American Journal of Physiology - Endocrinology and Metabolism
0193-1849
1522-1555
Mỹ
Cơ quản chủ quản: AMER PHYSIOLOGICAL SOC , American Physiological Society
Lĩnh vực:
Physiology (medical)PhysiologyEndocrinology, Diabetes and Metabolism
Phân tích ảnh hưởng
Thông tin về tạp chí
The American Journal of Physiology-Endocrinology and Metabolism publishes original, mechanistic studies on the physiology of endocrine and metabolic systems. Physiological, cellular, and molecular studies in whole animals or humans will be considered. Specific themes include, but are not limited to, mechanisms of hormone and growth factor action; hormonal and nutritional regulation of metabolism, inflammation, microbiome and energy balance; integrative organ cross talk; paracrine and autocrine control of endocrine cells; function and activation of hormone receptors; endocrine or metabolic control of channels, transporters, and membrane function; temporal analysis of hormone secretion and metabolism; and mathematical/kinetic modeling of metabolism. Novel molecular, immunological, or biophysical studies of hormone action are also welcome.
Các bài báo tiêu biểu
Role of the nitric oxide pathway in AMPK-mediated glucose uptake and GLUT4 translocation in heart muscle AMP-activated protein kinase (AMPK) is a serine-threonine kinase that regulates cellular metabolism and has an essential role in activating glucose transport during hypoxia and ischemia. The mechanisms responsible for AMPK stimulation of glucose transport are uncertain, but may involve interaction with other signaling pathways or direct effects on GLUT vesicular trafficking. One potential downstream mediator of AMPK signaling is the nitric oxide pathway. The aim of this study was to examine the extent to which AMPK mediates glucose transport through activation of the nitric oxide (NO)-signaling pathway in isolated heart muscles. Incubation with 1 mM 5-amino-4-imidazole-1-β-carboxamide ribofuranoside (AICAR) activated AMPK ( P < 0.01) and stimulated glucose uptake ( P < 0.05) and translocation of the cardiomyocyte glucose transporter GLUT4 to the cell surface ( P < 0.05). AICAR treatment increased phosphorylation of endothelial NO synthase (eNOS) ∼1.8-fold ( P < 0.05). eNOS, but not neuronal NOS, coimmunoprecipitated with both the α2 and α1 AMPK catalytic subunits in heart muscle. NO donors also increased glucose uptake and GLUT4 translocation ( P < 0.05). Inhibition of NOS with Nω -nitro-l-arginine and Nω -methyl-l-arginine reduced AICAR-stimulated glucose uptake by 21 ± 3% ( P < 0.05) and 25 ± 4% ( P < 0.05), respectively. Inhibition of guanylate cyclase with ODQ and LY-83583 reduced AICAR-stimulated glucose uptake by 31 ± 4% ( P < 0.05) and 22 ± 3% ( P < 0.05), respectively, as well as GLUT4 translocation to the cell surface ( P < 0.05). Taken together, these results indicate that activation of the NO-guanylate cyclase pathway contributes to, but is not the sole mediator of, AMPK stimulation of glucose uptake and GLUT4 translocation in heart muscle.
Tập 287 Số 5 - Trang E834-E841 - 2004
Chronically elevated plasma C-type natriuretic peptide level stimulates skeletal growth in transgenic mice C-type natriuretic peptide (CNP) plays a critical role in endochondral ossification through guanylyl cyclase-B (GC-B), a natriuretic peptide receptor subtype. Cartilage-specific overexpression of CNP enhances skeletal growth and rescues the dwarfism in a transgenic achondroplasia model with constitutive active mutation of fibroblast growth factor receptor-3. For future clinical application, the efficacy of CNP administration on skeletal growth must be evaluated. Due to the high clearance of CNP, maintaining a high concentration is technically difficult. However, to model high blood CNP concentration, we established a liver-targeted CNP-overexpressing transgenic mouse (SAP-CNP tgm). SAP-CNP tgm exhibited skeletal overgrowth in proportion to the blood CNP concentration and revealed phenotypes of systemic stimulation of cartilage bones, including limbs, paws, costal bones, spine, and skull. Furthermore, in SAP-CNP tgm, the size of the foramen magnum, the insufficient formation of which results in cervico-medullary compression in achondroplasia, also showed significant increase. CNP primarily activates GC-B, but under high concentrations it cross-reacts with guanylyl cyclase-A (GC-A), a natriuretic peptide receptor subtype of atrial natriuretic peptides (ANP) and brain natriuretic peptides (BNP). Although activation of GC-A could alter cardiovascular homeostasis, leading to hypotension and heart weight reduction, the skeletal overgrowth phenotype in the line of SAP-CNP tgm with mild overexpression of CNP did not accompany decrease of systolic blood pressure or heart weight. These results suggest that CNP administration stimulates skeletal growth without adverse cardiovascular effect, and thus CNP could be a promising remedy targeting achondroplasia.
Tập 297 Số 6 - Trang E1339-E1348 - 2009
Bone as an ion exchange system: evidence for a link between mechanotransduction and metabolic needs To detect whether the mutual interaction occurring between the osteocytes-bone lining cells system (OBLCS) and the bone extracellular fluid (BECF) is affected by load through a modification of the BECF-extracellular fluid (ECF; systemic extracellular fluid) gradient, mice metatarsal bones immersed in ECF were subjected ex vivo to a 2-min cyclic axial load of different amplitudes and frequencies. The electric (ionic) currents at the bone surface were measured by a vibrating probe after having exposed BECF to ECF through a transcortical hole. The application of different loads and different frequencies increased the ionic current in a dose-dependent manner. The postload current density subsequently decayed following an exponential pattern. Postload increment's amplitude and decay were dependent on bone viability. Dummy and static loads did not induce current density modifications. Because BECF is perturbed by loading, it is conceivable that OBLCS tends to restore BECF preload conditions by controlling ion fluxes at the bone-plasma interface to fulfill metabolic needs. Because the electric current reflects the integrated activity of OBLCS, its evaluation in transgenic mice engineered to possess genetic lesions in channels or matrix constituents could be helpful in the characterization of the mechanical and metabolic functions of bone.
Tập 282 Số 4 - Trang E851-E864 - 2002
Signaling and cytotoxic functions of 4-hydroxyalkenals The peroxidation of n-3 and n-6 polyunsaturated fatty acids (PUFAs) and of their hydroperoxy metabolites is a complex process. It is initiated by free oxygen radical-induced abstraction of a hydrogen atom from the lipid molecule followed by a series of nonenzymatic reactions that ultimately generate the reactive aldehyde species 4-hydroxyalkenals. The molecule 4-hydroxy- 2E-hexenal (4-HHE) is generated by peroxidation of n-3 PUFAs, such as linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid. The aldehyde product 4-hydroxy-2 E-nonenal (4-HNE) is the peroxidation product of n-6 PUFAs, such as arachidonic and linoleic acids and their 15-lipoxygenase metabolites, namely 15-hydroperoxyeicosatetraenoic acid (15-HpETE) and 13-hydroperoxyoctadecadienoic acid (13-HpODE). Another reactive peroxidation product is 4-hydroxy-2 E,6 Z-dodecadienal (4-HDDE), which is derived from 12-hydroperoxyeicosatetraenoic acid (12-HpETE), the 12-lipoxygenase metabolite of arachidonic acid. Hydroxyalkenals, notably 4-HNE, have been implicated in various pathophysiological interactions due to their chemical reactivity and the formation of covalent adducts with macromolecules. The progressive accumulation of these adducts alters normal cell functions that can lead to cell death. The lipophilicity of these aldehydes positively correlates to their chemical reactivity. Nonetheless, at low and noncytotoxic concentrations, these molecules may function as signaling molecules in cells. This has been shown mostly for 4-HNE and to some extent for 4-HHE. The capacity of 4-HDDE to generate such “mixed signals” in cells has received less attention. This review addresses the origin and cellular functions of 4-hydroxyalkernals.
Tập 299 Số 6 - Trang E879-E886 - 2010
Perturbation of glucose flux in the liver by decreasing F26P<sub>2</sub>levels causes hepatic insulin resistance and hyperglycemia Hepatic insulin resistance is one of the characteristics of type 2 diabetes and contributes to the development of hyperglycemia. How changes in hepatic glucose flux lead to insulin resistance is not clearly defined. We determined the effects of decreasing the levels of hepatic fructose 2,6-bisphosphate (F26P2 ), a key regulator of glucose metabolism, on hepatic glucose flux in the normal 129J mice. Upon adenoviral overexpression of a kinase activity-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, the enzyme that determines F26P2 level, hepatic F26P2 levels were decreased twofold compared with those of control virus-treated mice in basal state. In addition, under hyperinsulinemic conditions, hepatic F26P2 levels were much lower than those of the control. The decrease in F26P2 leads to the elevation of basal and insulin-suppressed hepatic glucose production. Also, the efficiency of insulin to suppress hepatic glucose production was decreased (63.3 vs. 95.5% suppression of the control). At the molecular level, a decrease in insulin-stimulated Akt phosphorylation was consistent with hepatic insulin resistance. In the low hepatic F26P2 states, increases in both gluconeogenesis and glycogenolysis in the liver are responsible for elevations of hepatic glucose production and thereby contribute to the development of hyperglycemia. Additionally, the increased hepatic gluconeogenesis was associated with the elevated mRNA levels of peroxisome proliferator-activated receptor-γ coactivator-1α and phospho enolpyruvate carboxykinase. This study provides the first in vivo demonstration showing that decreasing hepatic F26P2 levels leads to increased gluconeogenesis in the liver. Taken together, the present study demonstrates that perturbation of glucose flux in the liver plays a predominant role in the development of a diabetic phenotype, as characterized by hepatic insulin resistance.
Tập 291 Số 3 - Trang E536-E543 - 2006
Mice deficient in Group VIB phospholipase A<sub>2</sub>(iPLA<sub>2</sub>γ) exhibit relative resistance to obesity and metabolic abnormalities induced by a Western diet Phospholipases A2 (PLA2 ) play important roles in metabolic processes, and the Group VI PLA2 family is comprised of intracellular enzymes that do not require Ca2+ for catalysis. Mice deficient in Group VIA PLA2 (iPLA2 β) develop more severe glucose intolerance than wild-type (WT) mice in response to dietary stress. Group VIB PLA2 (iPLA2 γ) is a related enzyme distributed in membranous organelles, including mitochondria, and iPLA2 γ knockout (KO) mice exhibit altered mitochondrial morphology and function. We have compared metabolic responses of iPLA2 γ-KO and WT mice fed a Western diet (WD) with a high fat content. We find that KO mice are resistant to WD-induced increases in body weight and adiposity and in blood levels of cholesterol, glucose, and insulin, even though WT and KO mice exhibit similar food consumption and dietary fat digestion and absorption. KO mice are also relatively resistant to WD-induced insulin resistance, glucose intolerance, and altered patterns of fat vs. carbohydrate fuel utilization. KO skeletal muscle exhibits impaired mitochondrial β-oxidation of fatty acids, as reflected by accumulation of larger amounts of long-chain acylcarnitine (LCAC) species in KO muscle and liver compared with WT in response to WD feeding. This is associated with increased urinary excretion of LCAC and much reduced deposition of triacylglycerols in liver by WD-fed KO compared with WT mice. The iPLA2 γ-deficient genotype thus results in a phenotype characterized by impaired mitochondrial oxidation of fatty acids and relative resistance to the metabolic abnormalities induced by WD.
Tập 298 Số 6 - Trang E1097-E1114 - 2010
Glucose homeostasis, insulin secretion, and islet phospholipids in mice that overexpress iPLA<sub>2</sub>β in pancreatic β-cells and in iPLA<sub>2</sub>β-null mice Studies with genetically modified insulinoma cells suggest that group VIA phospholipase A2 (iPLA2 β) participates in amplifying glucose-induced insulin secretion. INS-1 insulinoma cells that overexpress iPLA2 β, for example, exhibit amplified insulin-secretory responses to glucose and cAMP-elevating agents. To determine whether similar effects occur in whole animals, we prepared transgenic (TG) mice in which the rat insulin 1 promoter (RIP) drives iPLA2 β overexpression, and two characterized TG mouse lines exhibit similar phenotypes. Their pancreatic islet iPLA2 β expression is increased severalfold, as reflected by quantitative PCR of iPLA2 β mRNA, immunoblotting of iPLA2 β protein, and iPLA2 β enzymatic activity. Immunofluorescence microscopic studies of pancreatic sections confirm iPLA2 β overexpression in RIP-iPLA2 β-TG islet β-cells without obviously perturbed islet morphology. Male RIP-iPLA2 β-TG mice exhibit lower blood glucose and higher plasma insulin concentrations than wild-type (WT) mice when fasting and develop lower blood glucose levels in glucose tolerance tests, but WT and TG blood glucose levels do not differ in insulin tolerance tests. Islets from male RIP-iPLA2 β-TG mice exhibit greater amplification of glucose-induced insulin secretion by a cAMP-elevating agent than WT islets. In contrast, islets from male iPLA2 β-null mice exhibit blunted insulin secretion, and those mice have impaired glucose tolerance. Arachidonate incorporation into and the phospholipid composition of RIP-iPLA2 β-TG islets are normal, but they exhibit reduced Kv2.1 delayed rectifier current and prolonged glucose-induced action potentials and elevations of cytosolic Ca2+ concentration that suggest a molecular mechanism for the physiological role of iPLA2 β to amplify insulin secretion.
Tập 294 Số 2 - Trang E217-E229 - 2008
MicroRNA-34a induces endothelial progenitor cell senescence and impedes its angiogenesis via suppressing silent information regulator 1 Endothelial progenitor cells (EPCs) play an important role in angiogenesis, which is essential for numerous physiological processes as well as tumor growth. Several microRNAs (miRNAs) have been reported to be involved in angiogenesis. MiR-34a, recently reported as a tumor suppressor, has been found to target silent information regulator 1 (Sirt1), leading to cell cycle arrest or apoptosis. However, the role of miR-34a in EPC-mediated angiogenesis was unknown. The present study tested the hypothesis that miR-34a inhibits EPC-mediated angiogenesis by inducing senescence via suppressing Sirt1. Bone marrow-derived EPCs from adult male Spraque-Dawley rats were used. Results of flow cytometry showed that EPCs after 7 days of culture expressed both stem cell markers CD34 and CD133 and endothelial cell markers VEGFR-2 (flk-1) and VE-cadherin. MiR-34a was expressed in normal EPCs, and overexpression of miR-34a via its mimic transfection significantly increased its expression and impaired in vitro EPC angiogenesis. MiR-34a overexpression led to a significantly increased EPC senescence, paralleled with an ∼40% Sirt1 reduction. Furthermore, knockdown of Sirt1 by its siRNA resulted in diminished EPC angiogenesis and increased senescence. Finally, overexpression of miR-34a increased the level of Sirt1 effector-acetylated forkhead box O transcription factors 1 (FoxO1), an effect mimicked in EPCs following Sirt1 knockdown. In conclusion, miR-34a impairs EPC-mediated angiogenesis by induction of senescence via inhibiting Sirt1.
Tập 299 Số 1 - Trang E110-E116 - 2010
Regulation of 5′AMP-activated protein kinase activity and substrate utilization in exercising human skeletal muscle The metabolic role of 5′AMP-activated protein kinase (AMPK) in regulation of skeletal muscle metabolism in humans is unresolved. We measured isoform-specific AMPK activity and β-acetyl-CoA carboxylase (ACCβ) Ser221 phosphorylation and substrate balance in skeletal muscle of eight athletes at rest, during cycling exercise for 1 h at 70% peak oxygen consumption, and 1 h into recovery. The experiment was performed twice, once in a glycogen-loaded (glycogen concentration ∼900 mmol/kg dry wt) and once in a glycogen-depleted (glycogen concentration ∼160 mmol/kg dry wt) state. At rest, plasma long-chain fatty acids (FA) were twofold higher in the glycogen-depleted than in the loaded state, and muscle α1 AMPK (160%) and α2 AMPK (145%) activities and ACCβ Ser221 phosphorylation (137%) were also significantly higher in the glycogen-depleted state. During exercise, α2 AMPK activity, ACCβ Ser221 phosphorylation, plasma catecholamines, and leg glucose and net FA uptake were significantly higher in the glycogen-depleted than in the glycogen-loaded state without apparent differences in muscle high-energy phosphates. Thus exercise in the glycogen-depleted state elicits an enhanced uptake of circulating fuels that might be associated with elevated muscle AMPK activation. It is concluded that muscle AMPK activity and ACCβ Ser221 phosphorylation at rest and during exercise are sensitive to the fuel status of the muscle. During exercise, this dependence may in part be mediated by humoral factors.
Tập 284 Số 4 - Trang E813-E822 - 2003
AMP-activated protein kinase, a metabolic master switch: possible roles in Type 2 diabetes Adenosine 5′-monophosphate-activated protein kinase (AMPK) now appears to be a metabolic master switch, phosphorylating key target proteins that control flux through metabolic pathways of hepatic ketogenesis, cholesterol synthesis, lipogenesis, and triglyceride synthesis, adipocyte lipolysis, and skeletal muscle fatty acid oxidation. Recent evidence also implicates AMPK as being responsible for mediating the stimulation of glucose uptake induced by muscle contraction. In addition, the secretion of insulin by insulin secreting (INS-1) cells in culture is modulated by AMPK activation. The net effect of AMPK activation is stimulation of hepatic fatty acid oxidation and ketogenesis, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipolysis and lipogenesis, stimulation of skeletal muscle fatty acid oxidation and muscle glucose uptake, and modulation of insulin secretion by pancreatic β-cells. In skeletal muscle, AMPK is activated by contraction. Type 2 diabetes mellitus is likely to be a disease of numerous etiologies. However, defects or disuse (due to a sedentary lifestyle) of the AMPK signaling system would be predicted to result in many of the metabolic perturbations observed in Type 2 diabetes mellitus. Increased recruitment of the AMPK signaling system, either by exercise or pharmaceutical activators, may be effective in correcting insulin resistance in patients with forms of impaired glucose tolerance and Type 2 diabetes resulting from defects in the insulin signaling cascade.
Tập 277 Số 1 - Trang E1-E10 - 1999