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Long-chain fatty acids (FAs) are components of plasma membranes and an efficient fuel source and also serve as metabolic regulators through FA signaling mediated by membrane FA receptors. Impaired tissue FA uptake has been linked to major complications of obesity, including insulin resistance, cardiovascular disease, and type 2 diabetes. Fatty acid interactions with a membrane receptor and the initiation of signaling can modify pathways related to nutrient uptake and processing, cell proliferation or differentiation, and secretion of bioactive factors. Here, we review the major membrane receptors involved in FA uptake and FA signaling. We focus on two types of membrane receptors for long-chain FAs: CD36 and the G protein-coupled FA receptors FFAR1 and FFAR4. We describe key signaling pathways and metabolic outcomes for CD36, FFAR1, and FFAR4 and highlight the parallels that provide insight into FA regulation of cell function.
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Diabetes Mellitus Tipo 2 , Humanos , Transducción de Señal/fisiología , Receptores Acoplados a Proteínas G/metabolismo , Ácidos Grasos/metabolismo , Membrana Celular/metabolismo , Antígenos CD36/metabolismoRESUMEN
Vaccenic acid (VA), the predominant ruminant-derivedtransfat in the food chain, ameliorates hyperlipidemia, yet mechanisms remain elusive. We investigated whether VA could influence tissue endocannabinoids (ECs) by altering the availability of their biosynthetic precursor, arachidonic acid (AA), in membrane phospholipids (PLs). JCR:LA-cprats were assigned to a control diet with or without VA (1% w/w),cis-9,trans-11 conjugated linoleic acid (CLA) (1% w/w) or VA+CLA (1% + 0.5% w/w) for 8 weeks. VA reduced the EC, 2-arachidonoylglycerol (2-AG), in the liver and visceral adipose tissue (VAT) relative to control diet (P< 0.001), but did not change AA in tissue PLs. There was no additive effect of combining VA+CLA on 2-AG relative to VA alone (P> 0.05). Interestingly, VA increased jejunal concentrations of anandamide and those of the noncannabinoid signaling molecules, oleoylethanolamide and palmitoylethanolamide, relative to control diet (P< 0.05). This was consistent with a lower jejunal protein abundance (but not activity) of their degrading enzyme, fatty acid amide hydrolase, as well as the mRNA expression of TNFα and interleukin 1ß (P< 0.05). The ability of VA to reduce 2-AG in the liver and VAT provides a potential mechanistic explanation to alleviate ectopic lipid accumulation. The opposing regulation of ECs and other noncannabinoid lipid signaling molecules by VA suggests an activation of benefit via the EC system in the intestine.
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Antiinflamatorios/farmacología , Ácidos Araquidónicos/metabolismo , Endocannabinoides/metabolismo , Etanolaminas/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/efectos de los fármacos , Síndrome Metabólico/metabolismo , Ácidos Oléicos/farmacología , Alcamidas Poliinsaturadas/metabolismo , Amidohidrolasas/genética , Amidohidrolasas/metabolismo , Animales , Antiinflamatorios/uso terapéutico , Células CACO-2 , Citocinas/genética , Citocinas/metabolismo , Suplementos Dietéticos , Modelos Animales de Enfermedad , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Intestinos/patología , Grasa Intraabdominal/efectos de los fármacos , Grasa Intraabdominal/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Lípidos de la Membrana/metabolismo , Ácidos Oléicos/uso terapéutico , ARN Mensajero/genética , ARN Mensajero/metabolismo , RatasRESUMEN
The liver coordinates the systemic response to nutrient deprivation and availability by producing glucose from gluconeogenesis during fasting and synthesizing lipids via de novo lipogenesis (DNL) when carbohydrates are abundant. Mitochondrial pyruvate metabolism is thought to play important roles in both gluconeogenesis and DNL. We examined the effects of hepatocyte-specific mitochondrial pyruvate carrier (MPC) deletion on the fasting-refeeding response. Rates of DNL during refeeding were impaired by liver MPC deletion, but this did not reduce intrahepatic lipid content. During fasting, glycerol is converted to glucose by two pathways; a direct cytosolic pathway essentially reversing glycolysis and an indirect mitochondrial pathway requiring the MPC. MPC deletion reduced the incorporation of 13C-glycerol into TCA cycle metabolites but not into newly synthesized glucose. However, suppression of glycerol metabolism did not affect glucose concentrations in fasted hepatocyte-specific MPC-deficient mice. Thus, glucose production by kidney and intestine may compensate for MPC deficiency in hepatocytes.
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The liver coordinates the systemic response to nutrient deprivation and availability by producing glucose from gluconeogenesis during fasting and synthesizing lipids via de novo lipogenesis (DNL) when carbohydrates are abundant. Mitochondrial pyruvate metabolism is thought to play important roles in both gluconeogenesis and DNL. We examined the effects of hepatocyte-specific mitochondrial pyruvate carrier (MPC) deletion on the fasting-refeeding response. Rates of DNL during refeeding were impaired by hepatocyte MPC deletion, but this did not reduce intrahepatic lipid content. During fasting, glycerol is converted to glucose by two pathways; a direct cytosolic pathway and an indirect mitochondrial pathway requiring the MPC. Hepatocyte MPC deletion reduced the incorporation of 13C-glycerol into TCA cycle metabolites, but not into new glucose. Furthermore, suppression of glycerol and alanine metabolism did not affect glucose concentrations in fasted hepatocyte-specific MPC-deficient mice, suggesting multiple layers of redundancy in glycemic control in mice.
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BackgroundIt is increasingly recognized that intestinal cells can store lipids after a meal, yet the effect of this phenomenon on lipid absorption patterns in insulin resistance remains unknown.MethodsThe kinetics of meal fat appearance were measured in insulin-sensitive (IS, n = 8) and insulin-resistant (IR, n = 8) subjects after sequential, isotopically labeled lunch and dinner meals. Plasma dynamics on triacylglycerol-rich (TAG-rich) lipoproteins and plasma hormones were analyzed using a nonlinear, non-steady state kinetic model.ResultsAt the onset of dinner, IS subjects showed an abrupt plasma appearance of lunch lipid consistent with the "second-meal effect," followed by slower appearance of dinner fat in plasma, resulting in reduced accumulation of dinner TAG of 48% compared with lunch. By contrast, IR subjects exhibited faster meal TAG appearance rates after both lunch and dinner. This effect of lower enterocyte storage between meals was associated with greater nocturnal and next-morning hyperlipidemia. The biochemical data and the kinetic analysis of second-meal effect dynamics are consistent with rapid secretion of stored TAG bypassing lipolysis and resynthesis. In addition, the data are consistent with a role for the diurnal pattern of plasma leptin in regulating the processing of dietary lipid.ConclusionThese data support the concept that intestinal lipid storage may be physiologically beneficial in IS subjects.Trial registrationClinicalTrials.gov NCT02020343.FundingThis study was supported by a grant from the American Diabetes Association (grant 1-13-TS-12).
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Grasas de la Dieta/metabolismo , Resistencia a la Insulina , Absorción Intestinal/fisiología , Intestinos/fisiología , Leptina , Metabolismo de los Lípidos/fisiología , Adulto , Distribución de la Grasa Corporal , Conducta Alimentaria/fisiología , Femenino , Humanos , Secreción de Insulina , Leptina/sangre , Leptina/metabolismo , Lipoproteínas/metabolismo , Masculino , Triglicéridos/metabolismoRESUMEN
The gastric epithelium is often exposed to injurious elements and failure of appropriate healing predisposes to ulcers, hemorrhage, and ultimately cancer. We examined the gastric function of CD36, a protein linked to disease and homeostasis. We used the tamoxifen model of gastric injury in mice null for Cd36 (Cd36-/-), with Cd36 deletion in parietal cells (PC-Cd36-/-) or in endothelial cells (EC-Cd36-/-). CD36 expresses on corpus ECs, on PC basolateral membranes, and in gastrin and ghrelin cells. Stomachs of Cd36-/- mice have altered gland organization and secretion, more fibronectin, and inflammation. Tissue respiration and mitochondrial efficiency are reduced. Phospholipids increased and triglycerides decreased. Mucosal repair after injury is impaired in Cd36-/- and EC-Cd36-/-, not in PC-Cd36-/- mice, and is due to defect of progenitor differentiation to PCs, not of progenitor proliferation or mature PC dysfunction. Relevance to humans is explored in the Vanderbilt BioVu using PrediXcan that links genetically-determined gene expression to clinical phenotypes, which associates low CD36 mRNA with gastritis, gastric ulcer, and gastro-intestinal hemorrhage. A CD36 variant predicted to disrupt an enhancer site associates (p < 10-17) to death from gastro-intestinal hemorrhage in the UK Biobank. The findings support role of CD36 in gastric tissue repair, and its deletion associated with chronic diseases that can predispose to malignancy.
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Antígenos CD36/genética , Mucosa Gástrica/metabolismo , Gastritis/genética , Hemorragia Gastrointestinal/genética , Úlcera Gástrica/genética , Animales , Antígenos CD36/metabolismo , Células Endoteliales/metabolismo , Femenino , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
INTRODUCTION: Excess energy intake by spectators at a sporting event (i.e., a tailgate) might cause acute negative health effects. However, limited data exist regarding the effects of overeating and alcohol consumption on lipid metabolism and the potential to gain intrahepatic triacylglycerols (IHTG). We tested the hypothesis that overconsumption of food and alcohol would significantly increase both hepatic de novo lipogenesis (DNL) and IHTG. METHODS: Eighteen males (mean ± SD, age: 31.4 ± 7.3 years, BMI: 32.1 ± 5.9 kg/m2) were given alcoholic drinks to elevate blood alcohol for 5 h, while highly palatable food was presented. Blood samples were collected and DNL in TG-rich lipoproteins (TRL) was measured by GC/MS, IHTG was measured via MRS (n = 15), and substrate oxidation was measured via indirect calorimetry. RESULTS: Subjects consumed 5087 ± 149 kcal (191 ± 25% excess of total daily energy needs including 171 ± 24 g alcohol), which increased plasma insulin, glucose, TG, and decreased NEFA (ANOVA p ≤ 0.003 for all). Both DNL and TRL-TG increased (p < 0.001), while IHTG did not change in the group as a whole (p = 0.229). Individual subject data revealed remarkably differing responses for IHTG (nine increased, five decreased, one did not change). Despite maintaining equal breath alcohol levels, subjects with IHTG elevations exhibited higher DNL, consumed 90% less alcohol (p = 0.048), tended to consume more carbohydrates, and exhibited lower whole-body fat oxidation (not significant) compared to those whose IHTG was reduced. DISCUSSION: This study demonstrates that acute excess energy intake may have differing effects on an individual's DNL and IHTG, and dietary carbohydrate may influence DNL more than alcohol.
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Consumo de Bebidas Alcohólicas , Carbohidratos de la Dieta , Hiperfagia , Metabolismo de los Lípidos , Adulto , Consumo de Bebidas Alcohólicas/metabolismo , Carbohidratos de la Dieta/metabolismo , Humanos , Hiperfagia/metabolismo , Hígado/metabolismo , Masculino , Deportes , Triglicéridos , Adulto JovenRESUMEN
Compared to low-fat diets, low-carbohydrate (CHO) diets cause weight loss (WL) over a faster time frame; however, it is unknown how changes in food cravings and eating behavior contribute to this more rapid WL in the early phases of dieting. We hypothesized that reductions in food cravings and improved eating behaviors would be evident even after a relatively short (4-week) duration of CHO-restriction, and that these changes would be associated with WL. Adult participants (n = 19, 53% males, mean ± SD: BMI = 34.1 ± 0.8 kg/m2; age 40.6 ± 1.9 years) consumed a CHO-restricted diet (14% CHO, 58% fat, 28% protein) for 4 weeks. Before and after the intervention, specific and total cravings were measured with the Food Craving Inventory (FCI) and eating behaviors assessed with the Three-Factor Eating questionnaire. Food cravings were significantly reduced at week 4, while women had significantly greater reductions in sweet cravings than men. Dietary restraint was significantly increased by 102%, while disinhibiton and hunger scores were reduced (17% and 22%, respectively, p < 0.05). Changes in cravings were unrelated to changes in body weight except for the change in high-fat cravings where those who lost the most weight experienced the least reductions in fat cravings (r = -0.458, p = 0.049). Changes in dietary restraint were inversely related to several FCI subscales. A short-term, low-CHO diet was effective in reducing food cravings. These data suggest that in subjects that have successfully lost weight on a low-CHO diet, those who craved high-fat foods at the onset were able to satisfy their cravings-potentially due to the high-fat nature of this restricted diet.
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Ansia , Dieta Baja en Carbohidratos , Ingestión de Alimentos , Alimentos/clasificación , Pérdida de Peso , Adulto , Conducta Alimentaria , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Increased aortic stiffness, measured by carotid-to-femoral pulse wave velocity (PWV), is an independent predictor of cardiovascular disease, and past data have shown that low-fat and low-energy diets, fed for 8-24 weeks, lower PWV. The purpose of this study was to determine whether a reduction in PWV would be achieved by dietary carbohydrate (CHO) restriction, shown to bring about weight loss over a shorter timeframe. Men (n = 10, age: 41.8 ± 10.2 years, BMI: 34.2 ± 3.0 kg/m2 (mean ± SD)) and women (n = 10, age: 38.6 ± 6.1 years, BMI: 33.5 ± 3.8 kg/m2) with characteristics of insulin resistance and the metabolic syndrome consumed a structured, CHO-restricted diet for 4 weeks (energy deficit, 645 kcal/day). For the whole group, subjects lost 5.4% ± 0.5% (P < 0.001) of body weight and experienced significant reductions in blood pressure (6%-8%), plasma insulin (34%), and triglycerides (34%). PWV was reduced by 6% ± 2% (7.1 ± 0.2 m/s to 6.7 ± 0.2 m/s, P = 0.008) and surprisingly, in women, it fell significantly (from 7.2 ± 0.3 m/s to 6.3 ± 0.3 m/s, P = 0.028), while no changes were observed in men (7.2 ± 0.3 vs. 7.0 ± 0.3 m/s, P = 0.144). This is the first study to demonstrate that weight loss can improve PWV in as little as 4 weeks and that dietary CHO restriction may be an effective treatment for reducing aortic stiffness in women. Future studies are needed to establish the mechanisms by which dietary CHO restriction may confer more cardiovascular benefits to women than to men.
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Aorta/fisiología , Dieta Baja en Carbohidratos , Sobrepeso , Análisis de la Onda del Pulso , Pérdida de Peso/fisiología , Adulto , Carbohidratos de la Dieta , Ingestión de Alimentos , Femenino , Humanos , Resistencia a la Insulina/fisiología , Masculino , Persona de Mediana Edad , Sobrepeso/dietoterapia , Sobrepeso/epidemiología , Sobrepeso/fisiopatologíaRESUMEN
During reduced energy intake, skeletal muscle maintains homeostasis by rapidly suppressing insulin-stimulated glucose utilization. Loss of this adaptation is observed with deficiency of the fatty acid transporter CD36. A similar loss is also characteristic of the insulin-resistant state where CD36 is dysfunctional. To elucidate what links CD36 to muscle glucose utilization, we examined whether CD36 signaling might influence insulin action. First, we show that CD36 deletion specific to skeletal muscle reduces expression of insulin signaling and glucose metabolism genes. It decreases muscle ceramides but impairs glucose disposal during a meal. Second, depletion of CD36 suppresses insulin signaling in primary-derived human myotubes, and the mechanism is shown to involve functional CD36 interaction with the insulin receptor (IR). CD36 promotes tyrosine phosphorylation of IR by the Fyn kinase and enhances IR recruitment of P85 and downstream signaling. Third, pretreatment for 15 min with saturated fatty acids suppresses CD36-Fyn enhancement of IR phosphorylation, whereas unsaturated fatty acids are neutral or stimulatory. These findings define mechanisms important for muscle glucose metabolism and optimal insulin responsiveness. Potential human relevance is suggested by genome-wide analysis and RNA sequencing data that associate genetically determined low muscle CD36 expression to incidence of type 2 diabetes.
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Antígenos CD36/fisiología , Glucosa/metabolismo , Insulina/metabolismo , Músculo Esquelético/metabolismo , Receptor de Insulina/metabolismo , Animales , Antígenos CD36/genética , Células CHO , Metabolismo de los Hidratos de Carbono/genética , Células Cultivadas , Cricetinae , Cricetulus , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/genética , Femenino , Humanos , Resistencia a la Insulina/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal/genéticaRESUMEN
Cardiovascular disease (CVD) is the leading cause of death in the United States. Although the role of habitual lifestyle factors such as physical activity and dietary patterns in increasing CVD risk has long been appreciated, less is known about how acute daily activities may cumulatively contribute to long-term disease risk. Here, the term acute refers to metabolic responses occurring in a short period of time after eating, and the goal of this article is to review recently identified stressors that can occur after meals and during the sleep-wake cycle to affect macronutrient metabolism. It is hypothesized that these events, when repeated on a regular basis, contribute to the observed long-term behavioral risks identified in population studies. In this regard, developments in research methods have supported key advancements in 3 fields of macronutrient metabolism. The first of these research areas is the focus on the immediate postmeal metabolism, spanning from early intestinal adsorptive events to the impact of incretin hormones on these events. The second topic is a focus on the importance of meal components on postprandial vasculature function. Finally, some of the most exciting advances are being made in understanding dysregulation in metabolism early in the day, due to insufficient sleep, that may affect subsequent processing of nutrients throughout the day. Key future research questions are highlighted which will lead to a better understanding of the relations between nocturnal, basal (fasting), and early postmeal events, and aid in the development of optimal sleep and targeted dietary patterns to reduce cardiometabolic risk.
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Enfermedades Cardiovasculares/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Grasas de la Dieta/metabolismo , Endotelio Vascular/metabolismo , Enterocitos/metabolismo , Absorción Intestinal , Estrés Oxidativo , Animales , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/inmunología , Congresos como Asunto , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/inmunología , Endotelio Vascular/inmunología , Metabolismo Energético , Enterocitos/inmunología , Humanos , Resistencia a la Insulina , Periodo Posprandial , Riesgo , Trastornos del Sueño-Vigilia/fisiopatología , Estados Unidos/epidemiologíaRESUMEN
Obesity and its metabolic complications have emerged as the epidemic of the new millennia. The use of obese rodent models continues to be a productive component of efforts to understand the concomitant metabolic complications of this disease. In 1978, the JCR:LA-cp rat model was developed with an autosomal recessive corpulent (cp) trait resulting from a premature stop codon in the extracellular domain of the leptin receptor. Rats that are heterozygous for the cp trait are lean-prone, while those that are homozygous (cp/cp) spontaneously display the pathophysiology of obesity as well as a metabolic syndrome (MetS)-like phenotype. Over the years, there have been formidable scientific contributions that have originated from this rat model, much of which has been reviewed extensively up to 2008. The premise of these earlier studies focused on characterizing the pathophysiology of MetS-like phenotype that was spontaneously apparent in this model. The purpose of this review is to highlight areas of recent advancement made possible by this model including; emerging appreciation of the "thrifty gene" hypothesis in the context of obesity, the concept of how chronic inflammation may drive obesogenesis, the impact of acute forms of inflammation to the brain and periphery during chronic obesity, the role of dysfunctional insulin metabolism on lipid metabolism and vascular damage, and the mechanistic basis for altered vascular function as well as novel parallels between the human condition and the female JCR:LA-cp rat as a model for polycystic ovary disease (PCOS).
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OBJECTIVE: Statins are widely used for the treatment of hyperlipidemia to reduce cardiovascular disease (CVD) risk. Intriguingly, recent reports suggest that whilst statins are effective in reducing hepatic cholesterol synthesis, they in turn may up-regulate intestinal cholesterol absorption. The direct effects and/or mechanisms of this phenomenon remain largely unknown. The aim of this study was to investigate the potential for statins to increase intestinal lipid absorption and/or secretion in a rodent model of the metabolic syndrome (MetS). METHODS AND RESULTS: Mets JCR:LA-cp rats received a 1% cholesterol diet containing Simvastatin (0.01% w/w), for 8 weeks. Fasting and postprandial plasma biochemical profile was assessed using enzymatic assays and a modified apoB48 (chylomicron; CM) western blotting protocol. Statin treatment reduced fasting plasma TG (-49%), cholesterol (-24%) and postprandial plasma apoB48 (-58%). The intestinal secretion of lipids into mesenteric lymph was assessed using lymph fistulae procedures. Interestingly, MetS rats treated with statin secreted greater cholesterol (1.9-fold) and TG (1.5-fold) per apoB48 particle, into mesenteric lymph. This was shown to be as a result of simvastatin-induced increase in intestinal cholesterol absorption (31.5%). Experiments using in vivo inhibition of lipoprotein lipase (LPL; poloxamer-407) demonstrated statin treatment reduced hepatic cholesterol secretion (-49%), but significantly increased hepatic (73%) TG secretion in MetS rats. Statin treatment also increased the expression of genes involved in lipid synthesis (Hmgcr, Srebp1, Fas, Acc; 33-67%) and reduced those involved in efflux (Abca1, Abcg8; -36 to 73%) in enterocytes and liver of MetS rats versus untreated control. CONCLUSIONS: In a rodent model of MetS, statin treatment adversely up-regulates intestinal lipid secretion as a result of increased intestinal cholesterol absorption, and increases the intestinal expression of genes involved in lipid synthesis; effects which may confound clinical benefits to remnant dyslipidemia.