gACRP30, the globular subunit of adipocyte complement-related protein of 30 kDa (ACRP30), improves insulin sensitivity and increases fatty acid oxidation. The mechanism by which gACRP30 exerts these effects is unknown. Here, we examined if gACRP30 activates AMP-activated protein kinase (AMPK), an enzyme that has been shown to increase muscle fatty acid oxidation and insulin sensitivity. Incubation of rat extensor digitorum longus (EDL), a predominantly fast twitch muscle, with gACRP30 (2.5 g͞ml) for 30 min led to 2-fold increases in AMPK activity and phosphorylation of both AMPK on Thr-172 and acetyl CoA carboxylase (ACC) on Ser-79. Accordingly, concentration of malonyl CoA was diminished by 30%. In addition, gACRP30 caused a 1.5-fold increase in 2-deoxyglucose uptake. Similar changes in malonyl CoA and ACC were observed in soleus muscle incubated with gACRP30 (2.5 g͞ml), although no significant changes in AMPK activity or 2-deoxyglucose uptake were detected. When EDL was incubated with full-length hexameric ACRP30 (10 g͞ml), AMPK activity and ACC phosphorylation were not altered. Administration of gACRP30 (75 g) to C57 BL͞6J mice in vivo led to increased AMPK activity and ACC phosphorylation and decreased malonyl CoA concentration in gastrocnemius muscle within 15-30 min. Both in vivo and in vitro, activation of AMPK was the first effect of gACRP30 and was transient, whereas alterations in malonyl CoA and ACC occurred later and were more sustained. Thus, gACRP30 most likely exerts its actions on muscle fatty acid oxidation by inactivating ACC via activation of AMPK and perhaps other signal transduction proteins.diabetes ͉ insulin sensitivity ͉ obesity ͉ malonyl CoA

The adipose tissue-derived hormone adiponectin improves insulin sensitivity and its circulating levels are decreased in obesityinduced insulin resistance. Here, we report the generation of a mouse line with a genomic disruption of the adiponectin locus. We aimed to identify whether these mice develop insulin resistance and which are the primary target tissues affected in this model. Using euglycemic/insulin clamp studies, we demonstrate that these mice display severe hepatic but not peripheral insulin resistance. Furthermore, we wanted to test whether the lack of adiponectin magnifies the impairments of glucose homeostasis in the context of a dietary challenge. When exposed to high fat diet, adiponectin null mice rapidly develop glucose intolerance. Specific PPAR␥ agonists such as thiazolidinediones (TZDs) improve insulin sensitivity by mechanisms largely unknown. Circulating adiponectin levels are significantly up-regulated in vivo upon activation of PPAR␥. Both TZDs and adiponectin have been shown to activate AMP-activated protein kinase (AMPK) in the same target tissues. We wanted to address whether the ability of TZDs to improve glucose tolerance is dependent on adiponectin and whether this improvement involved AMPK activation. We demonstrate that the ability of PPAR␥ agonists to improve glucose tolerance in ob/ob mice lacking adiponectin is diminished. Adiponectin is required for the activation of AMPK upon TZD administration in both liver and muscle. In summary, adiponectin is an important contributor to PPAR␥-mediated improvements in glucose tolerance through mechanisms that involve the activation of the AMPK pathway.Adiponectin/ACRP30 (adipocyte complement-related protein of 30 kDa), an adipocyte-specific secretory protein, has been shown to modulate insulin sensitivity; however, the mechanism(s) by which it acts are not fully understood (1). A number of clinical studies revealed a strong link between whole body insulin sensitivity and circulating adiponectin levels (2). Furthermore, circulating adiponectin is negatively correlated with the body mass index (3). Weight reduction leads to a significant increase in adiponectin plasma levels slightly preceding improvements in insulin sensitivity, thus suggesting a causative role of adiponectin in enhancing insulin sensitivity (4). Adiponectin null mouse models were described previously, however, with somewhat varying outcomes regarding their metabolic phenotype. Kubota et al. (5) noted mild insulin resistance under basal conditions in heterozygotes (60% reduction in adiponectin serum levels) and more severe insulin resistance in adiponectin null animals. This report differed from adiponectin null mice described by Maeda et al. (6) that showed nearly normal insulin sensitivity when fed on a standard laboratory diet but developed severe insulin resistance in as few as 2 weeks on a high fat/high sucrose diet. However, a third independent report of adiponectin null mice by Ma et al. (7) described an unexpected increase in fatty acid oxidation in skeletal muscle...