We investigated the effects of eicosapentaenoic acid (EPA) on prevention (P) and reversal (R) of high saturated-fat (HF) diet-induced obesity and glucose-insulin homeostasis. Male C57BL/6J mice were fed low-fat (LF; 10% energy from fat), HF (45% energy from fat), or a HF-EPA-P (45% energy from fat; 36 g/kg EPA) diet for 11 wk. A 4th group was initially fed HF for 6 wk followed by the HF-EPA-R diet for 5 wk. As expected, mice fed the HF diet developed obesity and glucose intolerance. In contrast, mice fed the HF-EPA-P diet maintained normal glucose tolerance despite weight gain compared with the LF group. Whereas the HF group developed hyperglycemia and hyperinsulinemia, both HF-EPA groups (P and R) exhibited normal glycemia and insulinemia. Further, plasma adiponectin concentration was lower in the HF group but was comparable in the LF and HF-EPA groups, suggesting a role of EPA in preventing and improving insulin resistance induced by HF feeding. Further analysis of adipose tissue adipokine levels and proteomic studies in cultured adipocytes indicated that dietary EPA supplementation of HF diets was associated with reduced adipose inflammation and lipogenesis and elevated markers of fatty acid oxidation. In C57BL/6J mice, EPA minimized saturated fat-induced insulin resistance and this is in part mediated by its effects on fatty acid oxidation and inflammation.

Obesity is associated with the metabolic syndrome, a significant risk factor for developing type 2 diabetes and cardiovascular diseases. Chronic low-grade inflammation occurring in the adipose tissue of obese individuals is causally linked to the pathogenesis of insulin resistance and the metabolic syndrome. Although the exact trigger of this inflammatory process is unknown, adipose tissue hypoxia, endoplasmic reticular stress, and saturated fatty acid-mediated activation of innate immune processes have been identified as important processes in these disorders. Furthermore, macrophages and T lymphocytes have important roles in orchestrating this immune process. Although energy restriction leading to weight loss is the primary dietary intervention to reverse these obesity-associated metabolic disorders, other interventions targeted at alleviating adipose tissue inflammation have not been explored in detail. In this regard, (n-3) PUFA of marine origin both prevent and reverse high-fat-diet-induced adipose tissue inflammation and insulin resistance in rodents. We provide an update on the pathogenesis of adipose tissue inflammation and insulin resistance in obesity and discuss potential mechanisms by which (n-3) PUFA prevent and reverse these changes and the implications in human health.

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Serum C-reactive protein (CRP) is a biomarker for chronic inflammation and a sensitive risk factor for cardiovascular diseases. Though CRP has been reported to be related to food intake, there is no documentation of a direct association with flavonoid intake. We aimed to test the associations between dietary flavonoid intake and serum CRP concentrations among U.S. adults after adjusting for dietary, sociodemographic, and lifestyle factors. Data from the NHANES 1999-2002 were used for this cross-sectional study. Subjects were > or = 19-y-old adults (n = 8335), and did not include pregnant and/or lactating women. Flavonoid intake of U.S. adults was estimated by the USDA flavonoid databases matched with a 24-h dietary recall in NHANES 1999-2002. The serum CRP concentration was higher in women, older adults, blacks, and smokers, and in those with high BMI or low exercise level, and in those taking NSAID, than in their counterparts (P < 0.01). Intakes of apples and vegetables were inversely associated with serum CRP concentrations after adjusting for covariates (P < 0.05). Total flavonoid and also individual flavonol, anthocyanidin, and isoflavone intakes were inversely associated with serum CRP concentration after adjusting for the covariates (P < 0.05). Among the flavonoid compounds investigated, quercetin, kaempferol, malvidin, peonidin, daidzein, and genistein had inverse associations with serum CRP concentration (P < 0.05). These associations did not change even after the additional adjustment for fruit and vegetable consumption. Our findings demonstrate that intake of dietary flavonoids is inversely associated with serum CRP concentrations in U.S. adults. Intake of flavonoid-rich foods may thus reduce inflammation-mediated chronic diseases.

Given the role that diet and other environmental factors play in the development of obesity and type 2 diabetes, the implication of different epigenetic processes is being investigated. Although it is well known that external factors can cause cell type-dependent epigenetic changes, including DNA methylation, histone tail modifications, and chromatin remodeling, the regulation of these processes, the magnitude of the changes and the cell types in which they occur, the individuals more predisposed, and the more crucial stages of life remain to be elucidated. There is evidence that obese and diabetic people have a pattern of epigenetic marks different from nonobese and nondiabetic individuals. The main long-term goals in this field are the identification and understanding of the role of epigenetic marks that could be used as early predictors of metabolic risk and the development of drugs or diet-related treatments able to delay these epigenetic changes and even reverse them. But weight gain and insulin resistance/diabetes are influenced not only by epigenetic factors; different epigenetic biomarkers have also been identified as early predictors of weight loss and the maintenance of body weight after weight loss. The characterization of all the factors that are able to modify the epigenetic signatures and the determination of their real importance are hindered by the following factors: the magnitude of change produced by dietary and environmental factors is small and cumulative; there are great differences among cell types; and there are many factors involved, including age, with multiple interactions between them. Adv. Nutr. 5: 71-81, 2014.

Inflammation plays a major role in the development of chronic diseases such as cardiovascular disease and Type 2 diabetes. Further, it was demonstrated that obese animals and humans have significantly higher levels of circulating proinflammatory cytokines, such as interleukin-6 (IL-6). The aim of this study was to determine whether adipose tissue could be a major source of circulating IL-6 in leptin-deficient obese (ob/ob) mice by comparing the expression of IL-6 in different tissues of ob/ob mice. Our secondary goal was to determine whether preadipocytes are the source of adipose tissue IL-6. The ob/ob mice had higher levels of plasma IL-6 (P < 0.05) and adipose tissue IL-6 mRNA (P < 0.05) compared with lean mice. Interestingly, IL-6 mRNA levels of liver and spleen were not different between ob/ob and lean mice, whereas adipose tissue IL-6 mRNA levels were higher in the ob/ob mice compared with lean mice (P < 0.05). In addition, we showed that IL-6 secretion from the adipose tissue stromal vascular fraction cells was higher than that from fully differentiated adipocytes (P < 0.001). We further demonstrated that 3T3-L1 preadipocytes had significantly higher levels of lipopolysaccharide (LPS)-stimulated IL-6 mRNA and IL-6 secretion than differentiated 3T3-L1 adipocytes. Taken together, these data suggest that adipose tissue and preadipocytes from the adipose tissue stromal vascular fraction may contribute significantly to the increased plasma IL-6 levels in ob/ob mice.

Although leptin is known for its regulation of food intake, it has many emerging roles in immune function. To better define the role of leptin in hematopoietic processes, a leptin-deficient obese mouse (ob/ob) and C57BL/6 lean wild-type controls were compared. Despite their large size and consumption of substantial amounts of nutrients, the ob/ob mice had only 60% as many nucleated cells in their marrow as controls. The greatest impact of leptin deficiency was on the B cell compartment that had 70% fewer cells, reducing the absolute number of pre-B and immature B cells to 21% and 12% of normal, respectively, and indicating a significant reduction in lymphopoiesis in ob/ob mice. Whereas the proportion of myeloids remained nearly normal in the obese mice, they also exhibited a reduction of 40% and 25%, respectively, in absolute numbers of granulocytes and monocytes. Seven days of provision of recombinant leptin promoted substantial lymphopoiesis, increasing the numbers of B cells in the marrow of the obese mice twofold, while doubling and tripling, respectively, the numbers of pre-B and immature B cells. Twelve days of supplementation brought these subpopulations to near-normal proportions. Leptin treatment also facilitated myelopoiesis such that the marrow of the obese mice contained normal numbers of monocytes and granulocytes after 7 days. Taken together, the data support an important role for leptin in sustaining lymphopoiesis and myelopoiesis.obesity ͉ ob/ob mouse ͉ pre-B cell ͉ pre-T cell

We have shown that the age-associated increase in lipopolysaccharide (LPS)-stimulated macrophages (M) prostaglandin E 2 (PGE 2 ) production is because of ceramide-induced up-regulation of cyclooxygenase (COX)-2 transcription that leads to increased COX-2 expression and enzyme activity. To determine the mechanism of the age-related and ceramide-dependent increase in COX-2 transcription, we investigated the role of various transcription factors involved in COX-2 gene expression. The results showed that LPS-initiated activations of both consensus and COX-2-specific NF-B, but not AP-1 and CREB, were significantly higher in M from old mice than those from young mice. We further showed that the higher NF-B activation in old M was because of greater IB degradation in the cytoplasm and p65 translocation to the nucleus. An IB phosphorylation inhibitor, Bay 11-7082, inhibited NF-B activation, as well as PGE 2 production, COX activity, COX-2 protein, and mRNA expression in both young and old M. Similar results were obtained by blocking NF-B binding activity using a NF-B decoy. Furthermore, NF-B inhibition resulted in significantly greater reduction in PGE 2 production and COX activity in old compared with young M. Addition of ceramide to the young M, in the presence or absence of LPS, increased NF-B activation in parallel with PGE 2 production. Bay 11-7082 or NF-B decoy prevented this ceramide-induced increase in NF-B binding activity and PGE 2 production. These findings strongly suggest that the age-associated and ceramide-induced increase in COX-2 transcription is mediated through higher NF-B activation, which is, in turn, because of a greater IB degradation in old M.It is well documented that T cell-mediated immune function declines in old animals and elderly humans compared with their young counterparts (1, 2). The age-associated dysregulation in macrophages (M) 1 contributes to the impaired T cell function with aging. We, as well as others, have demonstrated that immune cells, including M, from old animals and humans produced more PGE 2 than those from their young counterparts (3-7). We further showed that the increased PGE 2 production by M contributes to the decline in T cell-mediated function with aging (8).Cyclooxygenase (COX) is the rate-limiting enzyme that catalyzes the conversion of arachidonic acid (AA) to PG endoperoxide (PGH 2 ), which is further converted to different PGs and thromboxane. COX is hence a key factor in PG synthesis. Two isoforms of COX have been identified: a constitutive form, COX-1 (9, 10), and the inducible counterpart, COX-2 (11, 12). We have demonstrated that the age-associated increase in M PGE 2 production is because of higher COX activity in M from old mice compared with those from young mice. This increased COX activity is, in turn, a result of increased expression of COX-2 protein and mRNA (13). In a recent study, we further demonstrated that the age-related increase in COX-2 mRNA was because of a higher level of ceramide in old M compared with those of young, which induced up-regu...