ResearchPad - metabolism-and-regulation https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Distinct iron homeostasis in C57BL/6 and Balb/c mouse strains]]> https://www.researchpad.co/article/N567d8dc8-9bb5-4cb4-9865-61edda999224 Relative to C57BL/6 mice (BL6), Balb/c mice harbor more circulating, tissue and labile iron pool (LIP), which correlates with their generally heightened expression of key iron‐regulatory proteins like divalent metal transporter 1 (DMT1) andferroportin. Accordingly, such strain‐level differences in iron homeostasis could explain the dissimilar degree of developing pro‐inflammatory responses, followed by hypoferremia, in response to inflammatory challenge like lipopolysaccharides (LPS), which occurs more rapidly in BL6 mice than Balb/c mice.

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<![CDATA[Metabolic changes during pregnancy in glucose‐intolerant NZO mice: A polygenic model with prediabetic metabolism]]> https://www.researchpad.co/article/N7d1aff3c-4c37-44e4-a38a-f0102ec2938b The aim of this work was to evaluate metabolic changes during pregnancy within the polygenic NZO mouse model and if it is a suitable one for the human disease. NZO mice showed early alterations in glucose homeostasis and insulin secretion, but no overt diabetes. Interestingly, the preconceptionally impaired glucose tolerance did not deteriorate during gestation despite a proliferation defect of Langerhans islets.

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<![CDATA[Model‐based data analysis of individual human postprandial plasma bile acid responses indicates a major role for the gallbladder and intestine]]> https://www.researchpad.co/article/Ndad3d676-77e0-4ed8-b6fc-053ede7bb5c4

Abstract

Background

Bile acids are multifaceted metabolic compounds that signal to cholesterol, glucose, and lipid homeostasis via receptors like the Farnesoid X Receptor (FXR) and transmembrane Takeda G protein‐coupled receptor 5 (TGR5). The postprandial increase in plasma bile acid concentrations is therefore a potential metabolic signal. However, this postprandial response has a high interindividual variability. Such variability may affect bile acid receptor activation.

Methods

In this study, we analyzed the inter‐ and intraindividual variability of fasting and postprandial bile acid concentrations during three identical meals on separate days in eight healthy lean male subjects using a statistical and mathematical approach.

Main findings

The postprandial bile acid responses exhibited large interindividual and intraindividual variability. The individual mathematical models, which represent the enterohepatic circulation of bile acids in each subject, suggest that interindividual variability results from quantitative and qualitative differences of distal active uptake, colon transit, and microbial bile acid transformation. Conversely, intraindividual variations in gallbladder kinetics can explain intraindividual differences in the postprandial responses.

Conclusions

We conclude that there is considerable inter‐ and intraindividual variation in postprandial plasma bile acid levels. The presented personalized approach is a promising tool to identify unique characteristics of underlying physiological processes and can be applied to investigate bile acid metabolism in pathophysiological conditions.

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<![CDATA[Role of sodium‐dependent Pi transporter/Npt2c on Pi homeostasis in klotho knockout mice different properties between juvenile and adult stages]]> https://www.researchpad.co/article/N1b0c87a0-6340-43f5-84b9-f8529f1e5e90

Abstract

SLC34A3/NPT2c/NaPi‐2c/Npt2c is a growth‐related NaPi cotransporter that mediates the uptake of renal sodium‐dependent phosphate (Pi). Mutation of human NPT2c causes hereditary hypophosphatemic rickets with hypercalciuria. Mice with Npt2c knockout, however, exhibit normal Pi metabolism. To investigate the role of Npt2c in Pi homeostasis, we generated α‐klotho−/−/Npt2c−/− (KL2cDKO) mice and analyzed Pi homeostasis. α‐Klotho−/− (KLKO) mice exhibit hyperphosphatemia and markedly increased kidney Npt2c protein levels. Genetic disruption of Npt2c extended the lifespan of KLKO mice similar to that of α‐Klotho−/−/Npt2a−/− mice. Adult KL2cDKO mice had hyperphosphatemia, but analysis of Pi metabolism revealed significantly decreased intestinal and renal Pi (re)absorption compared with KLKO mice. The 1,25‐dihydroxy vitamin D3 concentration was not reduced in KL2cDKO mice compared with that in KLKO mice. The KL2cDKO mice had less severe soft tissue and vascular calcification compared with KLKO mice. Juvenile KL2cDKO mice had significantly reduced plasma Pi levels, but Pi metabolism was not changed. In Npt2cKO mice, plasma Pi levels began to decrease around the age of 15 days and significant hypophosphatemia developed within 21 days. The findings of the present study suggest that Npt2c contributes to regulating plasma Pi levels in the juvenile stage and affects Pi retention in the soft and vascular tissues in KLKO mice.

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<![CDATA[Osmotic diuresis by SGLT2 inhibition stimulates vasopressin‐induced water reabsorption to maintain body fluid volume]]> https://www.researchpad.co/article/Nbf986e8d-3c67-4a62-bc16-5b5f6c51fdf7

Abstract

Most of the filtered glucose is reabsorbed in the early proximal tubule by the sodium‐glucose cotransporter SGLT2. The glycosuric effect of the SGLT2 inhibitor ipragliflozin is linked to a diuretic and natriuretic effect that activates compensatory increases in fluid and food intake to stabilize body fluid volume (BFV). However, the compensatory mechanisms that are activated on the level of renal tubules remain unclear. Type 2 diabetic Goto‐Kakizaki (GK) rats were treated with vehicle or 0.01% (in diet) ipragliflozin with free access to fluid and food. After 8 weeks, GK rats were placed in metabolic cages for 24‐hr. Ipragliflozin decreased body weight, serum glucose and systolic blood pressure, and increased fluid and food intake, urinary glucose and Na+ excretion, urine volume, and renal osmolar clearance, as well as urine vasopressin and solute‐free water reabsorption (TcH2O). BFV, measured by bioimpedance spectroscopy, and fluid balance were similar among the two groups. Urine vasopressin in ipragliflozin‐treated rats was negatively and positively associated with fluid balance and TcH2O, respectively. Ipragliflozin increased the renal membrane protein expression of SGLT2, aquaporin (AQP) 2 phosphorylated at Ser269 and vasopressin V2 receptor. The expression of SGLT1, GLUT2, AQP1, and AQP2 was similar between the groups. In conclusion, the SGLT2 inhibitor ipragliflozin induced a sustained glucosuria, diuresis, and natriuresis, with compensatory increases in fluid intake and vasopressin‐induced TcH2O in proportion to the reduced fluid balance to maintain BFV. These results indicate that the osmotic diuresis induced by SGLT2 inhibition stimulates compensatory fluid intake and renal water reabsorption to maintain BFV.

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<![CDATA[Hypovolemia and reduced hemoglobin mass in patients with heart failure and preserved ejection fraction]]> https://www.researchpad.co/article/N1b60bae1-f630-4f15-b84c-91bbf61c2926

Abstract

A fundamental tenet of heart failure (HF) pathophysiology hinges on a propensity for fluid retention leading to blood volume (BV) expansion and hemodilution. Whether this can be applied to heart failure patients with preserved ejection fraction (HFpEF) remains uncertain. The present study sought to determine BV status and key hormones regulating fluid homeostasis and erythropoiesis in HFpEF patients. BV and hemoglobin mass (Hbmass) were determined with high‐precision, automated carbon monoxide (CO) rebreathing in 20 stable HFpEF patients (71.5 ± 7.3 years, left ventricular ejection fraction = 55.7 ± 4.0%) and 15 healthy age‐ and sex‐matched control individuals. Additional measurements comprised key circulating BV‐regulating hormones such as pro‐atrial natriuretic peptide (proANP), copeptin, aldosterone and erythropoietin (EPO), as well as central hemodynamics and arterial stiffness via carotid–femoral pulse wave velocity (PWV). Carotid–femoral PWV was increased (+20%) in HFpEF patients versus control individuals. With respect to hematological variables, plasma volume (PV) did not differ between groups, whereas BV was decreased (−14%) in HFpEF patients. In consonance with the hypovolemic status, Hbmass was reduced (−27%) in HFpEF patients, despite they presented more than a twofold elevation of circulating EPO (+119%). Plasma concentrations of BV‐regulating hormones, including proANP (+106%), copeptin (+99%), and aldosterone (+62%), were substantially augmented in HFpEF patients. HFpEF patients may present with hypovolemia and markedly reduced Hbmass, underpinned by a generalized overactivation of endocrine systems regulating fluid homeostasis and erythropoiesis. These findings provide a novel perspective on the pathophysiological basis of the HFpEF condition.

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<![CDATA[Redundancy in regulation of lipid accumulation in skeletal muscle during prolonged fasting in obese men]]> https://www.researchpad.co/article/Nb142d122-e52c-4876-8fff-723a16365481

Abstract

Fasting in human subjects shifts skeletal muscle metabolism toward lipid utilization and accumulation, including intramyocellular lipid (IMCL) deposition. Growth hormone (GH) secretion amplifies during fasting and promotes lipolysis and lipid oxidation, but it is unknown to which degree lipid deposition and metabolism in skeletal muscle during fasting depends on GH action. To test this, we studied nine obese but otherwise healthy men thrice: (a) in the postabsorptive state (“CTRL”), (b) during 72‐hr fasting (“FAST”), and (c) during 72‐hr fasting and treatment with a GH antagonist (GHA) (“FAST + GHA”). IMCL was assessed by magnetic resonance spectroscopy (MRS) and blood samples were drawn for plasma metabolomics assessment while muscle biopsies were obtained for measurements of regulators of substrate metabolism. Prolonged fasting was associated with elevated GH levels and a pronounced GHA‐independent increase in circulating medium‐ and long‐chain fatty acids, glycerol, and ketone bodies indicating increased supply of lipid intermediates to skeletal muscle. Additionally, fasting was associated with a release of short‐, medium‐, and long‐chain acylcarnitines to the circulation from an increased β‐oxidation. This was consistent with a ≈55%–60% decrease in pyruvate dehydrogenase (PDHa) activity. Opposite, IMCL content increased ≈75% with prolonged fasting without an effect of GHA. We suggest that prolonged fasting increases lipid uptake in skeletal muscle and saturates lipid oxidation, both favoring IMCL deposition. This occurs without a detectable effect of GHA on skeletal muscle lipid metabolism.

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<![CDATA[Nandrolone‐induced nuclear accumulation of MyoD protein is mediated by Numb, a Notch inhibitor, in C2C12 myoblasts]]> https://www.researchpad.co/article/5b4be341463d7e7ed7cf61b5

Abstract

Signaling via the androgen receptor (AR) stimulates myogenic progenitor differentiation. In addition, myogenic differentiation factor D (MyoD) and Numb, a Notch inhibitor, play key roles in regulating myogenic differentiation. Nandrolone, an anabolic steroid, upregulates both MyoD and Numb expression in myogenic cells. However, the molecular mechanisms by which MyoD is upregulated by nandrolone are unclear. Moreover, the potential crosstalk between nandrolone, MyoD, and Numb is not well understood. With these considerations in mind, we examined the effects of nandrolone on the expression of MyoD mRNA and protein, and determined the interactions of MyoD and Numb in the presence or absence of nandrolone in differentiating C2C12 myoblasts. Nandrolone increased MyoD mRNA and protein expression and significantly enhanced nuclear translocation of MyoD protein. The later effect of nandrolone was blunted by siRNA against Numb. Immunoprecipitation (IP) studies confirmed that Numb forms complexes with MyoD. Chromatin IP revealed that in the presence of nandrolone, Numb is recruited to a region of the MyH7 promotor containing the E‐box to which MyoD binds. These data indicate that nandrolone‐regulated MyoD activation occurs mainly through a posttranslational mechanism which promotes MyoD nuclear accumulation, and suggest that this effect of nandrolone is, at least in part, mediated by Numb.

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<![CDATA[Plasma amino acid levels are elevated in young, healthy low birth weight men exposed to short‐term high‐fat overfeeding]]> https://www.researchpad.co/article/5b35f386463d7e4e15c1f832

Abstract

Low birth weight (LBW) individuals exhibit a disproportionately increased, incomplete fatty acid oxidation and a decreased glucose oxidation, compared with normal birth weight (NBW) individuals, and furthermore have an increased risk of developing insulin resistance and type 2 diabetes. We hypothesized that changes in amino acid metabolism may occur parallel to alterations in fatty acid and glucose oxidation, and could contribute to insulin resistance. Therefore, we measured fasting plasma levels of 15 individual or pools of amino acids in 18 LBW and 25 NBW men after an isocaloric control diet and after a 5‐day high‐fat, high‐calorie diet. We demonstrated that LBW and NBW men increased plasma alanine levels and decreased valine and leucine/isoleucine levels in response to overfeeding. Also, LBW men had higher alanine, proline, methionine, citrulline, and total amino acid levels after overfeeding compared with NBW men. Alanine and total amino acid levels tended to be negatively associated with the insulin‐stimulated glucose uptake after overfeeding. Therefore, the higher amino acid levels in LBW men could be a consequence of their reduction in skeletal muscle insulin sensitivity due to overfeeding with a possible increased skeletal muscle proteolysis and/or could potentially contribute to an impaired insulin sensitivity. Furthermore, the alanine level was negatively associated with the plasma acetylcarnitine level and positively associated with the hepatic glucose production after overfeeding. Thus, the higher alanine level in LBW men could be accompanied by an increased anaplerotic formation of oxaloacetate and thereby an enhanced tricarboxylic acid cycle activity and as well an increased gluconeogenesis.

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<![CDATA[Unexpected effects of the MIP‐CreER transgene and tamoxifen on β‐cell growth in C57Bl6/J male mice]]> https://www.researchpad.co/article/5bd0510e40307c64fb333bbe

Abstract

Transgenic mouse models have been fundamental in the discovery of factors that regulate β‐cell development, mass, and function. Several groups have recently shown that some of these models display previously uncharacterized phenotypes due to the transgenic system itself. These include impaired islet function and increased β‐cell mass due to the presence of a human growth hormone (hGH) minigene as well as impaired β‐cell proliferation in response to tamoxifen (TM) administration. We aimed to determine how these systems impact β‐cell mass and proliferation during high fat diet (HFD). To this end, we utilized C57Bl6/J male MIP‐CreER mice, which are known to express hGH, or wild‐type (WT) mice treated with vehicle corn oil or TM. In the absence of TM, MIP‐CreER mice fed a chow diet have increased β‐cell mass due to hypertrophy, whereas replication is unchanged. Similarly, after 1 week on HFD, MIP‐CreER mice have increased β‐cell mass compared to WT, and this is due to hypertrophy rather than increased proliferation. To assess the impact of TM on β‐cell proliferation and mass, WT mice were treated with vehicle corn oil or TM and then fed a chow diet or HFD for 3 days. We observed that TM‐treated mice have improved glucose homeostasis on chow diet but impaired β‐cell proliferation in response to 3 days HFD feeding. These results unveil additional complications associated with commonly used pancreas‐specific mouse models.

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<![CDATA[Carbonic anhydrase 2‐like in the giant clam, Tridacna squamosa: characterization, localization, response to light, and possible role in the transport of inorganic carbon from the host to its symbionts]]> https://www.researchpad.co/article/5b467fed463d7e5f40bc6df3

Abstract

The fluted giant clam, Tridacna squamosa, lives in symbiosis with zooxanthellae which reside extracellularly inside a tubular system. Zooxanthellae fix inorganic carbon (Ci) during insolation and donate photosynthate to the host. Carbonic anhydrases catalyze the interconversion of CO 2 and HCO3, of which carbonic anhydrase 2 (CA2) is the most ubiquitous and involved in many biological processes. This study aimed to clone a CA2 homolog (CA2‐like) from the fleshy and colorful outer mantle as well as the thin and whitish inner mantle of T. squamosa, to determine its cellular and subcellular localization, and to examine the effects of light exposure on its gene and protein expression levels. The cDNA coding sequence of CA2‐like from T. squamosa comprised 789 bp, encoding 263 amino acids with an estimated molecular mass of 29.6 kDa. A phenogramic analysis of the deduced CA2‐like sequence denoted an animal origin. CA2‐like was not detectable in the shell‐facing epithelium of the inner mantle adjacent to the extrapallial fluid. Hence, CA2‐like is unlikely to participate directly in light‐enhanced calcification. By contrast, the outer mantle, which contains the highest density of tertiary tubules and zooxanthellae, displayed high level of CA2‐like expression, and CA2‐like was localized to the tubule epithelial cells. More importantly, exposure to light induced significant increases in the protein abundance of CA2‐like in the outer mantle. Hence, CA2‐like could probably take part in the increased supply of inorganic carbon (Ci) from the host clam to the symbiotic zooxanthellae when the latter conduct photosynthesis to fix Ci during light exposure.

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<![CDATA[Effects of maternal western‐style diet on amniotic fluid volume and amnion VEGF profiles in a nonhuman primate model]]> https://www.researchpad.co/article/5c11619bd5eed0c484639f03

Abstract

During pregnancy, high fat diet (HFD) induces maternal obesity, insulin resistance, and placental inflammatory responses that compromise placental and fetal development. Whether maternal HFD would adversely affect amniotic fluid volume (AFV) has not been explored. Vascular endothelial growth factor (VEGF) is expressed in the amnion and has been proposed as a regulator of AFV. Our aim was to investigate the effects of HFD on AFV and the associated changes in VEGF and soluble VEGF receptor 1 (sFlt‐1) expression profiles in three amnion regions of a nonhuman primate model. Further, we examined the relationships between VEGF expression and HFD‐induced changes in maternal metabolic status. Japanese macaques were maintained on control or HFD and amniotic fluid index (AFI) was measured as an ultrasonic estimate of AFV. Amniotic fluid VEGF concentrations were determined by ELISA and amnion VEGF and sFlt‐1 mRNA levels by real‐time RT‐qPCR. HFD increased maternal plasma triglyceride while glucose levels were unchanged. Maternal weight gain was found in diet‐sensitive animals whereas amniotic fluid VEGF concentration was reduced in diet‐resistant animals. HFD did not alter AFI and there was no correlation between AFI and maternal weight or amniotic fluid VEGF concentrations. VEGF mRNA levels were lowest in secondary placental amnion while sFlt‐1 mRNA were lowest in the primary placental amnion. HFD did not affect amnion VEGF or sFlt‐1 mRNA expression. These findings suggest that although maternal HFD increased maternal weight in diet‐sensitive and reduced amniotic fluid VEGF concentrations in diet‐resistant phenotype, AFV as indicated by the AFI, was not significantly affected.

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<![CDATA[Neurovascular coupling response to cognitive examination in healthy controls: a multivariate analysis]]> https://www.researchpad.co/article/5c08b872d5eed0c484150026

Abstract

Cognitive testing with transcranial Doppler ultrasonography (TCD) has been used to assess neurovascular coupling (NVC), but few studies address its multiple contributions. Subcomponent analysis considers the relative myogenic (resistance area product, RAP) and metabolic (critical closing pressure (CrCP)) contributors. The aim of this study was to investigate the changes in subcomponents that occur with cognitive stimulation with the Addenbrooke's Cognitive Examination (ACEIII) in healthy controls. Healthy volunteers underwent continuous recording of bilateral TCD, heart rate (HR, three‐lead ECG), end‐tidal CO 2 (ETCO 2, capnography), and mean arterial pressure (MAP, Finometer). The study comprised a 5‐min baseline recording, followed by all 20 paradigms from the ACEIII. The cerebral blood flow velocity (CBFv) response was decomposed into the relative contributions (subcomponents); V BP (MAP), V CrCP (CrCP), and V RAP (RAP). Data are presented as peak population normalized mean changes from baseline, and median area under the curve (AUC). Forty bilateral datasets were obtained (27 female, 37 right hand dominant). V BP increased at task initiation in all paradigms but differed between tasks (range (SD): 4.06 (8.92)–16.04 (12.23) %, P < 0.05). HR, but not ETCO 2, also differed significantly (P < 0.05). Changes in V RAP reflected changes in MAP, but in some paradigms atypical responses were seen. V CrCP AUC varied significantly within paradigm sections (range [SD]: 18.4 [24.17] to 244.21 [243.21] %*s, P < 0.05). All paradigms demonstrated changes in subcomponents with cognitive stimulation, and can be ranked based on their relative presumed metabolic demand. The integrity of NVC requires further investigation in patient populations.

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