RESUMO
Abstract This study aimed to investigate the acute effects of oleic acid (OA) on glucose homeostasis in mice fed a standard chow diet (SCD) and a high-fructose, high-fat diet (HFrHFD); moreover, the role of free fatty acid receptor 1 (FFAR1) was evaluated. The mice in the two groups were further divided into three subgroups as follows: control, OA (40 mg/kg), and OA + GW1100 (0.4 mg/kg, selective FFAR1 blocker). After a 16-week feeding period, the mice received the drugs via intraperitoneal (i.p.) injection followed by an i.p. glucose tolerance test (IPGTT) 30 min later. After 3 days, the mice received the same drugs to examine the effects of the drugs on the hepatic levels of phosphatidylinositol-4,5-bisphosphate (PIP2) and diacylglycerol (DAG). OA in the SCD-fed mice significantly increased the blood glucose level (48%, P < 0.001) after 30 min of glucose load compared to that in the control group, but did not affect the levels of PIP2 and DAG. Pre-injection with GW1100 significantly decreased the area under the curve of the IPGTT (28%, P < 0.05) in the SCD group compared to that in the SCD + OA group. OA reduced the blood glucose level (35%, P < 0.001) after 120 min of glucose load in the HFrHFD-fed mice; in addition, it increased hepatic PIP2 (160%, P < 0.01) and decreased hepatic DAG (60%, P < 0.001) levels. Pre-injection with GW1100 blocked the effects of OA on hepatic PIP2 and DAG without affecting the glucose tolerance. In conclusion, OA acutely impaired the glucose tolerance in the SCD-fed mice by acting on FFAR1 but did not improve it in the HFrHFD-fed mice.
RESUMO
In the present study we investigated the involvement of free fatty acid (FFA) receptors in the anti-inflammatory role of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in dystrophic muscles, by administering FFA blockers in the mdx mouse model of dystrophy. Mdx mice (3 months-old) were treated with fish oil capsules (FDC Vitamins; 0.4 g EPA and 0.2 g DHA; gavage) alone or concomitant to FFA1 and FFA4 blockers (GW1100 and AH7614; i.p.). C57BL/10 mice (3 months-old) and untreated-mdx mice received mineral oil and were used as controls. After 1 month of treatment, plasma markers of myonecrosis (total and cardiac creatine kinase; CK), the levels of FFA1 and FFA4 and of the markers of inflammation, nuclear transcription factor kappa B (NFkB), tumor necrosis factor alpha (TNF-α) and interleukin 1ß (IL-1ß) were analyzed in the diaphragm muscle and heart by western blot. Fish oil significantly reduced total CK, cardiac CK and the levels of NFkB (diaphragm), and of TNF-α and IL-1ß (diaphragm and heart) in mdx. In the dystrophic diaphragm, FFA1 was increased compared to normal. Blockers of FFA1 and FFA4 significantly inhibited the effects of fish oil treatment in both dystrophic muscles. The anti-inflammatory effects of fish oil in dystrophic diaphragm muscle and heart were mediated through FFA1 and FFA4.
No presente estudo investigamos o envolvimento de receptores de ácidos graxos livres (FFA) no efeito anti-inflamatório dos ácidos eicosapentaenoico (EPA) e docosahexaenoico (DHA) em músculos distróficos, administrando bloqueadores de FFA no camundongo mdx, modelo de distrofia. Camundongos mdx (3 meses de idade) foram tratados com cápsulas de óleo de peixe (FDC Vitamins; 0.4 g EPA e 0.2 g DHA; gavagem) ou com cápsulas de óleo de peixe concomitante a bloqueadores de FFA1 e FFA4 (GW1100 e AH7614; i.p.). Camundongos C57BL/10 (3 meses de idade) e camundongos mdx não tratados receberam óleo mineral e serviram de controle. Após 1 mês de tratamento, marcadores plasmáticos de mionecrose (creatina quinase total e cardíaca; CK), os níveis de FFA1 e FFA4 e dos marcadores de inflamação fator de transcrição nuclear kappa B (NFkB, nuclear transcription factor kappa B), fator de necrose tumoral alpha (TNF-α, tumor necrosis factor alpha) e interleucina 1ß (IL-1ß) foram analisados no músculo diafragma e no coração através de western blot. O óleo de peixe reduziu de forma significativa a CK total, CK cardíaca e os níveis de NFkB (diafragma), TNF-α e IL-1ß (diafragma e coração) no mdx. No diafragma distrófico, FFA1 estava aumentado comparado ao normal. Os bloqueadores de FFA1 e FFA4 inibiram de forma significativa os efeitos do tratamento com óleo de peixe em ambos músculos distróficos. Os efeitos anti-inflamatórios do óleo de peixe nos músculos distróficos diafragma e cardíaco foram mediados por FFA1 e FFA4.
Assuntos
Creatina Quinase/sangue , Diafragma/metabolismo , Óleos de Peixe/farmacologia , Interleucina-1beta/metabolismo , Distrofia Muscular Animal/metabolismo , Miocárdio/metabolismo , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Biomarcadores/metabolismo , Camundongos Endogâmicos mdxRESUMO
Alzheimer's disease (AD) is a neurodegenerative disorder without a known cure or effective treatment. Research has identified several modifiable risk factors and suggested preventative measures to reduce the risk of developing AD, including alterations in diet. Polyunsaturated fatty acids (PUFAs) have been shown to regulate inflammatory responses in the central nervous system (CNS), the main site of inflammation in AD. In the CNS, microglia are immune cells responsible for the maintenance of homeostasis. However, in AD, microglia can become adversely activated, causing them to release increased levels of cytotoxins and inflammatory mediators, including nitric oxide (NO) and monocyte-chemoattractant protein (MCP)-1. We assessed the effects of two PUFAs, α-linolenic acid (ALA) and linoleic acid (LA), on select microglial immune functions, since the effects of these dietary fatty acids on neuroimmune responses are not well characterized. In BV-2 mouse microglia activated with lipopolysaccharide (LPS), exposure to LA reduced NO secretion and inducible nitric oxide synthase (iNOS) levels, whereas exposure to ALA reduced NO without a corresponding reduction of iNOS. Neither ALA nor LA altered MCP-1 levels or cytotoxins released by THP-1 human microglia-like cells stimulated with a combination of LPS and interferon (IFN)-γ. Specific receptor antagonists were used to demonstrate that the inhibitory effect of LA on NO secretion did not depend on the free fatty acid receptor (FFAR) 1 or FFAR4. Furthermore, gas chromatography with a flame ionization detector (GC-FID) revealed that exposure to LA or ALA did not alter the fatty acid composition of BV-2 microglia. Our data indicate that regulation of select microglial immune functions by ALA and LA could be one of the mechanisms underlying the observed link between certain dietary patterns and AD, such as reduced risk of cognitive decline and dementia associated with the Mediterranean diet.
Assuntos
Gorduras na Dieta/farmacologia , Ácido Linoleico/farmacologia , Microglia/efeitos dos fármacos , Óxido Nítrico/biossíntese , Ácido alfa-Linolênico/farmacologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/prevenção & controle , Animais , Linhagem Celular , Citocinas/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Lipídeos de Membrana/metabolismo , Camundongos , Microglia/imunologia , Microglia/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Receptores Acoplados a Proteínas G/fisiologia , Células THP-1RESUMO
A dietary influence on cancer progression has been evident for many decades, and dietary fatty acids, particularly long chain mono- and polyunsaturated fatty acids, have been shown to play significant roles in influencing growth of a variety of human cancers. The discovery of the family of cell-surface free-fatty acid receptors, which include the long-chain fatty acid receptors FFA1 and FFA4, suggest that many of the effects of dietary fats could be receptor-mediated. FFA4 is ubiquitously expressed and has recently been shown to modulate a variety of important anti-inflammatory and metabolic processes. Since FFA4 is currently an attractive drug target for treatment of metabolic disorders such as diabetes and obesity, understanding its role in cancer progression is critical towards the drug discovery process. In this research update, the current body of knowledge on the role of this receptor in regulating cancer cell proliferation, migration, and invasion, as well as in vivo tumorigenesis is reviewed.