Review
ACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism

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Abstract

In recent years, we have learned that adipocytes are not merely inert storage depots for triglycerides but rather highly active cells with potent autocrine, paracrine and endocrine functions. Adipose tissue secretes a large number of physiologically active polypeptides. Although leptin remains one of the best-studied examples of an adipocyte-specific secretory factor, recent reports describe potent physiological activities for another adipocyte-specific secreted protein, adipocyte complement-related protein of 30 kDa (Acrp30). Full-length versions of Acrp30 or its proteolytic fragments decrease the postprandial rise of plasma free fatty acids and improve postabsorptive insulin-mediated suppression of hepatic glucose output. A strong correlation between plasma Acrp30 levels and systemic insulin sensitivity is well established and the protein has putative anti-atherogenic properties that are relevant for the prevention of formation of atherosclerotic plaques. The current challenge is to understand the molecular mechanisms through which the protein exerts its multiple functions.

Section snippets

Discovery of a complement-related protein secreted from adipocytes

In 1995, the first description of the cDNA encoding Acrp30 was reported [3]. This cDNA was isolated by a subtractive hybridization screen comparing 3T3-L1 adipocytes with undifferentiated preadipocytes. The mRNA was induced over 100-fold during differentiation and was expressed exclusively in adipocytes. Developmentally, expression of the mRNA for Acrp30 is detected at late stages of embryogenesis, on day 17 of gestation [4]. This expression pattern is consistent with that seen in the mouse for

Structural aspects of the Acrp30 complex

The N-terminal collagenous domain of Acrp30 contains 22 repeats that follow the Gly-X-Y or Gly-X-Pro consensus for proteins forming collagenous triple helices. Acrp30 and its orthologs found in other species have several conserved prolines and lysines within the collagenous domain, and it is probable that these residues are mostly hydroxylated and necessary for the formation of a stable collagen triple helix.

The overall topology of Acrp30 bears a close resemblance to the structure of C1q. The

Metabolic effects of Acrp30 action

The original report describing the identification of the cDNA for Acrp30 also demonstrated its secretion from cells and its presence in mouse plasma [3]. Arita et al. [9] corroborated this finding in human plasma samples, showing comparable amounts of Acrp30 in humans and mice. With a newly cloned adipocyte-specific secretory protein in hand, several groups began to investigate the physiological functions of this protein. Hu et al. found that levels of transcripts for Acrp30 in white adipose

Pharmacological effects of recombinant Acrp30

To demonstrate the pharmacological functions of Acrp30, different groups have chosen different approaches for the production of bioactive ligands, in both bacterial and mammalian expression systems. These ligands and their methods of preparation differ significantly, and it is important to consider the structure and biogenesis of these ligands when interpreting results. Ouchi et al. [8] have used bacterially produced full-length Acrp30 in their experiments. Fruebis et al. [27] also produced

Why do we need Acrp30?

Several recently developed genetic models demonstrated that alterations in adipocytes, such as the adipose-specific ablation of the insulin-sensitive glucose transporter GLUT4 [34], cause insulin resistance in other tissues. Excess adipose tissue in obesity and lack of adipose tissue in lipodystrophic states are associated with insulin resistance and type 2 diabetes mellitus in human and animal studies 35, 36. Although this effect can be explained, in part, by alterations of leptin secretion,

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