at different stages of rat postnatal maturation.
- Anabolic bone therapies in 2014: New bone-forming treatments for osteoporosis. [JOURNAL ARTICLE]
- Nat Rev Endocrinol 2014 Dec 9.
- Immunology: The control of homeostasis in adipose tissue. [JOURNAL ARTICLE]
- Nat Rev Endocrinol 2014 Dec 9.