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.

Adiponectin (ACRP30), an adipocyte-secreted protein encoded by the APM1 gene, is known to modulate insulin sensitivity and glucose homeostasis, those effects protecting obese mice from diabetes. Plasma adiponectin levels correlate well with insulin sensitivity in humans, and are decreased in both type 2 diabetes (T2D) and obesity. We screened for single-nucleotide polymorphisms (SNPs) the APM1 gene coding and 5' sequences in 40 French Caucasians: 12 SNPs and 4 rare non-synonymous mutations of exon 3 were detected. The 10 most frequent SNPs were genotyped in 1373 T2D and obese French Caucasian subjects and in all subjects available from 148 T2D multiplex families. The screening for rare mutations of exon 3 was extended to 1246 T2D and obese French subjects and to the members of the 148 T2D multiplex families. A haplotype including SNPs -11391 and -11377, both located in the 5' sequences, was associated with adiponectin levels (P<0.0001) and with T2D (P=0.004). The presence of at least one non-synonymous mutation in exon 3 showed evidence of association with adiponectin levels (P=0.0009) and with T2D (P=0.005). We failed to detect an association with insulin resistance indexes. Although family-based association analysis with T2D did not reach significance, our results suggest that an at-risk haplotype of common variants located in the promoter and rare mutations in exon 3 contribute to the variation of the adipocyte-secreted adiponectin hormone level, and may be part of the genetic determinants for T2D in the French Caucasian population.

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Plasma net cholesteryl ester (CE) transfer and optimum cholesteryl ester transfer protein (CETP) activity were determined in primary hypertriglyceridemic (a = 11) and normolipidemic (a = 15) individuals. The hypertriglyceridemic group demonstrated threefold greater net CE transfer leading to enhanced accumulation of CE in VLDL. This increased net transfer was not accompanied by a change in CETP activity. In normolipidemia, but not in hypertriglyceridemia, net CE transfer correlated with VLDL triglyceride (r = 0.92, P < 0.001). In contrast, net CE transfer in hypertriglyceridemia, but not in normolipidemia, correlated with CETP activity (r = 0.73, P < 0.01). Correction of hypertriglyceridemia with bezafibrate reduced net CE transfer towards normal and restored the correlation with VLDL triglyceride (r = 0.90, P < 0.005) while suppressing the correlation with CETP activity. That net CE transfer depends on VLDL concentration was confirmed by an increase ofnet CE transfer in normolipidemic plasma supplemented with purified VLDL. Supplementation of purified CETP to normolipidemic plasma did not stimulate net CE transfer. In contrast, net CE transfer was enhanced by addition of CETP to both plasma supplemented with VLDL and hypertriglyceridemic plasma.