No abstract

In rodents, acute brain insulin action reduces blood glucose levels by suppressing the expression of enzymes in the hepatic gluconeogenic pathway, thereby reducing gluconeogenesis and endogenous glucose production (EGP). Whether a similar mechanism is functional in large animals, including humans, is unknown. Here, we demonstrated that in canines, physiologic brain hyperinsulinemia brought about by infusion of insulin into the head arteries (during a pancreatic clamp to maintain basal hepatic insulin and glucagon levels) activated hypothalamic Akt, altered STAT3 signaling in the liver, and suppressed hepatic gluconeogenic gene expression without altering EGP or gluconeogenesis. Rather, brain hyperinsulinemia slowly caused a modest reduction in net hepatic glucose output (NHGO) that was attributable to increased net hepatic glucose uptake and glycogen synthesis. This was associated with decreased levels of glycogen synthase kinase 3β (GSK3β) protein and mRNA and with decreased glycogen synthase phosphorylation, changes that were blocked by hypothalamic PI3K inhibition. Therefore, we conclude that the canine brain senses physiologic elevations in plasma insulin, and that this in turn regulates genetic events in the liver. In the context of basal insulin and glucagon levels at the liver, this input augments hepatic glucose uptake and glycogen synthesis, reducing NHGO without altering EGP.

Although fish oil has hypolipidemic and antiatherosclerotic properties, the potential for white adipose tissue (WAT) to mediate these effects has not been studied. LDL-receptor deficient (LDLR-/-) mice were fed high fat, olive oil-containing diets supplemented with additional olive oil or with fish oil for 12 wk. Fish oil feeding significantly reduced plasma lipid levels. In contrast, lipid storage in WAT was increased in fish oil-fed mice as evidenced by increased total fat (P < 0.05) and perigonadal WAT mass (P < 0.05), increased cholesterol storage (P < 0.001), and adipocyte hypertrophy. Despite increased adipose tissue mass, WAT-specific inflammation and insulin sensitivity were improved (P < 0.05), concomitant with reduced macrophage infiltration. Furthermore, fish oil increased WAT and plasma levels of adiponectin. In addition, fish oil feeding decreased the formation of proinflammatory F2- isoprostanes, markers of oxidative stress (P < 0.05). The increased WAT lipid storage in fish oil-fed mice was associated with reduced lipid accumulation in liver (P < 0.05) and decreased atherosclerotic lesion area (P < 0.05). Taken together, these data highlight the specific role of WAT in regulating dietary fish oil-mediated improvement in systemic lipid homeostasis and atherosclerosis.

Fish oil improves several features of metabolic

Hypertriglyceridemia is an important risk factor for atherosclerosis, especially in obesity. Macrophages are one of the primary cell types involved in atherogenesis and are thought to contribute to lesion formation through both lipid accumulation and proinflammatory gene expression. In this study, we sought to determine the direct impact of triglyceride (TG)-rich VLDL-induced lipid accumulation on macrophage proinflammatory processes. Incubation of mouse peritoneal macrophages with 100 mg/ml VLDL for 6 h led to 2.8-and 3.7-fold increases in intracellular TGs and FFAs, respectively (P , 0.05). The inflammatory proteins tumor necrosis factor-a, interleukin-1b, monocyte chemoattractant protein-1, intercellular adhesion molecule-1, matrix metalloproteinase 3 (MMP3), and macrophage inflammatory protein1a (MIP-1a) were all upregulated by at least 2-fold (P , 0.05) in a dose-dependent manner in VLDL-treated macrophages. The increase in inflammatory gene expression coincided with the phosphorylation of the mitogen-activated protein kinase (MAPK) pathway members extracellular signal-regulated kinase (ERK) 1/2, stress-activated protein kinase/c-Jun NH2-terminal kinase, and p38 MAPK and was ameliorated by U0126, an inhibitor of ERK1/2. Inhibition of extracellular TG hydrolysis with tetrahydrolipstatin (Orlistat) resulted in the absence of intracellular TG and FFA accumulation and was accompanied by the amelioration of ERK1/2 phosphorylation and MIP-1a gene expression. These data indicate that VLDL hydrolysis, and the subsequent accumulation of intracellular FFAs and TGs, plays a substantive role in mediating the proinflammatory effects of VLDL. These data have important implications for the direct proatherogenic effects of VLDL on macrophage-driven atherosclerosis.-Saraswathi, V., and A. H. Hasty. Traditionally, LDLs have been thought to be the key plasma lipoproteins involved in atherosclerotic lesion development. However, with the dramatic increase in the prevalence of obesity around the world, associated lipoprotein abnormalities such as hypertriglyceridemia have been brought into focus. In fact, hypertriglyceridemia is now regarded as one of the main contributing factors to the development of atherosclerotic disease (1, 2), although the exact mechanisms by which triglycerides (TGs) function in atherogenesis are unknown. TGs in fasting plasma are carried in VLDLs, and these VLDLs have been found within human and experimental atherosclerotic lesions (3, 4), providing a rationale to study their direct effects on macrophage functions such as foam cell formation and inflammation. It is well established that VLDL causes the accumulation of TGs and FFAs in macrophages (5-9). This can occur through three different mechanisms: 1) uptake of intact VLDL particles; 2) uptake of VLDL remnants resulting from lipoprotein lipase-mediated lipolysis; and 3) uptake of FFAs produced by VLDL lipolysis, which can be taken into cells through both passive diffusion and receptor-mediated mechanisms. Despite these known pathways of mac...