Metabolomic analysis of livers and serum from high-fat diet induced obese mice

Liver and serum metabolites of obese and lean mice fed on high fat or normal diets were analyzed using ultraperformance liquid chromatography-quadrupole-time-of-flight mass spectrometry, gas chromatography-mass spectrometry, and partial least-squares-discriminant analysis (PLS-DA). Obese and lean groups were clearly discriminated from each other on PLS-DA score plot and major metabolites contributing to the discrimination were assigned as lipid metabolites (fatty acids, phosphatidylcholines (PCs), and lysophosphatidylcholines (lysoPCs)), lipid metabolism intermediates (betaine, carnitine, and acylcarnitines), amino acids, acidic compounds, monosaccharides, and serotonin. A high-fat diet increased lipid metabolites but decreased lipid metabolism intermediates and the NAD/NADH ratio, indicating that abnormal lipid and energy metabolism induced by a high-fat diet resulted in fat accumulation via decreased β-oxidation. In addition, this study revealed that the levels of many metabolites, including serotonin, betaine, pipecolic acid, and uric acid, were positively or negatively related to obesity-associated diseases. On the basis of these metabolites, we proposed a metabolic pathway related to high-fat diet-induced obesity. These metabolites can be used to better understand obesity and related diseases induced by a hyperlipidic diet. Furthermore, the level changes of these metabolites can be used to assess the risk of obesity and the therapeutic effect of obesity management.     

Effects of dietary n-3 PUFA levels in early life on susceptibility to high-fat-diet-induced metabolic syndrome in adult mice

The maternal nutritional status during pregnancy and lactation was closely related to the growth and development of the fetus and infants, which had a profound impact on the health of the offspring. N-3 polyunsaturated fatty acid (PUFA) had been proved to have beneficial effects on glucolipid metabolism. However, the effects of dietary different n-3 PUFA levels for mother during pregnancy and lactation on susceptibility to high-fat-diet-induced metabolic syndrome for offspring in adulthood are still unclear. The maternal mice were fed with control, n-3 PUFA-deficient or fish oil-contained n-3 PUFA-rich diets during pregnancy and lactation, and the weaned offspring were fed with high-fat or low-fat diet for 13 weeks, then were subjected to oral glucose tolerance tests. The results showed that dietary n-3 PUFA-deficiency in early life could aggravate the high-fat-diet-induced glucolipid metabolism disorders, including glucose intolerance, insulin resistance, obesity, and dyslipidemia, thus increased the susceptibility to metabolic syndrome of adult mice. Notably, nutritional supplementation with n-3 PUFA in early life could significantly alleviate the glucose metabolism disorders by increasing insulin sensitivity, inhibiting gluconeogenesis and promoting glycogenesis. In addition, administration with n-3 PUFA in early life remarkably reduced serum and hepatic lipid profiles by mediating the expression of genes related to lipogenesis and β-oxidation of fatty acids. Dietary n-3 PUFA-deficiency in early life increases the susceptibility to metabolic syndrome of adult offspring, and nutritional supplementation with n-3 PUFA enhances the tolerance to a high-fat diet of adult offspring.     

Omega 3 rich diet modulates energy metabolism via GPR120-Nrf2 crosstalk in a novel antioxidant mouse model

With obesity rates reaching epidemic proportions, more studies concentrated on reducing the risk and treating this epidemic are vital. Redox stress is an important metabolic regulator involved in the pathophysiology of cardiovascular disease, Type 2 diabetes, and obesity. Oxygen and nitrogen-derived free radicals alter glucose and lipid homeostasis in key metabolic tissues, leading to increases in risk of developing metabolic syndrome. Oxidants derived from dietary fat differ in their metabolic regulation, with numerous studies showing benefits from a high omega 3 rich diet compared to the frequently consumed “western diet” rich in saturated fat. Omega 3 (OM3) fatty acids improve lipid profile, lower inflammation, and ameliorate insulin resistance, possibly through maintaining redox homeostasis. This study is based on the hypothesis that altering endogenous antioxidant production and/or increasing OM3 rich diet consumption will improve energy metabolism and maintain insulin sensitivity. We tested the comparative metabolic effects of a diet rich in saturated fat (HFD) and an omega 3-enriched diet (OM3) in the newly developed ‘stress-less’ mice model that overexpresses the endogenous antioxidant catalase. Eight weeks of dietary intervention showed that mice overexpressing endogenous catalase compared to their wild-type controls when fed an OM3 enriched diet, in contrast to HFD, activated GPR120-Nrf2 cross-talk to maintain balanced energy metabolism, normal circadian rhythm, and insulin sensitivity. These findings suggest that redox regulation of GPR120/FFAR4 might be an important target in reducing risk of metabolic syndrome and associated diseases.     

Lipid metabolism and liver inflammation. I. Hepatic fatty acid uptake: possible role in steatosis

Hepatic steatosis is a growing public health concern. Nonalcoholic fatty liver is increasingly common in Western societies and may lead to steatohepatitis, fibrosis, and cirrhosis, possibly triggered by lipid peroxidation. The relation of fatty liver to obesity, type II diabetes, and/or metabolic syndrome is significant. One aspect these related disorders share is increased serum-free fatty acids, which may be taken up by hepatocytes. Uptake of fatty acids in excess of metabolic requirements will lead to storage as triglycerides, resulting in steatosis and providing substrate for lipid peroxidation. Fatty acid uptake may be crucial to understanding steatosis.     

DNA microarrays to define and search for genes associated with obesity

One of the major goals of this review was to identify obesity-specific gene profiles in animal models to help comprehend the pathogenic mechanisms and the prediction of the phenotypic outcomes of obesity and its associated metabolic diseases. The genomic examination of insulin-sensitive tissues, such as the adipose and hepatic tissues, has provided a wealth of information about the changes in gene expression in obesity and its associated metabolic diseases. The overexpression of genes related to inflammation, immune response, adhesion molecules, and lipid metabolism is a major characteristic of white adipose tissue, while the overexpression of the genes related to lipid metabolism, adipocyte differentiation, defense, and stress responses is noticeable in the non-alcoholic fatty liver of obese rodents. The hepatic-gene expression profiles led us to hypothesize that in obese rodents, the livers are supplied with large amounts of free fatty acids under conditions associated with obesity either through increased fatty acid biosynthesis or through decreased fatty acid oxidation, which may lead to increased mitochondrial respiratory activity. The wide list of genes that were identified in previous studies could be a source of potential therapeutic targets because most of these genes are involved in the key mechanisms of obesity development, from adipocyte differentiation to the disturbance of metabolism.     

Improved n-3 fatty acid status does not modulate insulin resistance in fa/fa Zucker rats

The objective was to examine the effect of polyunsaturated fatty acid type (plant vs fish oil-derived n-3, compared to n-6 fatty acids in the presence of constant proportions of saturated, monounsaturated and polyunsaturated fatty acids) on obesity, insulin resistance and tissue fatty acid composition in genetically obese rats. Six-week-old fa/fa and lean Zucker rats were fed with a 10% (w/w) mixed fat diet containing predominantly flax-seed, menhaden or safflower oils for 9 weeks. There was no effect of dietary lipid on obesity, oral glucose tolerance (except t=60 min insulin), pancreatic function or molecular markers related to insulin, glucose and lipid metabolism, despite increased n-3 fatty acids in muscle and adipose tissue. The menhaden oil diet reduced fasting serum free fatty acids in both fa/fa and lean rats. These data suggest that n-3 composition does not alter obesity and insulin resistance in the fa/fa Zucker rat model when dietary lipid classes are balanced.     

Dietary n-3 polyunsaturated fatty acids modify fatty acid composition in hepatic and abdominal adipose tissue of sucrose-induced obese rats

The fatty acid profile of hepatocytes and adipocytes is determined by the composition of the dietary lipids. It remains unclear which fatty acid components contribute to the development or reduction of insulin resistance. The present work examined the fatty acid composition of both tissues in sucrose-induced obese rats receiving fish oil to determine whether the effect of dietary (n-3) polyunsaturated fatty acids (PUFAs) on the reversion of metabolic syndrome in these rats is associated to changes in the fatty acid composition of hepatocyte and adipocyte membrane lipids. Animals with metabolic syndrome were divided into a corn–canola oil diet group and a fish oil diet group, and tissues fatty acids composition were analyzed after 6 weeks of dietary treatment. Fatty acid profiles of the total membrane lipids were modified by the fatty acid composition of the diets fed to rats. N-3 PUFAs levels in animals receiving the fish oil diet plus sucrose in drinking water were significantly higher than in animals under corn–canola oil diets. It is concluded that in sucrose-induced obese rats, consumption of dietary fish oil had beneficial effects on the metabolic syndrome and that such effects would be conditioned by the changes in the n-3 PUFAs composition in hepatic and adipose tissues because they alter membrane properties and modify the type of substrates available for the production of active lipid metabolites acting on insulin resistance and obesity.     

Fatty acid mobilization and their use in adipose tissue

An excess of fat mass excess predisposes to multiple complications such as type 2 diabetes, cardiovascular diseases or cancer. A dysregulation of lipid metabolism contributes to the development of obesity and the metabolic syndrome. Recent data on lipid mobilization in adipose tissue have revealed a complex pathway involving a human specific hormonal control of lipolysis via the natriuretic peptides and a new triglyceride lipase, ATGL. Activation of fatty acid reesterification and oxidation can lead to an increase in fatty acid utilization. Targeting these key steps of lipid metabolism (adipose tissue lipolysis and fatty acid oxidation) constitutes a potential strategy for the treatment of obesity and associated metabolic disorders.     

The metabolic cascade leading to eicosanoid precursors--desaturases, elongases, and phospholipases A2--is altered in Zucker fatty rats

Metabolic syndrome characterized by insulin resistance and obesity is accompanied by severe lipid metabolism perturbations and chronic low-grade inflammation. However, many unresolved questions remained regarding the regulation that underlie dyslipidemia, particularly the regulation of the metabolic cascade (synthesis and release) leading to eicosanoid precursors release. This study was undertaken to investigate the regulation of desaturases/elongases and phospholipases A(2) during the establishment of metabolic syndrome. Our results showed that delta-6 desaturase as well as elongase-6 expressions were upregulated in 3-month-old Zucker fatty rats as compared to lean littermates, independently of SREBP-1c activation. We also demonstrated for the first time an increase of liver group VII phospholipase A(2) gene expression in the obese animals together with a strong specific inhibition of type IVA and VIA phospholipases A(2). These results suggest that the regulation of unsaturated fatty acids biosynthesis and signalling cascade could contribute to the development of liver lipid dysregulation related to metabolic syndrome and may be considered as new potential targets in such pathological conditions.     

Dietary fat,fatty acid composition in plasma and the metabolic syndrome

PURPOSE OF REVIEW: The metabolic syndrome, a cluster of disorders often including abdominal obesity, is associated with a high risk of cardiovascular disease and premature death. Insulin resistance is a key feature of the metabolic syndrome. Observational studies have indicated that the type of fat in the diet may be related to the development of insulin resistance and the metabolic syndrome, also independent of possible effects on body weight. Dietary surveys are often imprecise. One way to monitor the type of fat in the diet is to record the fatty acid composition in plasma. This review summarizes recent data on the relationships between fatty acid composition in plasma and insulin resistance, diabetes and other disorders related to the metabolic syndrome. RECENT FINDINGS: Insulin resistance and insulin resistant states are often associated with the fatty acid pattern in plasma, characterized by an increased proportion of palmitic (16 : 0) and a low proportion of linoleic (18 : 2 n-6) acids, with a distribution of other fatty acids indicating an increased activity of delta-9 and delta-6 desaturase. This shows that there may be a causal relationship between the type of fat in the diet and insulin action, an assumption supported by recent dietary intervention studies. SUMMARY: In a public health perspective these results, from both observational and intervention studies, underline the importance of fat quality in the diet for the development of a number of prevalent diseases. Taken together with several earlier studies and recent epidemiological findings, they give strong support to present dietary guidelines.     

Omega-3 fatty acids in obesity and metabolic syndrome: a mechanistic update

Strategies to reduce obesity have become public health priorities as the prevalence of obesity has risen in the United States and around the world. While the anti-inflammatory and hypotriglyceridemic properties of long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs) are well known, their antiobesity effects and efficacy against metabolic syndrome, especially in humans, are still under debate. In animal models, evidence consistently suggests a role for n-3 PUFAs in reducing fat mass, particularly in the retroperitoneal and epididymal regions. In humans, however, published research suggests that though n-3 PUFAs may not aid weight loss, they may attenuate further weight gain and could be useful in the diet or as a supplement to help maintain weight loss. Proposed mechanisms by which n-3 PUFAs may work to improve body composition and counteract obesity-related metabolic changes include modulating lipid metabolism; regulating adipokines, such as adiponectin and leptin; alleviating adipose tissue inflammation; promoting adipogenesis and altering epigenetic mechanisms.     

Novel qualitative aspects of tissue fatty acids related to metabolic regulation: lessons from Elovl6 knockout

Insulin resistance, often associated with obesity, precipitates metabolic syndrome, type 2 diabetes, and finally, atherosclerosis. Sources of excess energy cause abnormal accumulation of tissue lipids leading to cellular dysfunction through cellular stress and inflammation. This process is often referred to as lipotoxicity. Until date, effective approaches that aim to overcome insulin resistance involve amelioration of obesity by caloric restriction and/or exercise. Quantitative control of lipids, especially triglycerides and fatty acids in adipose and other tissues, and plasma can be addressed using these measures. However, altering tissue lipid composition may provide another strategy to prevent or control lipotoxicity. Endogenous fatty acid synthesis plays a crucial role in determining tissue energy states. As a target gene of SREBP-1 that controls lipogenesis we identified a unique enzyme, Elovl6, which is responsible for the final step in endogenous saturated fatty acid synthesis, thereby controlling tissue fatty acid composition. Elovl6-deficient mice become obese and develop hepatosteatosis when fed a high-fat diet or when mated to leptin-deficient ob/ob mice. However, the mice exhibited marked protection from hyperinsulinemia, hyperglycemia, and hyperleptinemia. Hepatic fatty acid composition is a novel determinant of insulin sensitivity independent of cellular energy balance. Inhibiting Elovl6 activity may provide a novel therapeutic approach for treating insulin resistance, diabetes, metabolic syndrome, and cardiovascular risks by circumventing obesity problems. In this review, we consider fatty acid metabolism and lipotoxicity, and discuss the role of Elovl6 in newly recognized aspects of metabolic regulation.     

GPR120的研究进展

游离脂肪酸作为组织能量来源以及介导各种细胞进程的信号分子,其生理功能长期以来受到广泛关注。外周游离脂肪酸水平的升高与肥胖、脂代谢紊乱以及糖尿病紧密相关。GPR120作为一新的长链脂肪酸受体,参与调节体内一系列的代谢过程,如激素分泌、细胞增殖及脂质生成等。作为肥胖、糖尿病的潜在治疗靶标,值得更深入的研究。     

Fatty acids increase the circulating levels of oxidative stress factors in mice with diet-induced obesity via redox changes of albumin

Plasma concentrations of free fatty acids are increased in metabolic syndrome, and the increased fatty acids may cause cellular damage via the induction of oxidative stress. The present study was designed to determine whether the increase in fatty acids can modify the free sulfhydryl group in position 34 of albumin (Cys34) and enhance the redox-cycling activity of the copper-albumin complex in high-fat diet-induced obese mice. The mice were fed with commercial normal diet or high-fat diet and water ad libitum for 3 months. The high-fat diet-fed mice developed obesity, hyperlipemia, and hyperglycemia. The plasma fatty acid/albumin ratio also significantly increased in high-fat diet-fed mice. The increased fatty acid/albumin ratio was associated with conformational changes in albumin and the oxidation of sulfhydryl groups. Moreover, an ascorbic acid radical, an index of redox-cycling activity of the copper-albumin complex, was detected only in the plasma from obese mice, whereas the plasma concentrations of ascorbic acid were not altered. Plasma thiobarbituric acid reactive substances were significantly increased in the high-fat diet group. These results indicate that the increased plasma fatty acids in the high-fat diet group resulted in the activated redox cycling of the copper-albumin complex and excessive lipid peroxidation.     

Postnatal overfeeding promotes early onset and exaggeration of high-fat diet-induced nonalcoholic fatty liver disease through disordered hepatic lipid metabolism in rats

Exposure to overnutrition in critical or sensitive developmental periods may increase the risk of developing obesity and metabolic syndrome in adults. Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome, but the relationship among postnatal nutrition, lipid metabolism, and NAFLD progression during development remains poorly understood. Here we investigated in a rat model whether postnatal overfeeding increases susceptibility to NAFLD in response to a high-fat diet. Litters from Sprague-Dawley dams were culled to three (small litters) or ten (normal litters) pups and then weaned onto a standard or high-fat diet at postnatal day 21 to generate normal-litter, small-litter, normal-litter/high-fat, and small-litter/high-fat groups. At age 16 weeks, the small-litter and both high-fat groups showed obesity, dyslipidemia, and insulin resistance. Hepatic disorders appeared earlier in the small-litter/high-fat rats with greater liver mass gain and higher hepatic triglycerides and steatosis score versus normal-litter/high-fat rats. Hepatic acetyl-CoA carboxylase activity and mRNA expression were increased in small-litter rats and aggravated in small-litter/high-fat rats but not in normal-litter/high-fat rats. The high expression in small-litter/high-fat rats coincided with high sterol regulatory element-binding protein-1c mRNA and protein expression. However, mRNA expression of enzymes involved in hepatic fatty acid oxidation (carnitine palmitoyltransferase 1) and output (microsomal triglyceride transfer protein) was decreased under a high-fat diet regardless of litter size. In conclusion, overfeeding related to small-litter rearing during lactation contributes to the NAFLD phenotype when combined with a high-fat diet, possibly through up-regulated hepatic lipogenesis.     

Interactive effects of maternal and weaning high linoleic acid intake on hepatic lipid metabolism,oxylipins profile and hepatic steatosis in offspring

Non-alcoholic fatty liver disease (NAFLD) has been described as a hepatic manifestation of the metabolic syndrome. When several studies correlated maternal linoleic acid (LA) intake with the development of obesity, only few links have been made between n-6 fatty acid (FA) and NAFLD. Herein, we investigated the influence of both maternal and weaning high LA intake on lipid metabolism and susceptibility to develop later metabolic diseases in offspring. Pregnant rats were fed a control-diet (2% LA) or a LA-rich diet (12% LA) during gestation and lactation. At weaning, offspring was assigned to one of the two diets, i.e., either maintained on the same maternal diet or fed the other diet for 6 months. Physiological, biochemical parameters and hepatic FA metabolism were analyzed. We demonstrated that the interaction between the maternal and weaning LA intake altered metabolism in offspring and could lead to hepatic steatosis. This phenotype was associated with altered hepatic FA content and lipid metabolism. Interaction between maternal and weaning LA intake led to a specific pattern of n-6 and n-3 oxylipins that could participate to the development of hepatic steatosis in offspring. Our findings highlight the significant interaction between maternal and weaning high LA intake to predispose offspring to later metabolic disease and support the predictive adaptive response hypothesis.     

Obesity and the gut microbiota: does up-regulating colonic fermentation protect against obesity and metabolic disease?

Obesity is now considered a major public health concern globally as it predisposes to a number of chronic human diseases. Most developed countries have experienced a dramatic and significant rise in obesity since the 1980s, with obesity apparently accompanying, hand in hand, the adoption of "Western"-style diets and low-energy expenditure lifestyles around the world. Recent studies report an aberrant gut microbiota in obese subjects and that gut microbial metabolic activities, especially carbohydrate fermentation and bile acid metabolism, can impact on a number of mammalian physiological functions linked to obesity. The aim of this review is to present the evidence for a characteristic "obese-type" gut microbiota and to discuss studies linking microbial metabolic activities with mammalian regulation of lipid and glucose metabolism, thermogenesis, satiety, and chronic systemic inflammation. We focus in particular on short-chain fatty acids (SCFA) produced upon fiber fermentation in the colon. Although SCFA are reported to be elevated in the feces of obese individuals, they are also, in contradiction, identified as key metabolic regulators of the physiological checks and controls mammals rely upon to regulate energy metabolism. Most studies suggest that the gut microbiota differs in composition between lean and obese individuals and that diet, especially the high-fat low-fiber Western-style diet, dramatically impacts on the gut microbiota. There is currently no consensus as to whether the gut microbiota plays a causative role in obesity or is modulated in response to the obese state itself or the diet in obesity. Further studies, especially on the regulatory role of SCFA in human energy homeostasis, are needed to clarify the physiological consequences of an "obese-style" microbiota and any putative dietary modulation of associated disease risk.     

TNF-α mediates the stimulation of sclerostin expression in an estrogen-deficient condition

Obesity consists in fat accumulation leading to increase in adipose cells number and size. Adipocyte membrane biophysical properties are critical to maintain cellular viability in metabolically healthy obesity. This study investigated the effect of the genetic background and dietary protein restriction on fat tissue lipid composition, adipocyte membrane fluidity and water permeability using the pig as experimental model. Twenty-four male pigs from distinct genotypes, lean and obese, were fed on normal and reduced protein diets within a 2 × 2 factorial arrangement (two genotypes and two diets). Backfat thickness was twofold higher in obese than in lean pigs but unrelated to dietary protein level. In contrast, total fatty acids in the subcutaneous adipose tissue were dependent on both breed and diet, with increased lipid content promoted by the fatty genotype and by the restriction of dietary protein. Adipose membranes isolated from obese pig's subcutaneous fat tissue showed higher permeability to water, in line with an increased fluidity. Moreover, the reduced content of dietary protein influenced positively the fluidity of adipose membranes. Neither genotype nor diet affected total cholesterol concentration in the adipose membranes. Membrane-saturated fatty acids' content was influenced by genotype, while membrane-polyunsaturated fatty acids, particularly from the n-6 family, was influenced by diet. The ratio of oleic (18:1c9)/linoleic (18:2n-6) acids was positively correlated with membrane fluidity. All together, these findings reinforce the genetic background as a determinant player on adipose membrane biophysical properties and point to the dietary protein level as an important factor for subcutaneous lipid deposition as well as for regulation of membrane function, factors that may have impact on human obesity and metabolic syndrome.