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Soluble epoxide hydrolase (Ephx2, sEH) is a bifunctional enzyme with COOH-terminal hydrolase and [NH.sub.2]-terminal phosphatase activities. sEH converts epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), and the phosphatase activity is suggested to be involved in cholesterol metabolism. EETs participate in a wide range of biological functions, including regulation of vascular tone, renal tubular transport, cardiac contractility, and inflammation. Inhibition of sEH is a potential approach for enhancing the biological activity of EETs. Therefore, disruption of sEH activity is becoming an attractive therapeutic target for both cardiovascular and inflammatory diseases. To define the physiological role of sEH, we characterized a knockout mouse colony lacking expression of the Ephx2 gene. Lack of sEH enzyme is characterized by elevation of EET to DHET ratios in both the linoleate and arachidonate series in plasma and tissues of both female and male mice. In male mice, this lack of expression was also associated with decreased plasma testosterone levels, sperm count, and testicular size. However, this genotype was still able to sire litters. Plasma cholesterol levels also declined in this genotype. Behavior tests such as anxiety-like behavior and hedonic response were also examined in Ephx2-null and WT mice, as all can be related to hormonal changes. Null mice showed a level of anxiety with a decreased hedonic response. In conclusion, this study provides a broad biochemical, physiological, and behavioral characterization of the Ephx2-null mouse colony and suggests a mechanism by which sEH and its substrates may regulate circulating levels of testosterone through cholesterol biosynthesis and metabolism. cholesterol; fertility

Obesity is commonly associated with development of insulin resistance and systemic evidence of inflammation. Macrophages contribute to inflammatory amplification in obesity and may contribute directly to insulin resistance and the development of nonalcoholic fatty liver disease through the production of inflammatory cytokines, including tumor necrosis factor (TNF)-[alpha]. To test this hypothesis, we transplanted male wild-type (WT) and TNF-[alpha] deficient (KO) mice with either TNF-[alpha]-sufficient (TNF-[[alpha].sup.+/+]) or TNF-[alpha]-deficient (TNF-[[alpha].sup.-/-]) bone marrow. After consuming a high-fat diet for 26 wk, metabolic and morphometric characteristics of the animals were analyzed. While there were no differences in terms of relative weight gain, body composition analysis yielded a lower relative adipose and higher relative lean mass in mice lacking TNF-[alpha], which was partially explained by reduced epididymal fat pad and liver weight. TNF-[[alpha].sup.-/-] [right arrow] KO mice exhibited enhanced insulin sensitivity compared with that observed in TNF-[[alpha].sup.+/+] [right arrow]KO mice; remarkably, no protection against insulin resistance was provided by transplanting TNF-[[alpha].sup.-/-] bone marrow in WT mice compared with TNF[[alpha].sup.+/+] [right arrow] WT. The preserved insulin sensitivity seen in TNF-[[alpha].sup.+/+] [right arrow] KO mice provided protection against the development of hepatic steatosis. Taken together, these data indicate that macrophage-derived TNF-[arrow] contributes to the pattern and extent of fat accumulation and insulin resistance in diet-induced obesity; however, this contribution is negligible in the presence of host-derived TNF-[arrow]. cytokine; inflammation; hyperinsulinemic-euglycemic clamping

A classical perspective of cardiovascular risk does not adequately account for all of the cardiovascular events associated with obesity and diabetes. The combination of hypertriglyceridemia, glucose intolerance and inflammation is linked with increased production of the primary inhibitor of endogenous thrombolysis, plasminogen activator inhibitor-1 (PAI-1). Recent data suggest that PAI-1 contributes directly to the complications of obesity, including type 2 diabetes, coronary arterial thrombi, and may even influence the accumulation of visceral fat. Therefore, direct inhibition of PAI-1 might not only provide a new therapeutic strategy for reducing cardiovascular risk, but may also have beneficial effects on obesity and insulin resistance.