RESUMEN
Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been reported to improve insulin sensitivity and glucose homeostasis in animal models of insulin resistance, but the involved mechanisms still remain unresolved. In this study, we evaluated the effects of fish oil (FO), a source of n-3 PUFAs, on obesity, insulin resistance and muscle mitochondrial function in mice fed a high-fat diet (HFD). C57Bl/6 male mice, 8 weeks old, were divided into four groups: control diet (C), high-fat diet (H), C+FO (CFO) and H+FO (HFO). FO was administered by oral gavage (2 g/kg b.w.), three times a week, starting 4 weeks before diet administration until the end of the experimental protocol. HFD-induced obesity and insulin resistance associated with impaired skeletal muscle mitochondrial function, as indicated by decreased oxygen consumption, tricarboxylic acid cycle intermediate (TCAi) contents (citrate, α-ketoglutarate, malate and oxaloacetate), oxidative phosphorylation protein content and mitochondrial biogenesis. These effects were associated with elevated reactive oxygen species production, decreased PGC1-a transcription and reduced Akt phosphorylation. The changes induced by the HFD were partially attenuated by FO, which decreased obesity and insulin resistance and increased mitochondrial function. In the H group, FO supplementation also improved oxygen consumption; increased TCAi content, and Akt and AMPK phosphorylation; and up-regulated mRNA expression of Gpat1, Pepck, catalase and mitochondrial proteins (Pgc1α, Pparα, Cpt1 and Ucp3). These results suggest that dietary FO attenuates the deleterious effects of the HFD (obesity and insulin resistance) by improving skeletal muscle mitochondrial function.
Asunto(s)
Aceites de Pescado/farmacología , Resistencia a la Insulina , Mitocondrias Musculares/fisiología , Obesidad/dietoterapia , Adiposidad/efectos de los fármacos , Animales , Fármacos Antiobesidad/farmacología , Catalasa/metabolismo , Dieta Alta en Grasa/efectos adversos , Suplementos Dietéticos , Ácidos Grasos/análisis , Ácidos Grasos/metabolismo , Ácidos Grasos Omega-3/farmacología , Peróxido de Hidrógeno/metabolismo , Masculino , Ratones Endogámicos C57BL , Mitocondrias Musculares/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiología , Obesidad/etiología , Proteínas/genética , Proteínas/metabolismoRESUMEN
KEY POINTS: Fish oil (FO), rich in omega-3 polyunsaturated fatty acids, has beneficial effects on changes induced by obesity and partially prevents associated comorbidities. The effects of FO on adipocytes from different adipose tissue depots in high-fat (HF) diet induced obese mice have not been uninvestigated. This is the first study to examine the effects of FO on changes in metabolism and adipokine production in adipocytes from s.c. (inguinal; ING) or visceral (retroperitoneal; RP) white adipose depots in a HF diet-induced obese mice. Unlike most studies performed previously, FO supplementation was initiated 4 weeks before the induction of obesity. HF diet caused marked changes in ING (glucose uptake and secretion of adiponectin, tumour necrosis factor-α and interleukin-6 in ING) and RP (lipolysis, de novo lipogenesis and secretion of pro-inflammatory cytokines) adipose depots. Previous and concomitant FO administration prevented the changes in ING and RP adipocytes induced by the HF diet. ABSTRACT: In the present study, we investigated the effect of fish oil (FO) on metabolism and adipokine production by adipocytes from s.c. (inguinal; ING) and visceral (retroperitoneal; RP) white adipose depots in high-fat (HF) diet-induced obese mice. Mice were divided into CO (control diet), CO+FO, HF and HF+FO groups. The HF group presented higher body weight, glucose intolerance, insulin resistance, higher plasma total and low-density lipoprotein cholesterol levels, and greater weights of ING and RP adipose depots accompanied by hypertrophy of the adipocytes. FO exerted anti-obesogenic effects associated with beneficial effects on dyslipidaemia and insulin resistance in mice fed a HF diet (HF+FO group). HF raised RP adipocyte lipolysis and the production of pro-inflammatory cytokines and reduced de novo synthesis of fatty acids, whereas, in ING adipocytes, it decreased glucose uptake and adiponectin secretion but did not change lipolysis. Therefore, the adipose depots play different roles in HF diet-induced insulin resistance according to their location in the body. Concerning cytokine secretion, adipocytes per se in addition to white adopise tissue infiltrated leukocytes have to be considered in the aetiology of the comorbidities associated with obesity. Evidence is presented showing that previous and concomitant administration of FO can prevent changes in metabolism and the secretion of hormones and cytokines in ING and RP adipocytes induced by HF.
Asunto(s)
Adipocitos/efectos de los fármacos , Adipoquinas/metabolismo , Aceites de Pescado/farmacología , Grasa Intraabdominal/metabolismo , Obesidad/metabolismo , Grasa Subcutánea/metabolismo , Adipocitos/metabolismo , Animales , Células Cultivadas , Dieta Alta en Grasa/efectos adversos , Aceites de Pescado/uso terapéutico , Interleucina-6/metabolismo , Grasa Intraabdominal/citología , Grasa Intraabdominal/efectos de los fármacos , Lipólisis , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/tratamiento farmacológico , Obesidad/etiología , Grasa Subcutánea/citología , Grasa Subcutánea/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND/AIMS: To investigate the global changes in DNA methylation and methylation of the promoter region of the peroxisome proliferator-activated receptor gamma transcript variant 2 (Pparg2) gene resulting from a high-fat diet (HFD) and/or fish oil supplementation. METHODS: Fish oil, rich in omega-3 polyunsaturated fatty acids, or water was orally administered to male mice for 12 weeks. After the first 4 weeks, the animals were fed a control diet or an HFD until the end of the experimental protocol, when the epididymal fat, gastrocnemius muscle and liver were excised. RESULTS: Pparg2 mRNA expression was upregulated by obesity and downregulated by fish oil supplementation in the liver. In the gastrocnemius muscle, diet-induced obesity increased global DNA methylation. Fish oil prevented the decrease in Pparg2 promoter methylation induced by obesity in the gastrocnemius muscle. Regardless of the diet given, fish oil supplementation increased Pparg2 promoter methylation at CpG-263 in muscle and adipose tissue. CONCLUSION: HFD and fish oil modified global and Pparg2 promoter DNA methylation in a tissue-specific manner. Fish oil supplementation attenuated body weight gain, abolished the increase in Pparg2 expression in the liver and prevented the decrease in Pparg2 promoter methylation in the muscle induced by the HFD.
Asunto(s)
Metilación de ADN , Dieta Alta en Grasa/efectos adversos , Aceites de Pescado/administración & dosificación , Músculo Esquelético/metabolismo , Tejido Adiposo/metabolismo , Animales , Suplementos Dietéticos , Ácidos Grasos Omega-3/administración & dosificación , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Nutrigenómica , Obesidad/dietoterapia , Obesidad/genética , Obesidad/metabolismo , PPAR gamma/genética , Regiones Promotoras Genéticas , Distribución TisularRESUMEN
The aim of this study was to investigate whether treatment with tributyrin (Tb; a butyrate prodrug) results in protection against diet-induced obesity and associated insulin resistance. C57BL/6 male mice fed a standard chow or high-fat diet were treated with Tb (2 g/kg body wt, 10 wk) and evaluated for glucose homeostasis, plasma lipid profile, and inflammatory status. Tb protected mice against obesity and obesity-associated insulin resistance and dyslipidemia without food consumption being affected. Tb attenuated the production of TNFα and IL-1ß by peritoneal macrophages and their expression in adipose tissue. Furthermore, in the adipose tissue, Tb reduced the expression of MCP-1 and infiltration by leukocytes and restored the production of adiponectin. These effects were associated with a partial reversion of hepatic steatosis, reduction in liver and skeletal muscle content of phosphorylated JNK, and an improvement in muscle insulin-stimulated glucose uptake and Akt signaling. Although part of the beneficial effects of Tb are likely to be secondary to the reduction in body weight, we also found direct protective actions of butyrate reducing TNFα production after LPS injection and in vitro by LPS- or palmitic acid-stimulated macrophages and attenuating lipolysis in vitro and in vivo. The results, reported herein, suggest that Tb may be useful for the treatment and prevention of obesity-related metabolic disorders.