Adipocyte complement-related protein (30 kDa) (Acrp30), a secreted protein of unknown function, is exclusively expressed in differentiated adipocytes; its mRNA is decreased in obese humans and mice. Here we describe novel pharmacological properties of the protease-generated globular head domain of Acrp30 (gAcrp30). Acute treatment of mice with gAcrp30 significantly decreased the elevated levels of plasma free fatty acids caused either by administration of a high fat test meal or by i.v. injection of Intralipid. This effect of gAcrp30 was caused, at least in part, by an acute increase in fatty acid oxidation by muscle. As a result, daily administration of a very low dose of gAcrp30 to mice consuming a high-fat͞sucrose diet caused profound and sustainable weight reduction without affecting food intake. Thus, gAcrp30 is a novel pharmacological compound that controls energy homeostasis and exerts its effect primarily at the peripheral level.

The insulin-sensitizing effects of thiazolidinediones are thought to be mediated through peroxisome proliferator-activated receptor-␥, a nuclear receptor that is highly abundant in adipose tissue. It has been reported that adipocytes secrete a variety of proteins, including tumor necrosis factor-␣, resistin, plasminogen activator inhibitor-1, and adiponectin. Adiponectin is a fat cellsecreted protein that has been reported to increase fat oxidation and improve insulin sensitivity. Our aim was to study the effects of troglitazone on adiponectin levels in lean, obese, and diabetic subjects. Ten diabetic and 17 nondiabetic subjects (8 lean, BMI <27 kg/m 2 and 9 obese, BMI >27 kg/m 2 ) participated in the study. All subjects underwent an 80 mU ⅐ m ؊2 ⅐ min ؊1 hyperinsulinemic-euglycemic glucose clamp before and after 3 months' treatment with the thiazolidinedione (TZD) troglitazone (600 mg/day). Fasting plasma glucose significantly decreased in the diabetic group after 12 weeks of treatment compared with baseline (9.1 ؎ 0.9 vs. 11.1 ؎ 0.9 mmol/l, P < 0.005) but was unchanged in the lean and obese subjects. Fasting insulin for the entire group was significantly lower than baseline (P ‫؍‬ 0.02) after treatment. At baseline, glucose disposal rate (R d ) was lower in the diabetic subjects (3.4 ؎ 0.5 mg ⅐ kg ؊1 ⅐ min ؊1 ) than in the lean (12.3 ؎ 0.4) or obese subjects (6.7 ؎ 0.7) (P < 0.001 for both) and was significantly improved in the diabetic and obese groups (P < 0.05) after treatment, and it remained unchanged in the lean subjects. Baseline adiponectin levels were significantly lower in the diabetic than the lean subjects (9.0 ؎ 1.7 vs. 16.7 ؎ 2.7 g/ml, P ‫؍‬ 0.03) and rose uniformly in all subjects (12.2 ؎ 2.3 vs. 25.7 ؎ 2.6 g/ml, P < 10 -4 ) after treatment, with no significant difference detected among the three groups. During the glucose clamps, adiponectin levels were suppressed below basal levels in all groups (10.2 ؎ 2.3 vs. 12.2 ؎ 2.3 g/ml, P < 0.01). Adiponectin levels correlated with R d (r ‫؍‬ 0.46, P ‫؍‬ 0.016) and HDL cholesterol levels (r ‫؍‬ 0.59, P < 0.001) and negatively correlated with fasting insulin (r ‫؍‬ ؊0.39, P ‫؍‬ 0.042) and plasma triglyceride (r ‫؍‬ ؊0.61, P < 0.001). Our findings show that TZD treatment increased adiponectin levels in all subjects, including normal subjects in which no other effects of TZDs are observed. Insulin also appears to suppress adiponectin levels. We have confirmed these results in normal rats. These findings suggest that adiponectin can be regulated by obesity, diabetes, TZDs, and insulin, and it may play a physiologic role in enhancing insulin sensitivity. Diabetes

The lipolysis stimulated receptor (LSR) recognizes apolipoprotein B/E-containing lipoproteins in the presence of free fatty acids, and is thought to be involved in the clearance of triglyceride-rich lipoproteins (TRL). The distribution of LSR in mice was studied by Northern blots, quantitative PCR and immunofluorescence. In the adult, LSR mRNA was detectable in all tissues tested except muscle and heart, and was abundant in liver, lung, intestine, kidney, ovaries and testes. During embryogenesis, LSR mRNA was detectable at 7.5 days post-coitum (E7) and increased up to E17 in parallel to prothrombin, a liver marker. In adult liver, immunofluorescence experiments showed a staining at the periphery of hepatocytes as well as in fetal liver at E12 and E15. These results are in agreement with the assumption that LSR is a plasma membrane receptor involved in the clearance of lipoproteins by liver, and suggest a possible role in steroidogenic organs, lung, intestine and kidney). To explore the role of LSR in vivo, the LSR gene was inactivated in 129/ Ola ES cells by removing a gene segment containing exons 2-5, and 129/Ola-C57BL/6 mice bearing the deletion were produced. Although heterozygotes appeared normal, LSR homozygotes were not viable, with the exception of three males, while the total progeny of genotyped wild-type and heterozygote pups was 345. Mortality of the homozygote embryos was observed between days 12.5 and 15.5 of gestation, a time at which their liver was much smaller than that of their littermates, indicating that the expression of LSR is critical for liver and embryonic development.Keywords: lipoprotein receptors; Northern-blot; quantitative PCR; immunofluorescence; gene-targetting.Lipids, absorbed exogenously by the intestine and synthesized endogenously by the liver, are secreted into the circulation as lipoproteins for their transport to tissues, where they are used mainly for membrane synthesis, steroidogenesis and fat storage. Dietary cholesterol, phospholipids, triglycerides (TG) and fat-soluble vitamins absorbed by the intestine after a meal are transported by chylomicrons into lymph, then into blood. Lipoprotein lipase (LPL), anchored to the surface of capillary endothelium, hydrolyzes TG of chylomicrons into free fatty acids (FFA) that are taken up by the underlying muscle and adipose tissues. Chylomicron remnants are then taken up by the liver [1]. Transport of lipids to tissues is achieved by very low density lipoproteins (VLDL) and low density lipoproteins (LDL). Excess cholesterol is removed from the peripheral cells by high density lipoproteins (HDL) that are able to return it to the liver for excretion via the LDL receptor (LDLR) or the scavenger receptor class BI (SR-BI) pathways. In the same way, HDL are also involved in the delivery of cholesterol to certain tissues, mainly steroidogenic organs. Apolipoprotein (apo) B and E containing-VLDL and chylomicron remnants bind with high affinity to the LDLR and the LDL receptor related protein (LRP) that mediates endocytosis of both particl...

SummaryMild hyperhomocysteinemia, due to genetic or to environmental factors, is now recognized as a risk factor for premature arterial disease, including peripheral arterial occlusion, thrombotic stroke and myocardial infarction. It is defined by either an increased level of fasting homocysteine or by an increased level after loading with methionine, which is more frequently altered than the former. We studied the hemostatic parameters in 88 patients with premature arterial disease (mean age 43 ± 11 years). We confirmed previously known hemostatic alterations described in vascular patients when compared to controls, but found that, among patients, some of these parameters were more altered in hyperhomocysteinemic patients. When fasting homocysteine was increased, higher alterations were found in factors VIIIc, von Wille- brand and thombin-antithrombin complexes were more elevated. When post-methionine load homocysteine was increased, alterations in fibrinolytic parameters were more pronounced.