Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0948265 (metabolic syndrome)
 24,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amino acid transport system B(0,+) was first characterized in detail in mouse blastocysts over two decades ago. Since then, this system has been shown to be involved in a wide array of developmental processes from blastocyst implantation in the uterus to adult obesity. Leucine uptake through system B(0,+) in blastocysts triggers mammalian target of rapamycin (mTOR) signalling. This signalling pathway selectively regulates development of trophoblast motility and the onset of the penetration stage of blastocyst implantation about 20 h later. Meanwhile, system B(0,+) becomes inactive in blastocysts a few hours before implantation in vivo. System B(0,+) can, however, be activated in preimplantation blastocysts by physical stimuli. The onset of trophoblast motility should provide the physiological physical stimulus activating system B(0,+) in blastocysts in vivo. Activation of system B(0,+) when trophoblast cells begin to penetrate the uterine epithelium would cause it to accumulate its preferred substrates, which include tryptophan, from uterine secretions. A low tryptophan concentration in external secretions next to trophoblast cells inhibits T-cell proliferation and rejection of the conceptus. Suboptimal system B(0,+) regulation of these developmental processes likely influences placentation and subsequent embryo nutrition, birth weight and risk of developing metabolic syndrome and obesity.
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PMID:System B0,+ amino acid transport regulates the penetration stage of blastocyst implantation with possible long-term developmental consequences through adulthood. 1625 Dec 51

High-protein diets have been shown to promote weight loss, to improve glucose homeostasis and to increase energy expenditure and fat oxidation. We aimed to study whether leucine supplementation is able to mimic the alleviating effects of high-protein diets on metabolic syndrome parameters in mice fed high-fat diet. Male C57BL/6 mice were fed for 20 weeks with semisynthetic high-fat diets (20% w/w of fat) containing either an adequate (10% protein, AP) or high (50% protein, HP) amount of whey protein, or an AP diet supplemented with L-leucine corresponding to the leucine content of the HP diet (6% leucine, AP+L). Body weight and composition, energy expenditure, glucose tolerance, hepatic triacylglycerols (TG), plasma parameters as well as expression levels of mRNA and proteins in different tissues were measured. HP feeding resulted in decreased body weight, body fat and hepatic TG accumulation, as well as increased insulin sensitivity compared to AP. This was linked to an increased total and resting energy expenditure (REE), decreased feed energy efficiency, increased skeletal muscle (SM) protein synthesis, reduced hepatic lipogenesis and increased white fat lipolysis. Leucine supplementation had effects that were intermediate between HP and AP with regard to body composition, liver TG content, insulin sensitivity, REE and feed energy efficiency, and similar effects as HP on SM protein synthesis. However, neither HP nor AP+L showed an activation of the mammalian target of rapamycin pathway in SM. Leucine supplementation had no effect on liver lipogenesis and white fat lipolysis compared to AP. It is concluded that the essential amino acid leucine is able to mimic part but not all beneficial metabolic effects of HP diets.
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PMID:Comparison of high-protein diets and leucine supplementation in the prevention of metabolic syndrome and related disorders in mice. 2240 95

The physiological importance of vasopressin inactivation has long been appreciated, but the mechanisms and potential pathophysiologic roles of this process remain active subjects of research. Human Placental Leucine Aminopeptidase (P-LAP, encoded by the LNPEP gene) is an important determinant of vasopressinase activity during pregnancy and is associated with gestational diabetes insipidus and preeclampsia. Insulin-Regulated Aminopeptidase (IRAP), the rodent homologue of P-LAP, is coregulated with the insulin-responsive glucose transporter, GLUT4, in adipose and muscle cells. Recently, the Tether containing a UBX domain for GLUT4 (TUG) protein was shown to mediate the coordinated regulation of water and glucose homeostasis. TUG sequesters IRAP and GLUT4 intracellularly in the absence of insulin. Insulin and other stimuli cause the proteolytic cleavage of TUG to mobilize these proteins to the cell surface, where IRAP acts to terminate the activity of circulating vasopressin. Intriguingly, genetic variation in LNPEP is associated with the vasopressin response and mortality during sepsis, and increased copeptin, a marker of vasopressin secretion, is associated with cardiovascular and metabolic disease. We propose that in the setting of insulin resistance in muscle, increased cell-surface IRAP and accelerated vasopressin degradation cause a compensatory increase in vasopressin secretion. The increased vasopressin concentrations present at the kidneys then contribute to hypertension in the metabolic syndrome. Further analyses of metabolism and of vasopressin and copeptin may yield novel insights into a unified pathophysiologic mechanism linking insulin resistance and hypertension, and potentially other components of the metabolic syndrome, in humans.
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PMID:Vasopressin inactivation: Role of insulin-regulated aminopeptidase. 3213 46

Type 2 diabetes (T2D) and cardiovascular disease (CVD) share many risk factors such as obesity, unhealthy lifestyle, and metabolic syndrome, whose accumulation over years leads to disease onset. However, while lowering plasma low-density lipoprotein cholesterol (LDLC) is cardio-protective, novel evidence have recognised a role for common LDLC-lowering variants ( e.g. in HMGCR, PCSK9, and LDLR) and widely used hypocholesterolemic drugs that mimic the effects of some of these variants (statins) in higher risk for T2D. As these conditions decrease plasma LDLC by increasing tissue-uptake of LDL, a role for LDL receptor (LDLR) pathway was proposed. While underlying mechanisms remain to be fully elucidated, work from our lab reported that native LDL directly provoke the dysfunction of human white adipose tissue (WAT) and the activation of WAT NLRP3 (Nucleotide-binding domain and Leucine-rich repeat Receptor, containing a Pyrin domain 3) inflammasome, which play a major role in the etiology of T2D. However, while elevated plasma numbers of apolipoprotein B (apoB)-containing lipoproteins (measured as apoB, mostly as LDL) is associated with WAT dysfunction and related risk factors for T2D in our cohort, this relation was strengthened in regression analysis by lower plasma proprotein convertase subtilisin/kexin type 9 (PCSK9). This supports a central role for upregulated pathway of LDLR and/or other receptors regulated by PCSK9 such as cluster of differentiation 36 (CD36) in LDL-induced anomalies. Targeting receptor-mediated uptake of LDL into WAT may reduce WAT inflammation, WAT dysfunction, and related risk for T2D without increasing the risk for CVD.
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PMID:LDL, LDL receptors, and PCSK9 as modulators of the risk for type 2 diabetes: a focus on white adipose tissue. 3270 Oct 68