Besides its multiple peripheral effects adiponectin may amel

Besides its multiple peripheral effects adiponectin may ameliorate insulin resistance by acting in the brain, and intracerebroventricular administration of adiponectin in rodents decreases body weight by stimulating energy expenditure [13]. Adiponectin most likely crosses the blood-CSF-barrier (BCB) and/or the blood-brain barrier (BBB) [14], [15] and is about 1000-fold lower concentrated in human cerebrospinal fluid (CSF) than in serum [8], [14], [15]. Similar to systemic adiponectin, CSF adiponectin is higher in females [15] and the trimeric and hexameric isoforms are predominantly found in human CSF [8]. AdipoR1 and AdipoR2 protein are expressed in the hypothalamus and the paraventricular nucleus further indicating that adiponectin exerts a specific role in the c-Myc tag [14]. AdipoR1 and AdipoR2 exert similar effects but also have individual signalling preferences. Whereas phosphorylation of extracellular regulated kinase 1/2 may depend on both receptors, AdipoR1 is more prominent in AMP-activated protein kinase (AMPK) phosphorylation, and AdipoR2 is involved in PPARα activation [10], [16], [17]. How the signals are transduced from the adiponectin receptors to downstream molecules, however, remains largely unknown. So far adaptor protein containing pleckstrin homology domain, phosphotyrosine binding (PTB) domain and leucine zipper motif 1 (APPL1), endoplasmic reticulum protein 46 (ERp46), activated protein kinase C1 (RACK1) and protein kinase CK2β subunit (CK2β) have been identified to directly interact with adiponectin receptors and their role has been mainly studied for AdipoR1 signalling. This review article will give a short summary on the identification and function of adiponectin receptor associated proteins.
Progestin and AdipoQ receptor family AdipoR1 and AdipoR2 belong to the recently described progestin and AdipoQ receptor (PAQR) family named after the two initially described ligands, progestin and adipoQ [18]. The eleven proteins currently identified as PAQR family members have a conserved structure/topology with invariant intracellular amino acid residues [18]. These proteins are grouped into three classes based on sequence similarities. Class I receptors are expressed in nearly all eukaryotes with the most prominent members AdipoR1 (PAQR1) and AdipoR2 (PAQR2). Class II proteins are non-classical receptors for the steroid hormone progesteron including mPRα (PAQR7). The most diverged family members are the class III members PAQR10 and -11 where no agonist has been identified yet [18].
Heterologous expression of AdipoR1 and AdipoR2 in yeast Kupchak et al. have demonstrated that overexpression of AdipoR1 in yeast alone is sufficient to induce downstream signalling whereas AdipoR2 is not active until stimulated with adiponectin. Downstream molecules in yeast are RAS2 (RAS GTPase family member), TPK1 (catalytic subunit of cAMP-dependent protein kinase, isoform 1), TPK2 (TPK isoform 2), TPK3 (TPK isoform 3), SIP1 (Snf1 Ser/Thr-specific protein kinase beta subunit), SNF4 (Snf1 protein kinase gamma subunit), SIP3 (activator of transcription related to Snf1), NRG1 (transcriptional repressor that functions in glucose repression of a subset of Snf1-regulated genes) and NRG2 for both receptors [19], [20]. Snf1 is the yeast homolog of mammalian AMP-activated protein kinase (AMPK), and involved in nutrient sensing in lower organisms [19]. Basal and agonist-induced signalling of AdipoR1 and agonist-induced signalling of AdipoR2 are blocked by a ceramidase inhibitor indicating that sphingoid base second messengers are involved in signal transduction [20]. Ceramides are generated in several tissues and cells upon lipopolysaccharide and TNF stimulation and excess ceramide may contribute to insulin resistance [21], [22]. TNF, which is like adiponectin a member of the C1q/TNF protein family [23], antagonizes AdipoR1 and AdipoR2 activity in yeast, but this blockade seems to be independent of downstream signalling pathways [20].