RESUMEN
Obesity-induced inflammation, or meta-inflammation, plays key roles in metabolic syndrome and is a significant risk factor in diabetes and cardiovascular disease. To investigate causal links between obesity, meta-inflammation, and insulin signaling we established a Drosophila model to determine how elevated dietary fat and changes in the levels and balance of saturated fatty acids (SFAs) and polyunsaturated fatty acids (PUFAs) influence inflammation. We observe negligible effect of saturated fatty acid on inflammation but marked enhancement or suppression by omega-6 and omega-3 PUFAs, respectively. Using combined lipidomic and genetic analysis, we show omega-6 PUFA enhances meta-inflammation by producing linoleic acid-derived lipid mediator 9-hydroxy-octadecadienoic acid (9-HODE). Transcriptome analysis reveals 9-HODE functions by regulating FOXO family transcription factors. We show 9-HODE activates JNK, triggering FOXO nuclear localisation and chromatin binding. FOXO TFs are important transducers of the insulin signaling pathway that are normally down-regulated by insulin. By activating FOXO, 9-HODE could antagonise insulin signaling providing a molecular conduit linking changes in dietary fatty acid balance, meta-inflammation, and insulin resistance.
Asunto(s)
Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Proteína Forkhead Box O3/metabolismo , Factores de Transcripción Forkhead/metabolismo , Ácido Linoleico/metabolismo , Obesidad/metabolismo , Animales , Animales Modificados Genéticamente , Núcleo Celular/metabolismo , Cromatina/metabolismo , Grasas de la Dieta/efectos adversos , Modelos Animales de Enfermedad , Drosophila/genética , Proteínas de Drosophila/genética , Ácidos Grasos Omega-3/metabolismo , Ácidos Grasos Omega-3/farmacología , Proteína Forkhead Box O3/genética , Factores de Transcripción Forkhead/genética , Regulación de la Expresión Génica/efectos de los fármacos , Células HeLa , Humanos , Inflamación/inducido químicamente , Inflamación/metabolismo , Insulina/metabolismo , Ácido Linoleico/farmacología , Ácidos Linoleicos Conjugados/genética , Ácidos Linoleicos Conjugados/metabolismo , Ácidos Linoleicos Conjugados/farmacología , Obesidad/inducido químicamente , Unión Proteica , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transcriptoma , TransfecciónRESUMEN
In dairy cows the milk associated energy output in early lactation exceeds the input via voluntary feed intake. To spare glucose for mammary lactose synthesis, peripheral insulin sensitivity (IS) is reduced and fat mobilization is stimulated. For these processes a link between IS and the endocrine functions of adipose tissue (AT) is likely; we thus aimed to characterise the mRNA expression from bovine AT derived proteins and receptors that are related to IS according to the literature in metabolically active tissues plus systemic IS throughout lactation. Conjugated linoleic acids (CLA) reduce milk fat thus decreasing the milk drain of energy and potentially dampening lipolysis, but may also affect IS. Subcutaneous (s.c.) AT and liver from pluriparous cows receiving either control fat or CLA supplement (100 g/day from 1 to 182 days in milk each) were biopsied covering week -3 to 36 relative to parturition. In an additional trial with primiparous cows treated analogously and slaughtered on days in milk 1, 42 or 105, samples from liver, udder, skeletal muscle and 3 visceral and 3 s.c. AT were obtained and assayed for mRNA abundance of adiponectin, its receptors, leptin, leptin receptor, PPARγ, PPARγ2, IL-6, and TNF-α. In pluriparous animals, the mRNA abundance of most of the target genes decreased after parturition in s.c. AT but increased in liver. In primiparous cows, AT depot specific differences were mostly related to retroperitoneal AT; adiponectin receptor 1 and TNF-α were affected predominantly. CLA effects in primiparous cows were largely limited to decreased PPARγ2 mRNA abundance in udder tissue. In pluriparous cows, insulin secretion was increased by CLA resulting in decreased systemic IS but without consistent changes in tissue target mRNA abundance. The temporal gene expression profiles from the adipokines and related receptors support their coactive function in adapting to the needs of lactation.
Asunto(s)
Tejido Adiposo/metabolismo , Grasas/metabolismo , Resistencia a la Insulina/genética , Lactancia/genética , Lactancia/metabolismo , Adiponectina/genética , Adiponectina/metabolismo , Animales , Bovinos , Grasa Intraabdominal/metabolismo , Ácidos Linoleicos Conjugados/genética , Ácidos Linoleicos Conjugados/metabolismo , Hígado/metabolismo , Estudios Longitudinales , Leche/metabolismo , PPAR gamma/genética , PPAR gamma/metabolismo , Parto/genética , Parto/metabolismo , ARN Mensajero/genética , Receptores de Adiponectina/genética , Receptores de Adiponectina/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Physicochemical properties and fatty acid profiles of meat from Bos indicus, Bos taurus and crossbred B. taurus×B. indicus bullocks (n=216), finished on pasture or grain, were used to estimate the effects of heterosis. Meat quality and fatty acid profiles generally benefited with crossbreeding, but the advantages from heterosis differed among finishing systems. The Warner-Bratzler shear-force in fresh and aged meat was reduced due to heterosis in pasture-finishing, but the effect was minor under grain-finishing. With pasture-finishing, heterosis caused an increase of 5% in CLA concentration, but few other changes in fatty acid profiles. In grain-finishing, heterosis caused a reduction in intramuscular fat and cholesterol, increased amounts of PUFA, n-6 fatty acids and PUFA/SFA ratio, and a decline in atherogenic index. The Δ(9) desaturase estimated activity in crossbreds showed a behavior close to B. indicus, suggesting the existence of few loci and a dominance genetic effect on enzymes involved in fatty acid synthesis and metabolism.
Asunto(s)
Alimentación Animal , Cruzamiento , Dieta , Grasas de la Dieta/metabolismo , Ácidos Grasos/genética , Vigor Híbrido , Carne/análisis , Crianza de Animales Domésticos/métodos , Animales , Aterosclerosis/inducido químicamente , Bovinos , Colesterol en la Dieta/metabolismo , Grano Comestible , Ácidos Grasos/metabolismo , Ácidos Grasos Insaturados/genética , Ácidos Grasos Insaturados/metabolismo , Sitios Genéticos , Ácidos Linoleicos Conjugados/genética , Ácidos Linoleicos Conjugados/metabolismo , Carne/normas , Músculo Esquelético/metabolismo , Poaceae , Especificidad de la Especie , Estearoil-CoA Desaturasa/genética , Estearoil-CoA Desaturasa/metabolismo , Estrés MecánicoRESUMEN
The biological activities and mechanisms of action of individual transoctadecenoic acids (trans-18:1 FA) have not been completely elucidated. We examined the effects of several individual trans-18:1 FA isomers and trans-10, cis-12 conjugated linoleic acid (CLA) on fat synthesis, and expression of lipogenic genes in mammary and liver tissue in lactating mice. From d 6 to 10 postpartum, 30 lactating C57BL/6J mice were randomly assigned to either a control (CTR) diet containing 20 g/kg oleic acid or diets in which the oleic acid was either completely replaced by partially hydrogenated vegetable oil (PHVO), trans-7 18:1 (T7), trans-9 18:1 (T9), or trans-11 18:1 (T11) or partially replaced with 6.66 g/kg trans-10, cis-12 CLA. Milk fat percentage was decreased by CLA (44%), T7 (27%), and PHVO (23%), compared with CTR. In the mammary gland, CLA decreased the expression of genes related to de novo FA synthesis, desaturation, triacylglycerol formation, and transcriptional regulation. PHVO and T7 diets decreased the expression of 1-acylglycerol-3-phosphate O-acyltransferase and thyroid hormone responsive SPOT14 homolog (THRSP) mRNA. In contrast, dietary trans FA (tFA) did not affect hepatic lipogenic gene expression. However, mice fed CLA, T7, and PHVO diets had increased liver weights due to hepatic steatosis. Trans-7 18:1 was extensively desaturated to trans-7, cis-9 CLA in mammary and liver tissues. Dietary trans-7 18:1 could lead to milk fat depression in lactating mice, possibly through its desaturation product trans-7, cis-9 CLA. Also, the differences between the effects of trans-10, cis-12 CLA and other tFA could be attributed to its effects on carbohydrate response element binding protein and PPARgamma, in addition to sterol regulatory element binding transcription factor 1c and THRSP.
Asunto(s)
Grasas de la Dieta/administración & dosificación , Ácidos Linoleicos Conjugados/metabolismo , Metabolismo de los Lípidos/fisiología , Lipogénesis/genética , Glándulas Mamarias Animales/metabolismo , Leche/metabolismo , Ácidos Grasos trans/metabolismo , 1-Acilglicerol-3-Fosfato O-Aciltransferasa/genética , 1-Acilglicerol-3-Fosfato O-Aciltransferasa/metabolismo , Animales , Hígado Graso , Femenino , Regulación de la Expresión Génica , Isomerismo , Lactancia , Ácidos Linoleicos Conjugados/genética , Metabolismo de los Lípidos/genética , Hígado/metabolismo , Ratones , Ratones Endogámicos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Ácido Oléico , Tamaño de los Órganos , Aceites de Plantas , ARN Mensajero/metabolismo , Distribución Aleatoria , Estereoisomerismo , Ácidos Grasos trans/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND & AIMS: The molecular targets for the protective actions of conjugated linoleic acid (CLA) on experimental inflammatory bowel disease (IBD) are unknown. We used a loss-of-function approach to investigate whether CLA ameliorated colitis through a peroxisome proliferator-activated receptor gamma (PPAR gamma)-dependent mechanism. METHODS: The expression of PPAR gamma, delta, and their target genes in the colon of mice fed control or CLA-supplemented diets was assayed after a 7-day dextran sodium sulfate (DSS) challenge by quantitative real-time polymerase chain reaction (PCR). Additionally, nuclear factor-kappa B (NF-kappaB) p65 activation was quantified in the colon. To determine the involvement of PPAR gamma in the mechanism of action of CLA directly, specific deletions of PPAR gamma in the colon were performed in mice by using the Cre-lox recombination system. Colonic PPAR gamma null mice and wild-type littermates were fed either a CLA-supplemented or a control diet for 42 days and challenged with 2.5% DSS. The therapeutic efficacy of CLA also was examined by using the CD4 + CD45RB hi transfer colitis model. RESULTS: CLA induced PPAR gamma and delta, transcriptionally modulated PPAR gamma and delta-responsive gene clusters involved in lipid metabolism (uncoupling protein [UCP]1, UCP3, PPAR gamma coactivator 1alpha [PGC-1alpha], and CD36) and epithelial cell maturation (Gob-4 and Keratin 20). Additionally, CLA repressed tumor necrosis factor alpha (TNF-alpha) expression and NF-kappaB activation while inducing the immunoregulatory cytokine transforming growth factor beta 1 (TGF-beta 1 ). Clinically, CLA ameliorated DSS- and CD4 + -induced colitis. Loss of the PPAR gamma gene in the colon abrogated the beneficial effects of CLA in DSS colitis. CONCLUSIONS: Our studies provide molecular evidence in vivo, suggesting that CLA ameliorates colitis through a PPAR gamma-dependent mechanism.