Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: Acetyl–CoA carboxylase inhibition and AMP-activated protein kinase activation

Abstract

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

Globular adiponectin increases GLUT4 translocation and glucose uptake but reduces glycogen synthesis in rat skeletal muscle cells

“…We subsequently investigated the effects of gAd on glucose uptake and metabolism in these cells. Consistent with previous observations in rat skeletal muscle and C 2 C 12 myocytes [6,10,11], gAd increased glucose uptake in L6 myotubes. Importantly, we have demonstrated that gAd increases glucose uptake by increasing the cell surface content of GLUT4myc.…”

“…This observation is in line with our data indicating that gAd increases the transport V max for glucose without altering the K m . Previous studies have suggested that adiponectin regulates glucose uptake via an AMP kinase-dependent mechanism [6,10]. AMP kinase activation by AICAR has been shown to increase glucose uptake via [24,25], or independently of [26] GLUT translocation.…”

“…Previous studies have reported that adiponectin increases glucose uptake in muscle cells [6,10,11] and fat cells [27], but few have examined the subsequent metabolism of glucose. Potential pathways of glucose metabolism in muscle cells include glycogen synthesis, glucose oxidation and lactate production [28].…”

“…Previous work has shown that adiponectin increases fat oxidation in muscle and liver, and that AMP kinase appears to play a central role in the regulation of lipid metabolism by adiponectin [6,9,10]. The transport of fat into mitochondria via the carnitine palmitoyl transferase 1 (CPT-1) transporter is required for oxidation to occur and this process is inhibited by malonyl CoA [10,36]. It has been suggested that the insulin-sensitising effects of adiponectin may be due to a decrease in malonyl CoA levels and increased fat oxidation [36].…”

“…Injection of adiponectin into rodents has been shown to decrease resting blood glucose levels and protect animals with dietinduced obesity from developing insulin resistance [6][7][8][9]. Treatment of isolated skeletal muscle or C 2 C 12 myocytes with adiponectin stimulates glucose transport [6,10,11], suggesting that this may be one mechanism by which adiponectin acts to alleviate hyperglycaemia. However, very little is known about the molecular mechanism by which adiponectin stimulates glucose uptake.…”