RESUMO
Hypertriglyceridemia is a risk factor for type 2 diabetes and cardiovascular disease (CVD). Plasma triglycerides (TGs) are a key factor for assessing the risk of diabetes or CVD. However, previous lipidomics studies have demonstrated that not all TG molecules behave the same way. Individual TGs with different fatty acid compositions are regulated differentially under various conditions. In addition, distinct groups of TGs were identified to be associated with increased diabetes risk (TGs with lower carbon number [C#] and double-bond number [DB#]), or with decreased risk (TGs with higher C# and DB#). In this study, we examined the effects of high-fat feeding in rats on plasma lipid profiles with special attention to TG profiles. Wistar rats were maintained on either a low-fat (control) or high-fat diet (HFD) for 2 weeks. Plasma samples were obtained before and 2.5 h after a meal (n = 10 each) and subjected to lipidomics analyses. High-fat feeding significantly impacted circulating lipid profiles, with the most significant effects observed on TG profile. The effects of an HFD on individual TG species depended on DB# in their fatty acid chains; an HFD increased TGs with low DB#, associated with increased diabetes risk, but decreased TGs with high DB#, associated with decreased risk. These changes in TGs with an HFD were associated with decreased indices of hepatic stearoyl-CoA desaturase (SCD) activity, assessed from hepatic fatty acid profiles. Decreased SCD activity would reduce the conversion of saturated to monounsaturated fatty acids, contributing to the increases in saturated TGs or TGs with low DB#. In addition, an HFD selectively depleted ω-3 polyunsaturated fatty acids (PUFAs), contributing to the decreases in TGs with high DB#. Thus, an HFD had profound impacts on circulating TG profiles. Some of these changes were at least partly explained by decreased hepatic SCD activity and depleted ω-3 PUFA.
Assuntos
Dieta Hiperlipídica , Ácidos Graxos Ômega-3 , Ratos Wistar , Triglicerídeos , Animais , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-3/sangue , Dieta Hiperlipídica/efeitos adversos , Ratos , Masculino , Ácidos Graxos não Esterificados/sangue , Ácidos Graxos não Esterificados/metabolismo , Estearoil-CoA Dessaturase/metabolismo , Hipertrigliceridemia/metabolismo , Hipertrigliceridemia/sangue , Hipertrigliceridemia/etiologia , LipidômicaRESUMO
Soluble epoxide hydrolase (sEH) is an important enzyme for metabolic and cardiovascular health. sEH converts FFA epoxides (EpFAs), many of which are regulators of various cellular processes, to biologically less active diols. In human studies, diol (sEH product) to EpFA (sEH substrate) ratios in plasma or serum have been used as indices of sEH activity. We previously showed these ratios profoundly decreased in rats during acute feeding, possibly reflecting decreases in tissue sEH activities. The present study was designed to test which tissue(s) these measurements in the blood represent and if factors other than sEH activity, such as renal excretion or dietary intake of EpFAs and diols, significantly alter plasma EpFAs, diols, and/or their ratios. The results show that postprandial changes in EpFAs and diols and their ratios in plasma were very similar to those observed in the liver but not in other tissues, suggesting that the liver is largely responsible for these changes in plasma levels. EpFAs and diols were excreted into the urine, but their levels were not significantly altered by feeding, suggesting that renal excretion of EpFAs and diols may not play a major role in postprandial changes in circulating EpFAs, diols, or their ratios. Diet intake had significant impacts on circulating EpFA and diol levels but not on diol-to-EpFA (D-to-E) ratios, suggesting that these ratios, reflecting sEH activities, may not be significantly affected by the availability of sEH substrates (i.e., EpFAs). In conclusion, changes in FFA D-to-E ratios in plasma may reflect those in the liver, which may in turn represent sEH activities in the liver, and they may not be significantly affected by renal excretion or the dietary intake of EpFAs and diols.
Assuntos
Epóxido Hidrolases , Compostos de Epóxi , Humanos , Ratos , Animais , Epóxido Hidrolases/metabolismo , Compostos de Epóxi/metabolismo , Fígado/metabolismoRESUMO
Oxylipins, oxidation products of unsaturated free fatty acids (FFAs), are involved in various cellular signaling systems. Among these oxylipins, FFA epoxides are associated with beneficial effects in metabolic and cardiovascular health. FFA epoxides are metabolized to diols, which are usually biologically less active, by soluble epoxide hydrolase (sEH). Plasma epoxide-diol ratios have been used as indirect measures of sEH activity. This study was designed to examine the effects of acute elevation of individual plasma FFAs on a variety of oxylipins, particularly epoxides, diols, and their ratios. We tested if FFA epoxide-diol ratios are altered by circulating FFA levels (i.e., substrate availability) independent of sEH activity. Wistar rats received a constant intravenous infusion of olive (70% oleic acid (OA)), safflower seed (72% linoleic acid (LA)), and fish oils (rich in ω-3 FFAs) as emulsions to selectively raise OA, LA, and ω-3 FFAs (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)), respectively. As expected, olive, safflower seed, and fish oil infusions selectively raised plasma OA (57%), LA (87%), EPA (70%), and DHA (54%), respectively (p < 0.05 for all). Raising plasma FFAs exerted substrate effects to increase hepatic and plasma epoxide and diol levels. These increases in epoxides and diols occurred to similar extents, resulting in no significant changes in epoxide-diol ratios. These data suggest that epoxide-diol ratios, often used as indices of sEH activity, are not affected by substrate availability or altered plasma FFA levels and that epoxide-diol ratios may be used to compare sEH activity between conditions of different circulating FFA levels.
Assuntos
Ácidos Graxos não Esterificados , Oxilipinas , Ratos , Animais , Ácidos Graxos não Esterificados/metabolismo , Oxilipinas/metabolismo , Epóxido Hidrolases/metabolismo , Compostos de Epóxi/metabolismo , Ratos Wistar , Ácidos Graxos Insaturados/metabolismo , Óleos de Peixe , Ácido Eicosapentaenoico , Ácido Linoleico , Ácidos Docosa-Hexaenoicos , Ácido OleicoRESUMO
Extracellular potassium (K+) homeostasis is achieved by a concerted effort of multiple organs and tissues. A limitation in studies of K+ homeostasis is inadequate techniques to quantify K+ fluxes into and out of organs and tissues in vivo. The goal of the present study was to test the feasibility of a novel approach to estimate K+ distribution and fluxes in vivo using stable K+ isotopes. 41K was infused as KCl into rats consuming control or K+-deficient chow (n = 4 each), 41K-to-39K ratios in plasma and red blood cells (RBCs) were measured by inductively coupled plasma mass spectrometry, and results were subjected to compartmental modeling. The plasma 41K/39K increased during 41K infusion and decreased upon infusion cessation, without altering plasma total K+ concentration ([K+], i.e., 41K + 39K). The time course of changes was analyzed with a two-compartmental model of K+ distribution and elimination. Model parameters, representing transport into and out of the intracellular pool and renal excretion, were identified in each rat, accurately predicting decreased renal K+ excretion in rats fed K+-deficient vs. control diet (P < 0.05). To estimate rate constants of K+ transport into and out of RBCs, 41K/39K were subjected to a simple model, indicating no effects of the K+-deficient diet. The findings support the feasibility of the novel stable isotope approach to quantify K+ fluxes in vivo and sets a foundation for experimental protocols using more complex models to identify heterogeneous intracellular K+ pools and to answer questions pertaining to K+ homeostatic mechanisms in vivo.
Assuntos
Potássio , Animais , Homeostase , Isótopos de Potássio , RatosRESUMO
Soluble epoxide hydrolase (sEH) converts several FFA epoxides to corresponding diols. As many as 15 FFA epoxide-diol ratios are measured to infer sEH activity from their ratios. Using previous data, we assessed if individual epoxide-diol ratios all behave similarly to reflect changes in sEH activity, and whether analyzing these ratios together increases the power to detect changes in in-vivo sEH activity. We demonstrated that epoxide-diol ratios correlated strongly with each other (P < 0.05), suggesting these ratios all reflect changes in sEH activity. Furthermore, we developed a modeling approach to analyze all epoxide-diol ratios simultaneously to infer global sEH activity, named SAMI (Simultaneous Analysis of Multiple Indices). SAMI improved power in detecting changes in sEH activity in animals and humans when compared to individual ratio estimates. Thus, we introduce a new powerful method to infer sEH activity by combining metabolomic determination and simultaneous analysis of all measurable epoxide-diol pairs.
Assuntos
Anorexia Nervosa/enzimologia , Epóxido Hidrolases/metabolismo , Compostos de Epóxi/sangue , Animais , Anorexia Nervosa/sangue , Anorexia Nervosa/patologia , Estudos de Casos e Controles , Modelos Animais de Doenças , Epóxido Hidrolases/sangue , Humanos , Masculino , Metaboloma , Camundongos , Oxilipinas/metabolismo , Ratos WistarRESUMO
Potassium homeostasis has a very high priority because of its importance for membrane potential. Although extracellular K+ is only 2% of total body K+, our physiology was evolutionarily tuned for a high-K+, low-Na+ diet. We review how multiple systems interface to accomplish fine K+ balance and the consequences for health and disease.
Assuntos
Dieta Saudável , Homeostase , Potássio na Dieta/metabolismo , Potássio/metabolismo , Adaptação Fisiológica , Aldosterona/metabolismo , Animais , Sistema Cardiovascular , Ingestão de Alimentos , Humanos , Rim/metabolismo , Potenciais da Membrana , Músculo Esquelético/metabolismo , Sódio/metabolismo , Sódio na DietaRESUMO
Inflammation is implicated in metabolic abnormalities in obesity and type 2 diabetes. Because θ-defensins have anti-inflammatory activities, we tested whether RTD-1, a θ-defensin, improves metabolic conditions in diet-induced obesity (DIO). DIO was induced by high-fat feeding in obese-prone CD rats from 4 wk of age. Starting at age 10 wk, the DIO rats were treated with saline or RTD-1 for 4 or 8 wk. DIO rats gained more weight than low-fat-fed controls. RTD-1 treatment did not alter body weight or calorie intake in DIO rats. Plasma glucose, FFA, triglyceride (TG), and insulin levels increased in DIO rats; RTD-1 normalized plasma glucose and FFA levels and showed tendencies to lower plasma insulin and TG levels. Hepatic and skeletal muscle TG contents increased in DIO rats; RTD-1 decreased muscle, but not hepatic, TG content. Insulin sensitivity, estimated using homeostasis model assessment of insulin resistance and the glucose clamp technique, decreased in DIO rats, but this change was markedly reversed by RTD-1. RTD-1 had no significant effects on plasma cytokine/chemokine levels or IL-1ß and TNF-α expression in liver or adipose tissues. RTD-1 treatment decreased hepatic expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, suggesting that the effect of RTD-1 on plasma glucose (or insulin action) might be mediated by its effect to decrease hepatic gluconeogenesis. Thus, RTD-1 ameliorated insulin resistance and normalized plasma glucose and FFA levels in DIO rats, supporting the potential of RTD-1 as a novel therapeutic agent for insulin resistance, metabolic syndrome, or type 2 diabetes.
Assuntos
Glicemia/metabolismo , Defensinas/farmacologia , Dieta Hiperlipídica , Ácidos Graxos não Esterificados/sangue , Insulina/fisiologia , Obesidade/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Defensinas/uso terapêutico , Insulina/sangue , Resistência à Insulina , Fígado/efeitos dos fármacos , Fígado/metabolismo , Obesidade/sangue , Obesidade/tratamento farmacológico , Obesidade/etiologia , Ratos , Triglicerídeos/sangueRESUMO
Dietary potassium loading results in rapid kaliuresis, natriuresis, and diuresis associated with reduced phosphorylation (p) of the distal tubule Na(+)-Cl(-) cotransporter (NCC). Decreased NCC-p inhibits NCC-mediated Na(+) reabsorption and shifts Na(+) downstream for reabsorption by epithelial Na(+) channels (ENaC), which can drive K(+) secretion. Whether the signal is initiated by ingesting potassium or a rise in plasma K(+) concentration ([K(+)]) is not understood. We tested the hypothesis, in male rats, that an increase in plasma [K(+)] is sufficient to reduce NCC-p and drive kaliuresis. After an overnight fast, a single 3-h 2% potassium (2%K) containing meal increased plasma [K(+)] from 4.0 ± 0.1 to 5.2 ± 0.2 mM; increased urinary K(+), Na(+), and volume excretion; decreased NCC-p by 60%; and marginally reduced cortical Na(+)-K(+)-2Cl(-) cotransporter (NKCC) phosphorylation 25% (P = 0.055). When plasma [K(+)] was increased by tail vein infusion of KCl to 5.5 ± 0.1 mM over 3 h, significant kaliuresis and natriuresis ensued, NCC-p decreased by 60%, and STE20/SPS1-related proline alanine-rich kinase (SPAK) phosphorylation was marginally reduced 35% (P = 0.052). The following were unchanged at 3 h by either the potassium-rich meal or KCl infusion: Na(+)/H(+) exchanger 3 (NHE3), NHE3-p, NKCC, ENaC subunits, and renal outer medullary K(+) channel. In summary, raising plasma [K(+)] by intravenous infusion to a level equivalent to that observed after a single potassium-rich meal triggers renal kaliuretic and natriuretic responses, independent of K(+) ingestion, likely driven by decreased NCC-p and activity sufficient to shift sodium reabsorption downstream to where Na(+) reabsorption and flow drive K(+) secretion.
Assuntos
Hiperpotassemia/sangue , Rim/metabolismo , Natriurese , Potássio/sangue , Sódio/urina , Animais , Modelos Animais de Doenças , Canais Epiteliais de Sódio/metabolismo , Hiperpotassemia/induzido quimicamente , Hiperpotassemia/fisiopatologia , Hiperpotassemia/urina , Infusões Intravenosas , Rim/fisiopatologia , Masculino , Fosforilação , Potássio/administração & dosagem , Potássio/urina , Canais de Potássio/metabolismo , Potássio na Dieta/sangue , Potássio na Dieta/urina , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Sódio/sangue , Trocador 3 de Sódio-Hidrogênio , Trocadores de Sódio-Hidrogênio/metabolismo , Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Fatores de TempoRESUMO
Overconsumption of dietary fat contributes to the development of obesity and metabolic syndrome. Recent evidence suggests that high dietary fat may promote these metabolic states not only by providing calories but also by inducing impaired control of energy balance. In normal metabolic states, fat interacts with various organs or receptors to generate signals for the regulation of energy balance. Many of these interactions are impaired by high-fat diets or in obesity, contributing to the development or maintenance of obesity. These impairments may arise largely from fundamental alterations in the hypothalamus where all peripheral signals are integrated to regulate energy balance. This review focuses on various mechanisms by which fat is sensed at different stages of ingestion, circulation, storage, and utilization to regulate food intake, and how these individual mechanisms are altered by high-fat diets or in obesity.
Assuntos
Ingestão de Alimentos/fisiologia , Homeostase/fisiologia , Metabolismo dos Lipídeos/fisiologia , Síndrome Metabólica/metabolismo , Obesidade/metabolismo , HumanosRESUMO
Renal K(+) excretion is increased rapidly following dietary K(+) intake, but the underlying molecular mechanisms are largely unknown. Sorensen and colleagues show that K(+) intake in mice provoked rapid and near-complete dephosphorylation of the renal distal convoluted tubule NaCl cotransporter, temporally associated with increases in both Na(+) and K(+) excretion. This response was independent of aldosterone and may be a crucial component of the acute homeostatic adaptation of the kidney to K(+) intake.
Assuntos
Rim/metabolismo , Potássio na Dieta/sangue , Receptores de Droga/metabolismo , Simportadores/metabolismo , Animais , Feminino , Masculino , Membro 3 da Família 12 de Carreador de SolutoRESUMO
The kidneys maintain extracellular K⺠homeostasis by altering K⺠excretion to match K⺠intake. Because this can occur without changes in plasma K⺠concentrations ([Kâº]), how the kidneys sense K⺠intake is unclear. We tested the hypothesis that the pituitary plays a critical role in signaling K⺠intake to the kidneys. If this hypothesis is true, hypophysectomy would impair kidney responses to altered K⺠intake. Hypophysectomized (Hypox) and sham-operated control rats (n = 8 each) were compared for their abilities to adjust K⺠excretion during a transition from normal to reduced (to one-third of normal) K⺠intake, followed by a reversal to normal K⺠intake. Food was provided only at night, and renal K⺠excretion was determined both for absorptive (night or feeding) and postabsorptive (day or nonfeeding) periods. In normal rats, both absorptive and postabsorptive renal K⺠excretion were changed in parallel to the changes in K⺠intake, indicating a rapid adaptation of normal kidneys to altered K⺠intake. In Hypox rats, whereas absorptive renal K⺠excretion was changed in response to changes in K⺠intake, postabsorptive K⺠excretion was not responsive (P < 0.001), indicating impaired renal responses to altered K⺠intake. In addition, Hypox rats, compared with control rats, showed K⺠intolerance (increases in plasma [Kâº]) upon feeding (i.e., K⺠intake) at night or following an intravenous K⺠infusion (P < 0.01), indicating an impairment of acute renal responses to K⺠intake. These data support that the pituitary plays a key role in the signaling of K⺠intake to the kidneys (and kidney responses to altered K⺠intake).
Assuntos
Homeostase/fisiologia , Hipofisectomia , Rim/efeitos dos fármacos , Hipófise/fisiologia , Potássio na Dieta/farmacologia , Potássio/metabolismo , Potássio/farmacologia , Adaptação Fisiológica/fisiologia , Aldosterona/sangue , Animais , Ritmo Circadiano/fisiologia , Corticosterona/farmacologia , Infusões Intravenosas , Rim/metabolismo , Rim/fisiopatologia , Modelos Animais , Hipófise/cirurgia , Potássio/administração & dosagem , Ratos , Ratos Wistar , Transdução de Sinais/fisiologiaRESUMO
The potassium homeostatic system is very tightly regulated. Recent studies have shed light on the sensing and molecular mechanisms responsible for this tight control. In addition to classic feedback regulation mediated by a rise in extracellular fluid (ECF) [K(+)], there is evidence for a feedforward mechanism: Dietary K(+) intake is sensed in the gut, and an unidentified gut factor is activated to stimulate renal K(+) excretion. This pathway may explain renal and extrarenal responses to altered K(+) intake that occur independently of changes in ECF [K(+)]. Mechanisms for conserving ECF K(+) during fasting or K(+) deprivation have been described: Kidney NADPH oxidase activation initiates a cascade that provokes the retraction of K(+) channels from the cell membrane, and muscle becomes resistant to insulin stimulation of cellular K(+) uptake. How these mechanisms are triggered by K(+) deprivation remains unclear. Cellular AMP kinase-dependent protein kinase activity provokes the acute transfer of K(+) from the ECF to the ICF, which may be important in exercise or ischemia. These recent advances may shed light on the beneficial effects of a high-K(+) diet for the cardiovascular system.
Assuntos
Homeostase/fisiologia , Potássio/fisiologia , Animais , Fenômenos Fisiológicos Cardiovasculares , Trato Gastrointestinal/fisiologia , Humanos , Rim/fisiologia , Músculo Esquelético/fisiologia , Potássio na Dieta/metabolismoRESUMO
As the most abundant cation in archaeal, bacterial, and eukaryotic cells, potassium (K+) is an essential element for life. While much is known about the machinery of transcellular and paracellular K transport-channels, pumps, co-transporters, and tight-junction proteins-many quantitative aspects of K homeostasis in biological systems remain poorly constrained. Here we present measurements of the stable isotope ratios of potassium (41K/39K) in three biological systems (algae, fish, and mammals). When considered in the context of our current understanding of plausible mechanisms of K isotope fractionation and K+ transport in these biological systems, our results provide evidence that the fractionation of K isotopes depends on transport pathway and transmembrane transport machinery. Specifically, we find that passive transport of K+ down its electrochemical potential through channels and pores in tight-junctions at favors 39K, a result which we attribute to a kinetic isotope effect associated with dehydration and/or size selectivity at the channel/pore entrance. In contrast, we find that transport of K+ against its electrochemical gradient via pumps and co-transporters is associated with less/no isotopic fractionation, a result that we attribute to small equilibrium isotope effects that are expressed in pumps/co-transporters due to their slower turnover rate and the relatively long residence time of K+ in the ion pocket. These results indicate that stable K isotopes may be able to provide quantitative constraints on transporter-specific K+ fluxes (e.g., the fraction of K efflux from a tissue by channels vs. co-transporters) and how these fluxes change in different physiological states. In addition, precise determination of K isotope effects associated with K+ transport via channels, pumps, and co-transporters may provide unique constraints on the mechanisms of K transport that could be tested with steered molecular dynamic simulations.
RESUMO
Nicotinic acid (NA) has been used as a lipid drug for five decades. The lipid-lowering effects of NA are attributed to its ability to suppress lipolysis in adipocytes and lower plasma FFA levels. However, plasma FFA levels often rebound during NA treatment, offsetting some of the lipid-lowering effects of NA and/or causing insulin resistance, but the underlying mechanisms are unclear. The present study was designed to determine whether a prolonged, continuous NA infusion in rats produces a FFA rebound and/or insulin resistance. NA infusion rapidly lowered plasma FFA levels (>60%, P < 0.01), and this effect was maintained for ≥5 h. However, when this infusion was extended to 24 h, plasma FFA levels rebounded to the levels of saline-infused control rats. This was not due to a downregulation of NA action, because when the NA infusion was stopped, plasma FFA levels rapidly increased more than twofold (P < 0.01), indicating that basal lipolysis was increased. Microarray analysis revealed many changes in gene expression in adipose tissue, which would contribute to the increase in basal lipolysis. In particular, phosphodiesterase-3B gene expression decreased significantly, which would increase cAMP levels and thus lipolysis. Hyperinsulinemic glucose clamps showed that insulin's action on glucose metabolism was improved during 24-h NA infusion but became impaired with increased plasma FFA levels after cessation of NA infusion. In conclusion, a 24-h continuous NA infusion in rats resulted in an FFA rebound, which appeared to be due to altered gene expression and increased basal lipolysis in adipose tissue. In addition, our data support a previous suggestion that insulin resistance develops as a result of FFA rebound during NA treatment. Thus, the present study provides an animal model and potential molecular mechanisms of FFA rebound and insulin resistance, observed in clinical studies with chronic NA treatment.
Assuntos
Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Ácidos Graxos não Esterificados/sangue , Hipolipemiantes/farmacologia , Resistência à Insulina/fisiologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Lipólise/efeitos dos fármacos , Niacina/farmacologia , Animais , Western Blotting , Catecolaminas/sangue , Corticosterona/sangue , Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Técnica Clamp de Glucose , Glicerol/metabolismo , Hipolipemiantes/administração & dosagem , Infusões Intravenosas , Lipase/metabolismo , Lipólise/genética , Masculino , Análise em Microsséries , Niacina/administração & dosagem , Fosforilação , RNA/biossíntese , RNA/genética , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Dietary K(+) intake may increase renal K(+) excretion via increasing plasma [K(+)] and/or activating a mechanism independent of plasma [K(+)]. We evaluated these mechanisms during normal dietary K(+) intake. After an overnight fast, [K(+)] and renal K(+) excretion were measured in rats fed either 0% K(+) or the normal 1% K(+) diet. In a third group, rats were fed with the 0% K(+) diet, and KCl was infused to match plasma [K(+)] profile to that of the 1% K(+) diet group. The 1% K(+) feeding significantly increased renal K(+) excretion, associated with slight increases in plasma [K(+)], whereas the 0% K(+) diet decreased K(+) excretion, associated with decreases in plasma [K(+)]. In the KCl-infused 0% K(+) diet group, renal K(+) excretion was significantly less than that of the 1% K(+) group, despite matched plasma [K(+)] profiles. We also examined whether dietary K(+) alters plasma profiles of gut peptides, such as guanylin, uroguanylin, glucagon-like peptide 1, and glucose-dependent insulinotropic polypeptide, pituitary peptides, such as AVP, α-MSH, and γ-MSH, or aldosterone. Our data do not support a role for these hormones in the stimulation of renal K(+) excretion during normal K(+) intake. In conclusion, postprandial increases in renal K(+) excretion cannot be fully accounted for by changes in plasma [K(+)] and that gut sensing of dietary K(+) is an important component of the regulation of renal K(+) excretion. Our studies on gut and pituitary peptide hormones suggest that there may be previously unknown humoral factors that stimulate renal K(+) excretion during dietary K(+) intake.
Assuntos
Trato Gastrointestinal/metabolismo , Rim/metabolismo , Potássio na Dieta/metabolismo , Potássio/sangue , Potássio/metabolismo , Aldosterona/sangue , Aldosterona/metabolismo , Amilorida/farmacologia , Animais , Glicemia , Regulação da Expressão Gênica/fisiologia , Masculino , Hormônios Hipofisários/genética , Hormônios Hipofisários/metabolismo , Período Pós-Prandial , Ratos , Ratos Wistar , Sódio/sangue , Bloqueadores dos Canais de Sódio/farmacologiaRESUMO
SCOPE: High sodium and low potassium (HNaLK) intake increases the risk of cardiovascular disease (CVD) and metabolic syndrome. The authors investigate if the dietary minerals interact with the gut microbiota to alter circulating lipid profiles, implicated in CVD and metabolic syndrome. METHODS AND RESULTS: Plasma samples from Wistar rats fed a control or HNaLK diet with or without antibiotic treatment (n = 7 each, a total of 28) are subjected to lipidomics analysis. Lipidomic data are then analyzed using statistical and bioinformatics tools, which detect numerous lipid species altered by the treatments, and consistently demonstrated interactions between the gut microbiota and the HNaLK diet in altering circulating lipids, mainly triglycerides (TGs). Two distinct TG groups differentially regulated by antibiotic treatment are identified. One group (cluster 1), representing the majority of TG species detected, is downregulated, whereas the other group (cluster 2) is upregulated by antibiotic treatment. Interestingly, cluster 2 TGs are also regulated by the diet. Cluster 2 TGs exhibit greater carbon-chain length and double-bond content and include TGs composed of very-long-chain polyunsaturated fatty acids, associated with reduced diabetes risk. CONCLUSION: The HNaLK diet interacts with gut bacteria to alter plasma lipid profiles, which may be related to its health effects.
Assuntos
Microbioma Gastrointestinal/fisiologia , Lipidômica , Potássio na Dieta/administração & dosagem , Sódio na Dieta/administração & dosagem , Triglicerídeos/sangue , Proteína 4 Semelhante a Angiopoietina/sangue , Animais , Antibacterianos/farmacologia , Ácidos Graxos não Esterificados/sangue , Ácidos Graxos Ômega-3/biossíntese , Masculino , Ratos , Ratos WistarRESUMO
SCOPE: High-sodium and low-potassium (HNaLK) content in Western diets increases the risk of hypertension and cardiovascular disease (CVD). It is investigated if the dietary minerals interact with gut bacteria to modulate circulating levels of biogenic amines, which are implicated in various pathologies, including hypertension and CVD. METHODS AND RESULTS: Using a metabolomic approach to target biogenic amines, the effects of gut bacteria depletion and HNaLK intake on circulating levels of biogenic amines in rats are examined. Forty-five metabolites whose plasma levels are significantly altered by gut bacteria depletion (p < 0.05) are found, indicating their regulation by gut bacteria. Many of them are not previously linked to gut bacteria; therefore, these data provide novel insights into physiological or pathological roles of gut bacteria. A number of plasma metabolites that are altered both by gut bacteria and HNaLK intake are also found, suggesting possible interactions of the diet and gut bacteria in the modulation of these metabolites. The diet effects are observed with significant changes in the gut bacterial taxa Porphyromonadaceae and Prevotellaceae (p < 0.05). CONCLUSION: The dietary minerals may regulate abundances of certain gut bacteria to alter circulating levels of biogenic amines, which may be linked to host physiology or pathology.
Assuntos
Aminas Biogênicas/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Potássio/farmacologia , Sódio/farmacologia , Animais , Antibacterianos/farmacologia , Sangue/efeitos dos fármacos , Sangue/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Masculino , Potássio/administração & dosagem , Potássio/sangue , Ratos Wistar , Sódio/administração & dosagem , Sódio/sangue , Aumento de Peso/efeitos dos fármacosRESUMO
We previously showed that insulin has a profound effect to suppress pyruvate dehydrogenase kinase (PDK) 4 expression in rat skeletal muscle. In the present study, we examined whether insulin's effect on PDK4 expression is impaired in acute insulin-resistant states and, if so, whether this change is accompanied by decreased insulin's effects to stimulate Akt and forkhead box class O (FOXO) 1 phosphorylation. To induce insulin resistance, conscious overnight-fasted rats received a constant infusion of Intralipid or lactate for 5 h, while a control group received saline infusion. Following the initial infusions, each group received saline or insulin infusion (n = 6 or 7 each) for an additional 5 h, while saline, Intralipid, or lactate infusion was continued. Plasma glucose was clamped at basal levels during the insulin infusion. Compared with the control group, Intralipid and lactate infusions decreased glucose infusion rates required to clamp plasma glucose by approximately 60% (P < 0.01), confirming the induction of insulin resistance. Insulin's ability to suppress PDK4 mRNA level was impaired in skeletal muscle with Intralipid and lactate infusions, resulting in two- to threefold higher PDK4 mRNA levels with insulin (P < 0.05). Insulin stimulation of Akt and FOXO1 phosphorylation was also significantly decreased with Intralipid and lactate infusions. These data suggest that insulin's effect to suppress PDK4 gene expression in skeletal muscle is impaired in insulin-resistant states, and this may be due to impaired insulin signaling for stimulation of Akt and FOXO1 phosphorylation. Impaired insulin's effect to suppress PDK4 expression may explain the association between PDK4 overexpression and insulin resistance in skeletal muscle.
Assuntos
Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Resistência à Insulina/fisiologia , Insulina/farmacologia , Músculo Esquelético/enzimologia , Proteínas Quinases/genética , Animais , Glicemia/análise , Northern Blotting , Emulsões Gordurosas Intravenosas/administração & dosagem , Ácidos Graxos não Esterificados/sangue , Fatores de Transcrição Forkhead/metabolismo , Insulina/sangue , Cinética , Ácido Láctico/administração & dosagem , Ácido Láctico/sangue , Masculino , Proteínas do Tecido Nervoso/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/análise , Ratos , Ratos WistarRESUMO
Epoxides of free fatty acids (FFAs), especially epoxyeicosatrienoic acids (EETs), are lipid mediators with beneficial effects in metabolic and cardiovascular (CV) health. FFA epoxides are quickly metabolized to biologically less active diols by soluble epoxide hydrolase (sEH). Inhibition of sEH, which increases EET levels, improves glucose homeostasis and CV health and is proposed as an effective strategy for the treatment of diabetes and CV diseases. Here, we show evidence that sEH activity is profoundly reduced in postprandial states in rats; plasma levels of 17 sEH products (i.e., FFA diols), detected by targeted oxylipin analysis, all decreased after a meal. In addition, the ratios of sEH product to substrate (sEH P/S ratios), which may reflect sEH activity, decreased ~70% on average 2.5 h after a meal in rats (P<.01). To examine whether this effect was mediated by insulin action, a hyperinsulinemic-euglycemic clamp was performed for 2.5 h, and sEH P/S ratios were assessed before and after the clamp. The clamp resulted in small increases rather than decreases in sEH P/S ratios (P<.05), indicating that insulin cannot account for the postprandial decrease in sEH P/S ratios. Interestingly, in rats treated with antibiotics to deplete gut bacteria, the postprandial effect to decrease sEH P/S ratios was completely abolished, suggesting that a gut bacteria-derived factor(s) may be responsible for the effect. Further studies are warranted to identify such a factor(s) and elucidate the mechanism by which sEH activity (or sEH P/S ratio) is reduced in postprandial states.
Assuntos
Epóxido Hidrolases/sangue , Microbioma Gastrointestinal/fisiologia , Insulina/metabolismo , Refeições , Modelos Biológicos , Estresse Oxidativo , Potássio na Dieta/administração & dosagem , Algoritmos , Animais , Antibacterianos/farmacologia , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/prevenção & controle , Eicosanoides/sangue , Eicosanoides/metabolismo , Epóxido Hidrolases/química , Epóxido Hidrolases/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Técnica Clamp de Glucose , Insulina/análise , Secreção de Insulina , Masculino , Estresse Oxidativo/efeitos dos fármacos , Oxilipinas/sangue , Período Pós-Prandial , Potássio na Dieta/uso terapêutico , Ratos Wistar , Reprodutibilidade dos Testes , SolubilidadeRESUMO
Previous rodent studies showed that when injected into the brain, free fatty acids (FFAs) reduced food intake in an oleate-specific manner. The present study was performed to test whether food intake is regulated by circulating FFAs in an oleate-specific manner. Male Wistar rats received an intravenous infusion of olive, safflower, or coconut oil (100mg/h), together with heparin, to raise circulating oleate, linoleate, or palmitate, respectively, and their effects on overnight food intake were evaluated. Compared to other oils, olive oil infusion showed a significantly greater effect to reduce food intake (P<0.01). Total caloric intake, the sum of the calories from the diet and infused oil, was significantly reduced with olive oil (P<0.01) but not with coconut or safflower oil infusion, suggesting an oleate-specific effect on caloric intake. To further test this idea, different groups of rats received an intravenous infusion of oleate, linoleate, or octanoate (0.5mg/h). Oleate infusion decreased overnight food intake by 26% (P<0.001), but no significant effect was seen with linoleate, octanoate, or vehicle infusion (P>0.05). The effects of olive oil or oleate infusion could not be explained by changes in plasma glucose, insulin, leptin, or total FFA levels. The olive oil effect on food intake was not reduced in vagotomized rats, suggesting that oleate sensing may not involve peripheral sensors. In contrast, olive oil's effect was attenuated in high-fat-fed rats, suggesting that this effect is regulated (or impaired) under physiological (or pathological) conditions. Taken together, the present study provides evidence that circulating oleate is sensed by the brain differentially from other FFAs to control feeding in rats.