Similar Datasets
Project description:Embryonic diapause in mammals leads to a reversible developmental arrest. While completely halted in many species, European roe deer (Capreolus capreolus) embryos display a continuous deceleration of proliferation. During a 4-mo period, the cell doubling time is 2 to 3 wk. During this period, the preimplantation blastocyst reaches a diameter of 4 mm, after which it resumes a fast developmental pace to subsequently implant. The mechanisms regulating this notable deceleration and reacceleration upon developmental resumption are unclear. We propose that amino acids of maternal origin drive the embryonic developmental pace. A pronounced change in the abundance of uterine fluid mTORC1-activating amino acids coincided with an increase in embryonic mTORC1 activity prior to the resumption of development. Concurrently, genes related to the glycolytic and phosphate pentose pathway, the TCA cycle, and one carbon metabolism were up-regulated. Furthermore, the uterine luminal epithelial transcriptome indicated increased estradiol-17β signaling, which likely regulates the endometrial secretions adapting to the embryonic needs. While mTORC1 was predicted to be inactive during diapause, the residual embryonic mTORC2 activity may indicate its involvement in maintaining the low yet continuous proliferation rate during diapause. Collectively, we emphasize the role of nutrient signaling in preimplantation embryo development. We propose selective mTORC1 inhibition via uterine catecholestrogens and let-7 as a mechanism regulating slow stem cell cycle progression.
| S-EPMC8536382 | biostudies-literature
Project description:mRNA sequencing of diapausing and embryos that resumed a fast rate of development to identify molecular factors involved in the regulation of embryonic diapause
2021-08-15 | GSE158805 | GEO
Project description:mRNA sequencing of diapausing and embryos that resumed a fast rate of development to identify molecular factors involved in the regulation of embryonic diapause
2021-08-15 | GSE158784 | GEO
Project description:Amino acids activate mTORC1 to release roe deer embryos from decelerated proliferation during diapause
| PRJNA666623 | ENA
Project description:Amino acids activate mTORC1 to release roe deer embryos from decelerated proliferation during diapause [Embryo]
| PRJNA666626 | ENA
Project description:Amino acids activate mTORC1 to release roe deer embryos from decelerated proliferation during diapause [Luminal epithelium]
| PRJNA666550 | ENA
Project description:Pancreas volume or mass varies more than 3-fold among adult humans. The heterogeneity is likely the result of genetics, diseases, and nutrition. Dietary protein intake and blood amino acid levels are known to affect pancreas mass, but the underlying mechanism is not well understood. The goal of this study is to determine how increased blood amino acid level (hyperaminoacidemia) induces pancreas expansion.Multiple complementary mouse and zebrafish models were used to study the impact of hyperaminoacidemia on pancreatic mass, acinar cell size and proliferation. Blood amino acid levels were manipulated by dietary protein content, or by pharmacologic or genetic interruption of glucagon signaling (IGS). The activation of mammalian target of rapamycin complex 1 (mTORC1) and Yes-associated protein 1 (YAP) were determined by pS6 and YAP staining. Sirolimus administration in mice and knockdown of solute carrier family 38 member 5b (slc38a5b) and yap/taz in zebrafish were used to determine the role of mTORC1, SLC38A5 and YAP/TAZ in acinar cell proliferation and pancreas expansion. We found that the IGS-induced pancreas expansion was the result of acinar cell proliferation and hypertrophy. Hyperaminoacidemia was the likely mediator as pancreas expansion was blunted by a low protein diet in mice and by knocking down the most highly expressed amino acid transporter gene, slc38a5b, in zebrafish lacking both glucagon receptor genes (gcgr-/-). In GCGR-Ab treated mice, inhibition of mTORC1 attenuated both hyperplasia and hypertrophy of acinar cells. There was a gene expression signature of YAP activation in acinar cells, consistent with increased YAP-expressing acinar cells in GCGR-Ab treated mice and increased fraction of acinar cells with nuclear YAP1 in gcgr-/- zebrafish. Knocking down yap1 or taz decreased mTORC1 activity and acinar cell hyperplasia and hypertrophy in gcgr-/- zebrafish. Hyperaminoacidemia leads to acinar cell proliferation and hypertrophy via activation of both mTORC1 and YAP pathways. The study discovered a previously unrecognized role of the YAP/Taz pathway in hyperaminoacidemia-induced acinar cell hypertrophy and hyperplasia.
2024-03-30 | GSE243695 | GEO
Project description:Amino acids are essential activators of mTORC1 via a complex containing RAG GTPases, RAGULATOR and the vacuolar ATPase. Sensing of amino acids causes translocation of mTORC1 to lysosomes, an obligate step for activation. To examine the spatial and temporal dynamics of this translocation, we used live imaging of the mTORC1 component RAPTOR and a cell permeant fluorescent analogue of di-leucine methyl ester. Translocation to lysosomes is a transient event, occurring within 2 min of aa addition and peaking within 5 min. It is temporally coupled with fluorescent leucine appearance in lysosomes and is sustained in comparison to aa stimulation. Sestrin2 and the vacuolar ATPase are negative and positive regulators of mTORC1 activity in our experimental system. Of note, phosphorylation of canonical mTORC1 targets is delayed compared to lysosomal translocation suggesting a dynamic and transient passage of mTORC1 from the lysosomal surface before targetting its substrates elsewhere.
| S-EPMC5059141 | biostudies-literature
Project description:Rab1A is a small GTPase known for its role in vesicular trafficking. Recent evidence indicates that Rab1A is essential for amino acids (aas) sensing and signaling to regulate mTORC1 in normal and cancer cells. However, Rab1A's in vivo function in mammals is not known. Here, we report the generation of tamoxifen (TAM)-induced whole body Rab1A knockout (Rab1A-/-) in adult mice. Rab1A-/- mice are viable but become hyperglycemic and glucose intolerant due to impaired insulin transcription and β-cell proliferation and maintenance. Mechanistically, Rab1A mediates AA-mTORC1 signaling, particularly branched chain amino acids (BCAA), to regulate the stability and localization of the insulin transcription factor Pdx1. Collectively, these results reveal a physiological role of aa-Rab1A-mTORC1 signaling in the control of whole-body glucose homeostasis in mammals. Intriguingly, Rab1A expression is reduced in β-cells of type 2 diabetes (T2D) patients, which is correlated with loss of insulin expression, suggesting that Rab1A downregulation contributes to T2D progression.
| S-EPMC8062038 | biostudies-literature
Project description:ObjectiveDietary protein dilution (PD) has been associated with metabolic advantages such as improved glucose homeostasis and increased energy expenditure. This phenotype involves liver-induced release of FGF21 in response to amino acid insufficiency; however, it has remained unclear whether dietary dilution of specific amino acids (AAs) is also required. Circulating branched chain amino acids (BCAAs) are sensitive to protein intake, elevated in the serum of obese humans and mice and thought to promote insulin resistance. We tested whether replenishment of dietary BCAAs to an AA-diluted (AAD) diet is sufficient to reverse the glucoregulatory benefits of dietary PD.MethodsWe conducted AA profiling of serum from healthy humans and lean and high fat-fed or New Zealand obese (NZO) mice following dietary PD. We fed wildtype and NZO mice one of three amino acid defined diets: control, total AAD, or the same diet with complete levels of BCAAs (AAD + BCAA). We quantified serum AAs and characterized mice in terms of metabolic efficiency, body composition, glucose homeostasis, serum FGF21, and tissue markers of the integrated stress response (ISR) and mTORC1 signaling.ResultsSerum BCAAs, while elevated in serum from hyperphagic NZO, were consistently reduced by dietary PD in humans and murine models. Repletion of dietary BCAAs modestly attenuated insulin sensitivity and metabolic efficiency in wildtype mice but did not restore hyperglycemia in NZO mice. While hepatic markers of the ISR such as P-eIF2? and FGF21 were unabated by dietary BCAA repletion, hepatic and peripheral mTORC1 signaling were fully or partially restored, independent of changes in circulating glucose or insulin.ConclusionsRepletion of BCAAs in dietary PD is sufficient to oppose changes in somatic mTORC1 signaling but does not reverse the hepatic ISR nor induce insulin resistance in type 2 diabetes during dietary PD.
| S-EPMC5518726 | biostudies-literature