Acrp30͞adiponectin is reduced in the serum of obese and diabetic individuals, and the genetic locus of adiponectin is linked to the metabolic syndrome. Recombinant adiponectin, administered to diet-induced obese mice, induced weight loss and improved insulin sensitivity. In muscle and liver, adiponectin stimulates AMP-activated protein kinase activation and fatty acid oxidation. To expression-clone molecules capable of binding adiponectin, we transduced a C2C12 myoblast cDNA retroviral expression library into Ba͞F3 cells and panned infected cells on recombinant adiponectin linked to magnetic beads. We identified T-cadherin as a receptor for the hexameric and high-molecular-weight species of adiponectin but not for the trimeric or globular species. Only eukaryotically expressed adiponectin bound to T-cadherin, implying that posttranslational modifications of adiponectin are critical for binding. An adiponectin mutant lacking a conserved N-terminal cysteine residue required for formation of hexamer and high-molecularweight species did not bind T-cadherin in coimmunoprecipitation studies. Although lacking known cellular functions, T-cadherin is expressed in endothelial and smooth muscle cells, where it is positioned to interact with adiponectin. Because T-cadherin is a glycosylphosphatidylinositol-anchored extracellular protein, it may act as a coreceptor for an as-yet-unidentified signaling receptor through which adiponectin transmits metabolic signals.A dipose tissue is not only a storage depot for lipid but also a regulator of metabolism, through hormones known as adipokines. One adipokine is adiponectin (also denoted Acrp30, for adipocyte complement-related protein of 30 kDa), a molecule secreted exclusively by differentiated adipocytes (1). Adiponectin, which has homology to C1q, is found in the serum as three distinct oligomers, namely trimer, hexamer, and a highmolecular-weight (HMW) species (2). Adiponectin levels are decreased in the serum of obese and diabetic people (3) and animal models of obesity and diabetes. Replenishment by any of several methods induces weight loss and correction of insulin resistance (4-6). The mechanisms by which adiponectin influences metabolism are not fully understood but involve increasing fatty-acid oxidation in muscle through AMP-activated protein kinase (AMPK) activation, as well as synergizing with insulin in the liver to increase glycogen stores and to inhibit gluconeogenesis (6, 7). In tissue culture and isolated muscle, the trimeric isoform and a trimeric globular C-terminal subdomain activate AMPK (7,8), whereas the hexamer and HMW isoforms activate NF-B (9). Adiponectin also has been implicated in the inflammatory process of the metabolic syndrome, and reduced adiponectin levels have been correlated with impaired forearm blood flow, possibly linking endothelial dysfunction with adiponectin levels (10).Analysis of the transmembrane pathways linking adiponectin to downstream signaling events has yielded conflicting results. Two recently described receptors that bind ad...

Acrp30/adiponectin is an adipocyte-derived serum protein with important roles in regulation of lipid and glucose metabolism, but which of its isoforms are biologically active remains controversial. We addressed this issue by first characterizing the structure of each individual Acrp30 oligomer and the determinants responsible for multimer formation.