We showed that deletion of T-cadherin results in a ~10 - fold increase in circulating adiponectin, indicating it is the major adiponectin receptor in the body, and obese mice lacking T-cadherin are diabetic due to an abnormal enhancement of hepatic gluconeogenesis. We will determine whether T- cadherin is important for adiponectin binding and signaling in liver and muscle using cultured tissues from T-cadherin -/- mice, and also C2C12 myoblasts and myotubes in which T-cadherin has been overexpressed or knocked down. In parallel we will investigate the ability of different adiponectin isoforms to activate AMPK in these tissues. How adiponectin receptors are coupled to activation of AMPK is unknown but adiponectin signaling is accompanied by an increase in 5'AMP. Our preliminary data strongly suggest that acyl CoA synthetases transduce adiponectin signals to AMPK by producing 5'AMP. We will test the hypothesis that Fatty Acid Transporters (FATPs) and/or acyl-CoA synthetases (Acsls) are signal transduction proteins essential for AMPK activation by adiponectin. Initially we will focus on FATP1 and Acsl1 in muscle;we will stably overexpress Acsl and FATPs proteins, individually and together, in C2C12 myoblasts and myotubes, and also use shRNA to knock down their expression. We will monitor effects of adiponectin activation of AMPK, ACC phosphorylation, and malonyl CoA levels. We will also determine whether adiponectin signals translocation of acyl-CoA synthetases or FATPs to the plasma membrane. As receptors and signaling proteins other than T-cadherin and AdipoR1 and R2 are certainly involved in adiponectin signaling, we will use new biotin-containing tri-functional cross-linking reagents and mass spectrometry- based proteomic approaches to determine whether T-cadherin, Acsl or FATP isoforms, AdipoR1 or R2, or unknown proteins are part of the signaling adiponectin receptor complex in C2C12 myoblasts and myotubes, muscle and liver. Recently we cloned a family of ten adiponectin paralogs conserved in human and mouse that share biological activities and signaling properties with adiponectin. We focused on CTRP9 since it, like adiponectin, is made predominantly by adipocytes, activates AMPK in cultured muscle, and forms heterooligomers with adiponectin. We hypothesize that CTRP9, like adiponectin, normally regulates metabolism of muscle and liver. Mainly by studying adiponectin -/- mice, CTRP9-/- mice, and double mutant CTRP9-/- adiponectin -/- mice we will determine the role of CTRP9 in AMPK activation in muscle and liver and in the regulation of whole- body glucose and fatty acid metabolism. Receptors for CTRP9 are unknown and thus we will use several approaches to identify and clone the CTRP9 receptor(s).

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Molecular and Cellular Endocrinology Study Section (MCE)
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Laughlin, Maren R
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Whitehead Institute for Biomedical Research
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