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1.
JCI Insight ; 7(16)2022 08 22.
Artículo en Inglés | MEDLINE | ID: mdl-35900871

RESUMEN

The epidermis is the outermost layer of skin. Here, we used targeted lipid profiling to characterize the biogeographic alterations of human epidermal lipids across 12 anatomically distinct body sites, and we used single-cell RNA-Seq to compare keratinocyte gene expression at acral and nonacral sites. We demonstrate that acral skin has low expression of EOS acyl-ceramides and the genes involved in their synthesis, as well as low expression of genes involved in filaggrin and keratin citrullination (PADI1 and PADI3) and corneodesmosome degradation, changes that are consistent with increased corneocyte retention. Several overarching principles governing epidermal lipid expression were also noted. For example, there was a strong negative correlation between the expression of 18-carbon and 22-carbon sphingoid base ceramides. Disease-specific alterations in epidermal lipid gene expression and their corresponding alterations to the epidermal lipidome were characterized. Lipid biomarkers with diagnostic utility for inflammatory and precancerous conditions were identified, and a 2-analyte diagnostic model of psoriasis was constructed using a step-forward algorithm. Finally, gene coexpression analysis revealed a strong connection between lipid and immune gene expression. This work highlights (a) mechanisms by which the epidermis is uniquely adapted for the specific environmental insults encountered at different body surfaces and (b) how inflammation-associated alterations in gene expression affect the epidermal lipidome.


Asunto(s)
Epidermis , Análisis de la Célula Individual , Carbono/metabolismo , Ceramidas/metabolismo , Epidermis/metabolismo , Humanos , Queratinocitos/metabolismo
2.
BMJ Open Diabetes Res Care ; 7(1): e000691, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31543975

RESUMEN

Objective: To examine the associations of fatty acids in the de novo lipogenesis (DNL) pathway, specifically myristic acid (14:0), palmitic acid (16:0), cis-palmitoleic acid (c16:1 n-7), cis-myristoleic acid (c14:1n5), stearic acid (18:0) and cis-oleic acid (c18:1 n-9), with 5-year risk of type 2 diabetes. We hypothesized that DNL fatty acids are associated with risk of type 2 diabetes independent of insulin sensitivity. Research design and methods: We evaluated 719 (mean age 55.1±8.5 years, 44.2% men, 42.3% Caucasians) participants from the Insulin Resistance Atherosclerosis Study. Multivariable logistic regression models with and without adjustment of insulin sensitivity were used to assess prospective associations of DNL fatty acids with incident type 2 diabetes. Results: Type 2 diabetes incidence was 20.3% over 5 years. In multivariable regression models, palmitic, palmitoleic, myristic, myristoleic and oleic acids were associated with increased risk of type 2 diabetes (p<0.05). Palmitic acid had the strongest association (OR per standard unit of palmitic acid 1.46; 95% CI 1.23 to 1.76; p<0.001), which remained similar with addition of insulin sensitivity and acute insulin response (AIR) to the model (OR 1.36; 95% CI 1.09 to 1.70, p=0.01). Oleic and palmitoleic acids were also independently associated with incident type 2 diabetes. In multivariable models, ratios of fatty acids corresponding to stearoyl CoA desaturase-1 and Elovl6 enzymatic activity were significantly associated with risk of type 2 diabetes independent of insulin sensitivity and AIR. Conclusions: We observed associations of DNL fatty acids with type 2 diabetes incidence independent of insulin sensitivity.


Asunto(s)
Aterosclerosis/complicaciones , Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/etiología , Ácidos Grasos/metabolismo , Resistencia a la Insulina , Lipogénesis , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Transducción de Señal
3.
Mol Metab ; 28: 58-72, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31422082

RESUMEN

OBJECTIVE: Saturated and trans fat consumption is associated with increased cardiovascular disease (CVD) risk. Current dietary guidelines recommend low fat and significantly reduced trans fat intake. Full fat dairy can worsen dyslipidemia, but recent epidemiological studies show full-fat dairy consumption may reduce diabetes and CVD risk. This dairy paradox prompted a reassessment of the dietary guidelines. The beneficial metabolic effects in dairy have been claimed for a ruminant-derived, trans fatty acid, trans-C16:1n-7 or trans-palmitoleate (trans-PAO). A close relative, cis-PAO, is produced by de novo lipogenesis and mediates inter-organ crosstalk, improving insulin-sensitivity and alleviating atherosclerosis in mice. These findings suggest trans-PAO may be a useful substitute for full fat dairy, but a metabolic function for trans-PAO has not been shown to date. METHODS: Using lipidomics, we directly investigated trans-PAO's impact on plasma and tissue lipid profiles in a hypercholesterolemic atherosclerosis mouse model. Furthermore, we investigated trans-PAO's impact on hyperlipidemia-induced inflammation and atherosclerosis progression in these mice. RESULTS: Oral trans-PAO supplementation led to significant incorporation of trans-PAO into major lipid species in plasma and tissues. Unlike cis-PAO, however, trans-PAO did not prevent organelle stress and inflammation in macrophages or atherosclerosis progression in mice. CONCLUSIONS: A significant, inverse correlation between circulating trans-PAO levels and diabetes incidence and cardiovascular mortality has been reported. Our findings show that trans-PAO can incorporate efficiently into the same pools that its cis counterpart is known to incorporate into. However, we found trans-PAO's anti-inflammatory and anti-atherosclerotic effects are muted due to its different structure from cis-PAO.


Asunto(s)
Aterosclerosis/prevención & control , Ácidos Grasos Monoinsaturados/química , Ácidos Grasos Monoinsaturados/farmacología , Animales , Aterosclerosis/metabolismo , Aterosclerosis/patología , Células Cultivadas , Masculino , Ratones , Ratones Noqueados
4.
Sci Transl Med ; 11(492)2019 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-31092695

RESUMEN

Sebum plays important physiological roles in human skin. Excess sebum production contributes to the pathogenesis of acne vulgaris, and suppression of sebum production reduces acne incidence and severity. We demonstrate that sebum production in humans depends on local flux through the de novo lipogenesis (DNL) pathway within the sebocyte. About 80 to 85% of sebum palmitate (16:0) and sapienate (16:1n10) were derived from DNL, based on stable isotope labeling, much higher than the contribution of DNL to triglyceride palmitate in circulation (~20%), indicating a minor contribution by nonskin sources to sebum lipids. This dependence on local sebocyte DNL was not recapitulated in two widely used animal models of sebum production, Syrian hamsters and Göttingen minipigs. Confirming the importance of DNL for human sebum production, an acetyl-CoA carboxylase inhibitor, ACCi-1, dose-dependently suppressed DNL and blocked synthesis of fatty acids, triglycerides, and wax esters but not free sterols in human sebocytes in vitro. ACCi-1 dose-dependently suppressed facial sebum excretion by ~50% (placebo adjusted) in human individuals dosed orally for 2 weeks. Sebum triglycerides, wax esters, and free fatty acids were suppressed by ~66%, whereas non-DNL-dependent lipid species, cholesterol, and squalene were not reduced, confirming selective modulation of DNL-dependent lipids. Last, individuals with acne vulgaris exhibited increased sebum production rates relative to individuals with normal skin, with >80% of palmitate and sapienate derived from DNL. These findings highlight the importance of local sebocyte DNL for human skin sebaceous gland biology and illuminate a potentially exploitable therapeutic target for the treatment of acne vulgaris.


Asunto(s)
Acetil-CoA Carboxilasa/antagonistas & inhibidores , Acné Vulgar/enzimología , Inhibidores Enzimáticos/farmacología , Lipogénesis , Sebo/metabolismo , Acetil-CoA Carboxilasa/metabolismo , Adolescente , Adulto , Animales , Células Cultivadas , Cricetinae , Inhibidores Enzimáticos/química , Femenino , Humanos , Lipogénesis/efectos de los fármacos , Masculino , Malonil Coenzima A/metabolismo , Persona de Mediana Edad , Ratas Wistar , Glándulas Sebáceas/efectos de los fármacos , Glándulas Sebáceas/metabolismo , Glándulas Sebáceas/patología , Sebo/efectos de los fármacos , Porcinos , Porcinos Enanos , Triglicéridos/biosíntesis , Adulto Joven
5.
J Lipid Res ; 58(11): 2171-2179, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28928169

RESUMEN

Recent evidence has documented distinct effects of individual saturated FAs (SFAs) on cardiometabolic outcomes, with potential protective effects from odd- and very long-chain SFAs (VLSFAs). Cross-sectional and prospective associations of individual serum SFAs (12:0, 14:0, 15:0, 16:0, 18:0, 20:0, 22:0, and total SFA) with proinflammatory biomarkers and adiponectin were investigated in 555 adults from the IRAS. Principal component analysis (PCA) of proinflammatory markers yielded three clusters: principal component (PC) 1: fibrinogen, white cell count, C-reactive protein; PC 2: plasminogen activator inhibitor-1 (PAI-1), TNF-α, IL-18; PC 3: IL-6 and IL-8. Cross-sectional analyses on proinflammatory PCs and adiponectin, and prospective analyses on 5 year PAI-1 and fibrinogen concentrations were conducted with multiple regression. Total SFA and 16:0 were positively associated with PC 1 and PC 2, and negatively associated with adiponectin. The 14:0 was positively associated with PC 1 and negatively associated with adiponectin. In contrast, 15:0, 20:0, and 22:0 were negatively associated with PC 2, and 20:0 and 22:0 were positively associated with adiponectin. The 18:0 was negatively associated with PC 3. Prospectively, 15:0, 18:0, 20:0, and 22:0 were negatively associated with 5 year PAI-1 concentrations. The results demonstrate that individual SFAs have distinct roles in subclinical inflammation, highlighting the unique metabolic impacts of individual SFAs.


Asunto(s)
Aterosclerosis/sangre , Ácidos Grasos/sangre , Resistencia a la Insulina , Adulto , Anciano , Aterosclerosis/epidemiología , Biomarcadores/sangre , Enfermedad Crónica , Estudios Transversales , Femenino , Fibrinógeno/metabolismo , Estudios de Seguimiento , Humanos , Inflamación/sangre , Masculino , Persona de Mediana Edad , Inhibidor 1 de Activador Plasminogénico/sangre
6.
Cell ; 167(4): 973-984.e12, 2016 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-27814523

RESUMEN

In obesity, macrophages and other immune cells accumulate in insulin target tissues, promoting a chronic inflammatory state and insulin resistance. Galectin-3 (Gal3), a lectin mainly secreted by macrophages, is elevated in both obese subjects and mice. Administration of Gal3 to mice causes insulin resistance and glucose intolerance, whereas inhibition of Gal3, through either genetic or pharmacologic loss of function, improved insulin sensitivity in obese mice. In vitro treatment with Gal3 directly enhanced macrophage chemotaxis, reduced insulin-stimulated glucose uptake in myocytes and 3T3-L1 adipocytes and impaired insulin-mediated suppression of glucose output in primary mouse hepatocytes. Importantly, we found that Gal3 can bind directly to the insulin receptor (IR) and inhibit downstream IR signaling. These observations elucidate a novel role for Gal3 in hepatocyte, adipocyte, and myocyte insulin resistance, suggesting that Gal3 can link inflammation to decreased insulin sensitivity. Inhibition of Gal3 could be a new approach to treat insulin resistance.


Asunto(s)
Galectina 3/sangre , Galectina 3/metabolismo , Adipocitos/metabolismo , Adipocitos/patología , Animales , Quimiotaxis , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Galectina 3/antagonistas & inhibidores , Galectina 3/genética , Hepatocitos/metabolismo , Hepatocitos/patología , Humanos , Insulina/sangre , Resistencia a la Insulina , Macrófagos/inmunología , Macrófagos/patología , Ratones , Ratones Noqueados , Células Musculares/metabolismo , Células Musculares/patología , Obesidad/inmunología , Obesidad/metabolismo , Obesidad/patología
7.
Sci Transl Med ; 8(358): 358ra126, 2016 09 28.
Artículo en Inglés | MEDLINE | ID: mdl-27683551

RESUMEN

De novo lipogenesis (DNL), the conversion of glucose and other substrates to lipids, is often associated with ectopic lipid accumulation, metabolic stress, and insulin resistance, especially in the liver. However, organ-specific DNL can also generate distinct lipids with beneficial metabolic bioactivity, prompting a great interest in their use for the treatment of metabolic diseases. Palmitoleate (PAO), one such bioactive lipid, regulates lipid metabolism in liver and improves glucose utilization in skeletal muscle when it is generated de novo from the obese adipose tissue. We show that PAO treatment evokes an overall lipidomic remodeling of the endoplasmic reticulum (ER) membranes in macrophages and mouse tissues, which is associated with resistance of the ER to hyperlipidemic stress. By preventing ER stress, PAO blocks lipid-induced inflammasome activation in mouse and human macrophages. Chronic PAO supplementation also lowers systemic interleukin-1ß (IL-1ß) and IL-18 concentrations in vivo in hyperlipidemic mice. Moreover, PAO prevents macrophage ER stress and IL-1ß production in atherosclerotic plaques in vivo, resulting in a marked reduction in plaque macrophages and protection against atherosclerosis in mice. These findings demonstrate that oral supplementation with a product of DNL such as PAO can promote membrane remodeling associated with metabolic resilience of intracellular organelles to lipid stress and limit the progression of atherosclerosis. These findings support therapeutic PAO supplementation as a potential preventive approach against complex metabolic and inflammatory diseases such as atherosclerosis, which warrants further studies in humans.


Asunto(s)
Aterosclerosis/tratamiento farmacológico , Aterosclerosis/patología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Ácidos Grasos Monoinsaturados/uso terapéutico , Inflamasomas/metabolismo , Animales , Apolipoproteínas E/deficiencia , Apolipoproteínas E/metabolismo , Apoptosis/efectos de los fármacos , Células Cultivadas , Citocinas/metabolismo , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Ácidos Grasos Monoinsaturados/farmacología , Inflamación/metabolismo , Inflamación/patología , Mediadores de Inflamación/metabolismo , Membranas Intracelulares/metabolismo , Lípidos , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Placa Aterosclerótica/patología
8.
Am J Physiol Endocrinol Metab ; 309(3): E293-301, 2015 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-26058862

RESUMEN

Docosahexaenoic acid (DHA 22:6n-3) and salicylate are both known to exert anti-inflammatory effects. This study investigated the effects of a novel bifunctional drug compound consisting of DHA and salicylate linked together by a small molecule that is stable in plasma but hydrolyzed in the cytoplasm. The components of the bifunctional compound acted synergistically to reduce inflammation mediated via nuclear factor κB in cultured macrophages. Notably, oral administration of the bifunctional compound acted in two distinct ways to mitigate hyperglycemia in high-fat diet-induced insulin resistance. In mice with diet-induced obesity, the compound lowered blood glucose by reducing hepatic insulin resistance. It also had an immediate glucose-lowering effect that was secondary to enhanced glucagon-like peptide-1 (GLP-1) secretion and abrogated by the administration of exendin(9-39), a GLP-1 receptor antagonist. These results suggest that the bifunctional compound could be an effective treatment for individuals with type 2 diabetes and insulin resistance. This strategy could also be employed in other disease conditions characterized by chronic inflammation.


Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Ácidos Docosahexaenoicos/uso terapéutico , Hipoglucemiantes/uso terapéutico , Resistencia a la Insulina , Obesidad/tratamiento farmacológico , Profármacos/uso terapéutico , Salicilatos/uso terapéutico , Administración Oral , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacología , Glucemia/análisis , Línea Celular Transformada , Línea Celular Tumoral , Células Cultivadas , Dieta Alta en Grasa/efectos adversos , Ácidos Docosahexaenoicos/administración & dosificación , Ácidos Docosahexaenoicos/farmacología , Péptido 1 Similar al Glucagón/agonistas , Péptido 1 Similar al Glucagón/antagonistas & inhibidores , Péptido 1 Similar al Glucagón/metabolismo , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacología , Hígado/efectos de los fármacos , Hígado/inmunología , Hígado/metabolismo , Hígado/patología , Macrófagos/citología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Obesidad/inmunología , Obesidad/metabolismo , Obesidad/fisiopatología , Estado Prediabético/etiología , Estado Prediabético/prevención & control , Profármacos/administración & dosificación , Profármacos/farmacología , Salicilatos/administración & dosificación , Salicilatos/farmacología , Transducción de Señal/efectos de los fármacos
10.
Am J Clin Nutr ; 100(6): 1532-40, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25411288

RESUMEN

BACKGROUND: Growing evidence suggests that dairy consumption is associated with lower type 2 diabetes risk. However, observational studies have reported inconsistent results, and few have examined dairy's association with the underlying disorders of insulin resistance and ß-cell dysfunction. OBJECTIVE: We investigated the association of the dairy fatty acid biomarkers pentadecanoic acid (15:0) and trans-palmitoleic acid (trans 16:1n-7) with type 2 diabetes traits by evaluating 1) prospective associations with incident diabetes after 5 y of follow-up and 2) cross-sectional associations with directly measured insulin resistance and ß-cell dysfunction. DESIGN: The study analyzed 659 adults without diabetes at baseline from the triethnic multicenter Insulin Resistance Atherosclerosis Study (IRAS). Diabetes status was assessed by using oral-glucose-tolerance tests. Frequently sampled intravenous-glucose-tolerance tests measured insulin sensitivity (SI) and ß-cell function [disposition index (DI)]. Serum fatty acids were quantified by using gas chromatography. Logistic and linear regression models were adjusted for demographic, lifestyle, and dietary variables. RESULTS: Serum 15:0 was a significant biomarker for total dairy intake in the IRAS cohort. It was associated with a decreased incident diabetes risk (OR: 0.73, P = 0.02) and was positively associated with log SI (ß: 0.84, P = 0.03) and log DI (ß: 2.21, P = 0.02) in fully adjusted models. trans 16:1n-7 was a marker of total partially hydrogenated dietary fat intake and was not associated with outcomes in fully adjusted models. CONCLUSIONS: Serum 15:0, a marker of short-term intake of this fatty acid, was inversely associated with diabetes risk in this multiethnic cohort. This study may contribute to future recommendations regarding the benefits of dairy products on type 2 diabetes risk.


Asunto(s)
Biomarcadores/sangre , Productos Lácteos , Diabetes Mellitus Tipo 2/sangre , Grasas de la Dieta/sangre , Ácidos Grasos/sangre , Adulto , Glucemia/metabolismo , Estudios Transversales , Etnicidad , Ácidos Grasos Monoinsaturados/sangre , Femenino , Estudios de Seguimiento , Prueba de Tolerancia a la Glucosa , Humanos , Resistencia a la Insulina , Células Secretoras de Insulina/metabolismo , Estilo de Vida , Modelos Lineales , Modelos Logísticos , Masculino , Persona de Mediana Edad , Estudios Prospectivos
11.
J Nutr ; 144(11): 1753-9, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25332473

RESUMEN

BACKGROUND: Previous human studies reported inconsistent effects of dietary protein and branched-chain amino acids (BCAAs) on insulin action and glucose metabolism. Similarly, it is unclear whether saturated fat (SF) intake influences these metabolic variables. OBJECTIVE: The objective of this study was to test the effects of high [30% of energy (%E)] vs. moderate (20%E) intakes of protein (primarily whey) on insulin action and lipid and lipoprotein concentrations in the context of both high (15%E) and low (7%E) SF diets. METHODS: The study was conducted as a randomized controlled trial in 158 overweight and obese men and women. After a 4-wk baseline diet [55%E carbohydrate, 15%E protein, 30%E fat (7%E SF)], participants were randomly assigned to 4 wk of either the baseline diet or 1 of 4 test diets containing 35%E carbohydrate and either 20%E or 30%E protein and either 7%E or 15%E SF. Frequently sampled i.v. glucose tolerance tests were administered after each dietary period. RESULTS: Other than significantly higher fasting glucose concentrations for high vs. moderate protein intakes with a low-fat diet (difference ± SE: 0.47 ± 0.14 mmol/L; P = 0.001), there were no significant effects of dietary protein or SF on glucose metabolism, plasma insulin, or concentrations of lipids and lipoproteins. Changes in plasma BCAAs across all diets were negatively correlated with changes in the metabolic clearance rate of insulin (ρ = -0.18, P = 0.03) and positively correlated with changes in the acute insulin response to glucose (ρ = 0.15, P = 0.05). CONCLUSIONS: These findings suggest that short-term intake of BCAAs can influence insulin dynamics. However, in this group of overweight and obese individuals, neither high protein nor SF intake affected insulin sensitivity or plasma concentrations of lipids and lipoproteins. This trial was registered at clinicaltrials.gov as NCT00508937.


Asunto(s)
Grasas de la Dieta/farmacología , Proteínas en la Dieta/farmacología , Resistencia a la Insulina , Lípidos/sangre , Lipoproteínas/sangre , Sobrepeso/sangre , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sobrepeso/metabolismo
12.
Obesity (Silver Spring) ; 22(12): 2570-8, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25251340

RESUMEN

OBJECTIVE: To identify metabolite patterns associated with childhood obesity, to examine relations of these patterns with measures of adiposity and cardiometabolic risk, and to evaluate associations with maternal peripartum characteristics. METHODS: Untargeted metabolomic profiling was used to quantify metabolites in plasma of 262 children (6-10 years). Principal components analysis was used to consolidate 345 metabolites into 18 factors and identified two that differed between obese (BMI ≥ 95‰; n = 84) and lean children (BMI < 85‰; n = 150). The relations of these factors with adiposity (fat mass, BMI, skinfold thicknesses) and cardiometabolic biomarkers (HOMA-IR, triglycerides, leptin, adiponectin, hsCRP, IL-6) using multivariable linear regression was then investigated. Finally, the associations of maternal prepregnancy obesity, gestational weight gain, and gestational glucose tolerance with the offspring metabolite patterns was examined. RESULTS: A branched-chain amino acid (BCAA)-related pattern and an androgen hormone pattern were higher in obese vs. lean children. Both patterns were associated with adiposity and worse cardiometabolic profiles. For example, each increment in the BCAA and androgen pattern scores corresponded with 6% (95% CI: 1, 13%) higher HOMA-IR. Children of obese mothers had 0.61 (0.13, 1.08) higher BCAA score than their counterparts. CONCLUSIONS: BCAA and androgen metabolites were associated with adiposity and cardiometabolic risk during mid-childhood. Maternal obesity may contribute to altered offspring BCAA metabolism.


Asunto(s)
Adiposidad , Enfermedades Cardiovasculares/prevención & control , Obesidad Infantil/metabolismo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Adiponectina/sangre , Índice de Masa Corporal , Proteína C-Reactiva/análisis , Enfermedades Cardiovasculares/etiología , Niño , Femenino , Hemoglobina Glucada/análisis , Humanos , Interleucina-6/sangre , Leptina/sangre , Masculino , Enfermedades Metabólicas/prevención & control , Obesidad/metabolismo , Obesidad Infantil/complicaciones , Embarazo , Complicaciones del Embarazo/metabolismo , Análisis de Componente Principal , Factores de Riesgo , Triglicéridos/sangre
13.
Nat Med ; 20(8): 942-7, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24997608

RESUMEN

It is well known that the ω-3 fatty acids (ω-3-FAs; also known as n-3 fatty acids) can exert potent anti-inflammatory effects. Commonly consumed as fish products, dietary supplements and pharmaceuticals, ω-3-FAs have a number of health benefits ascribed to them, including reduced plasma triglyceride levels, amelioration of atherosclerosis and increased insulin sensitivity. We reported that Gpr120 is the functional receptor for these fatty acids and that ω-3-FAs produce robust anti-inflammatory, insulin-sensitizing effects, both in vivo and in vitro, in a Gpr120-dependent manner. Indeed, genetic variants that predispose to obesity and diabetes have been described in the gene encoding GPR120 in humans (FFAR4). However, the amount of fish oils that would have to be consumed to sustain chronic agonism of Gpr120 is too high to be practical, and, thus, a high-affinity small-molecule Gpr120 agonist would be of potential clinical benefit. Accordingly, Gpr120 is a widely studied drug discovery target within the pharmaceutical industry. Gpr40 is another lipid-sensing G protein-coupled receptor, and it has been difficult to identify compounds with a high degree of selectivity for Gpr120 over Gpr40 (ref. 11). Here we report that a selective high-affinity, orally available, small-molecule Gpr120 agonist (cpdA) exerts potent anti-inflammatory effects on macrophages in vitro and in obese mice in vivo. Gpr120 agonist treatment of high-fat diet-fed obese mice causes improved glucose tolerance, decreased hyperinsulinemia, increased insulin sensitivity and decreased hepatic steatosis. This suggests that Gpr120 agonists could become new insulin-sensitizing drugs for the treatment of type 2 diabetes and other human insulin-resistant states in the future.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ácidos Grasos Omega-3/metabolismo , Resistencia a la Insulina/fisiología , Receptores Acoplados a Proteínas G/agonistas , Animales , Arginasa/biosíntesis , Linfocitos B Reguladores/inmunología , Secuencia de Bases , Diabetes Mellitus Tipo 2/genética , Ácidos Docosahexaenoicos/farmacología , Hígado Graso/tratamiento farmacológico , Hiperinsulinismo/tratamiento farmacológico , Inflamación , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Obesos , Datos de Secuencia Molecular , Óxido Nítrico Sintasa de Tipo II/biosíntesis , Obesidad/genética , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Linfocitos T Reguladores/inmunología
14.
Cell ; 157(6): 1339-1352, 2014 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-24906151

RESUMEN

Adipose tissue hypoxia and inflammation have been causally implicated in obesity-induced insulin resistance. Here, we report that, early in the course of high-fat diet (HFD) feeding and obesity, adipocyte respiration becomes uncoupled, leading to increased oxygen consumption and a state of relative adipocyte hypoxia. These events are sufficient to trigger HIF-1α induction, setting off the chronic adipose tissue inflammatory response characteristic of obesity. At the molecular level, these events involve saturated fatty acid stimulation of the adenine nucleotide translocase 2 (ANT2), an inner mitochondrial membrane protein, which leads to the uncoupled respiratory state. Genetic or pharmacologic inhibition of either ANT2 or HIF-1α can prevent or reverse these pathophysiologic events, restoring a state of insulin sensitivity and glucose tolerance. These results reveal the sequential series of events in obesity-induced inflammation and insulin resistance.


Asunto(s)
Adipocitos/metabolismo , Dieta Alta en Grasa , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Resistencia a la Insulina , Obesidad/metabolismo , Oxígeno/metabolismo , Translocador 2 del Nucleótido Adenina/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Hipoxia de la Célula , Ácidos Grasos/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Inflamación/metabolismo , Ácido Láctico/metabolismo , Ratones , Ratones Noqueados , Óxido Nítrico/metabolismo
15.
Clin Transl Sci ; 7(1): 74-81, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24422665

RESUMEN

The human microbiome harbors a massive diversity of microbes that effectively form an "organ" that strongly influences metabolism and immune function and hence, human health. Although the growing interest in the microbiome has chiefly arisen due to its impact on human physiology, the probable rules of operation are embedded in the roots of microbiology where chemical communication (i.e., with metabolites) is a dominant feature of coexistence. Indeed, recent examples in microbiome research offer the impression that the collective microbiome operates as an "apothecary," creating chemical concoctions that influence health and alter drug response. Although these principles are not unappreciated, the majority of emphasis is on metagenomics and research efforts often omit systematic efforts to interrogate the chemical component of the complex equation between microbial community and host phenotype. One of the reasons for this omission may be due to the inaccessibility to high-breadth, high-throughput, and scalable technologies. Since these technologies are now available, we propose that a more systematic effort to survey the host-microbiota chemical output be embedded into microbiome research as there is strong likelihood, and growing precedence, that this component may often be integral to developing our understanding of these ultimate apothecaries and how they impact human health.


Asunto(s)
Microbiota/fisiología , Biotransformación , Homeostasis , Humanos , Metaboloma , Metagenoma , Interacciones Microbianas , Percepción de Quorum , Xenobióticos/metabolismo
16.
Cell ; 155(1): 200-214, 2013 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-24074869

RESUMEN

Macrophage-mediated inflammation is a major contributor to obesity-associated insulin resistance. The corepressor NCoR interacts with inflammatory pathway genes in macrophages, suggesting that its removal would result in increased activity of inflammatory responses. Surprisingly, we find that macrophage-specific deletion of NCoR instead results in an anti-inflammatory phenotype along with robust systemic insulin sensitization in obese mice. We present evidence that derepression of LXRs contributes to this paradoxical anti-inflammatory phenotype by causing increased expression of genes that direct biosynthesis of palmitoleic acid and ω3 fatty acids. Remarkably, the increased ω3 fatty acid levels primarily inhibit NF-κB-dependent inflammatory responses by uncoupling NF-κB binding and enhancer/promoter histone acetylation from subsequent steps required for proinflammatory gene activation. This provides a mechanism for the in vivo anti-inflammatory insulin-sensitive phenotype observed in mice with macrophage-specific deletion of NCoR. Therapeutic methods to harness this mechanism could lead to a new approach to insulin-sensitizing therapies.


Asunto(s)
Ácidos Grasos Omega-3/metabolismo , Resistencia a la Insulina , Macrófagos/metabolismo , Co-Represor 1 de Receptor Nuclear/metabolismo , Receptores Nucleares Huérfanos/genética , Animales , Receptores X del Hígado , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Co-Represor 1 de Receptor Nuclear/genética
17.
Ann N Y Acad Sci ; 1278: 1-10, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23488557

RESUMEN

Nutritional biomarkers--biochemical, functional, or clinical indices of nutrient intake, status, or functional effects--are needed to support evidence-based clinical guidance and effective health programs and policies related to food, nutrition, and health. Such indices can reveal information about biological or physiological responses to dietary behavior or pathogenic processes, and can be used to monitor responses to therapeutic interventions and to provide information on interindividual differences in response to diet and nutrition. Many nutritional biomarkers are available; yet there has been no formal mechanism to establish consensus regarding the optimal biomarkers for particular nutrients and applications.


Asunto(s)
Biomarcadores , Conducta Alimentaria , Evaluación Nutricional , Estado Nutricional , Dieta , Ingestión de Alimentos , Ingestión de Energía , Salud , Humanos , Neoplasias
18.
Circ Res ; 111(4): 394-6, 2012 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-22859668

RESUMEN

Type 1 diabetics harbor a greatly elevated risk for progressive atherosclerosis and cardiovascular events, but the mechanistic basis for this phenomenon is not entirely clear. Although this link is likely to involve many factors, the specific activation of a lipid-driven inflammatory phenotype in monocytes and macrophages of people with type 1 diabetes is an attractive causal mechanism, due to the ability of inflamed macrophages to exacerbate plaque deposition, expansion, and instability.

19.
Cell Metab ; 15(5): 623-34, 2012 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-22560215

RESUMEN

The endoplasmic reticulum (ER) is a critical site of protein, lipid, and glucose metabolism, lipoprotein secretion, and calcium homeostasis. Many of the sensing, metabolizing, and signaling mechanisms for these pathways exist within or on the ER membrane domain. Here, we review the cellular functions of ER, how perturbation of ER homeostasis contributes to metabolic dysregulation and potential causative mechanisms of ER stress in obesity, with a particular focus on lipids, metabolic adaptations of ER, and the maintenance of its membrane homeostasis. We also suggest a conceptual framework of metabolic roundabout to integrate key mechanisms of insulin resistance and metabolic diseases.


Asunto(s)
Retículo Endoplásmico/metabolismo , Metabolismo de los Lípidos/fisiología , Hígado/metabolismo , Estrés Fisiológico/fisiología , Animales , Homeostasis/fisiología , Humanos
20.
Arterioscler Thromb Vasc Biol ; 32(2): 230-5, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22173228

RESUMEN

OBJECTIVE: Gpihbp1-deficient (Gpihbp1-/-) mice lack the ability to transport lipoprotein lipase to the capillary lumen, resulting in mislocalization of lipoprotein lipase within tissues, defective lipolysis of triglyceride-rich lipoproteins, and chylomicronemia. We asked whether GPIHBP1 deficiency and mislocalization of catalytically active lipoprotein lipase would alter the composition of triglycerides in adipose tissue or perturb the expression of lipid biosynthetic genes. We also asked whether perturbations in adipose tissue composition and gene expression, if they occur, would be accompanied by reciprocal metabolic changes in the liver. METHODS AND RESULTS: The chylomicronemia in Gpihbp1-/- mice was associated with reduced levels of essential fatty acids in adipose tissue triglycerides and increased expression of lipid biosynthetic genes. The liver exhibited the opposite changes: increased levels of essential fatty acids in triglycerides and reduced expression of lipid biosynthetic genes. CONCLUSIONS: Defective lipolysis in Gpihbp1-/- mice causes reciprocal metabolic perturbations in adipose tissue and liver. In adipose tissue, the essential fatty acid content of triglycerides is reduced and lipid biosynthetic gene expression is increased, whereas the opposite changes occur in the liver.


Asunto(s)
Tejido Adiposo/metabolismo , Metabolismo de los Lípidos/fisiología , Hígado/metabolismo , Receptores de Lipoproteína/deficiencia , Animales , Ácidos Grasos/metabolismo , Lipólisis/fisiología , Lipoproteína Lipasa/metabolismo , Masculino , Ratones , Ratones Noqueados , Modelos Animales , Receptores de Lipoproteína/genética , Triglicéridos/metabolismo
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