Adiponectin Activates AMP-activated Protein Kinase in Muscle Cells via APPL1/LKB1-dependent and Phospholipase C/Ca2+/Ca2+/Calmodulin-dependent Protein Kinase Kinase-dependent Pathways

Abstract

2؉release from the endoplasmic reticulum, which plays a minor role in AMPK activation. Our results show that in muscle cells adiponectin is able to activate AMPK via two distinct mechanisms as follows: a major pathway (the APPL1/LKB1-dependent pathway) that promotes the cytosolic localization of LKB1 and a minor pathway (the phospholipase C/Ca 2؉ / Ca 2؉ /calmodulin-dependent protein kinase kinase-dependent pathway) that stimulates Ca 2؉ release from intracellular stores.Adiponectin, an adipokine abundantly expressed in adipose tissue, exhibits anti-diabetic, anti-inflammatory, and antiatherogenic properties and hence is a potential therapeutic target for various metabolic diseases (1-3). The beneficial effects of adiponectin are mediated through the direct interaction of adiponectin with its cell surface receptors, AdipoR1 and AdipoR2 (4, 5). Adiponectin increases fatty acid oxidation and glucose uptake in muscle cells by activating AMP-activated protein kinase (AMPK) 3 (4, 6), which depends on the interaction of AdipoR1 with the adaptor protein APPL1 (Adaptor protein containing Pleckstrin homology domain, Phosphotyrosine binding domain, and Leucine zipper motif) (5). However, the underlying mechanisms by which APPL1 mediates adiponectin signaling to AMPK activation and other downstream targets remain unclear.AMPK is a serine/threonine protein kinase that acts as a master sensor of cellular energy balance in mammalian cells by regulating glucose and lipid metabolism (7,8). AMPK is composed of a catalytic ␣ subunit and two noncatalytic regulatory subunits, ␤ and ␥. The NH 2 -terminal catalytic domain of the AMPK␣ subunit is highly conserved and contains the activating phosphorylation site (Thr 172 ) (9). Two AMPK variants, ␣1 and ␣2, exist in mammalian cells that show different localization patterns. AMPK␣1 subunit is localized in non-nuclear fractions, whereas the AMPK␣2 subunit is found in both nucleus and non-nuclear fractions (10). Biochemical regulation of AMPK activation occurs through various mechanisms. An increase in AMP level stimulates the binding of AMP to the ␥ subunit, which induces a conformational change in the AMPK heterotrimer and results in AMPK activation (11). Studies have shown that the increase in AMPK activity is not solely via AMPdependent conformational change, rather via phosphorylation by upstream kinases, LKB1 and CaMKK. Dephosphorylation by protein phosphatases is also important in regulating the activity of AMPK (12).LKB1 has been considered as a constitutively active serine/ threonine protein kinase that is ubiquitously expressed in all tissues (13,14). Under conditions of high cellular energy stress, LKB1 acts as the primary AMPK kinase through an AMP-dependent mechanism (15-17). Under normal physiological conditions, LKB1 is predominantly localized in the nucleus. LKB1 is translocated to the cytosol, either by forming a heterotrimeric complex with Ste20-related adaptor protein

Bariatric surgery and bone disease: from clinical perspective to molecular insights

“…Interestingly, adiponectin was shown to increase after RNYGB. 19,78,79 Serotonin Serotonin is produced in both the gastrointestinal and central nervous systems. In the duodenum, enterochromaffin cells respond to mechanical stress by producing tryptophan hydroxylase 1, the rate-limiting catalyst of gut-derived serotonin (GDS) production.…”

Adiponectin ameliorates angiotensin II-induced vascular endothelial damage

“…Essential to activation of AMPK is its phosphorylation at Thr-172 by an upstream kinase. It has been reported that adiponectin is able to activate AMPK by increasing its phosphorylation at Thr-172 (Zhou et al 2009). On the other hand, the requirement of AMPK for energy-dependent and independent mechanisms of apoptosis induced by Ang II has been previously demonstrated (Day et al 2011).…”

Infusion of a Lipid Emulsion Modulates AMPK and Related Proteins in Rat Liver, Muscle, and Adipose Tissues

“…Following 6 days of LE administration, no difference in muscle AMPK and LKB1 association was observed (Figure 3c). Recent evidence suggests that phosphorylation of LKB1 at Ser-428 promotes its export from the nucleus resulting in activation of AMPK (23). Thus, we also measured LKB1 phosphorylation in skeletal muscle.…”

“…Studies indicate that adiponectin is able to active CaMKK and AMPK in mouse skeletal muscle tissues and C 2 C 12 myoblasts by inducing intracellular Ca 2+ release. This pathway occurs independently to LKB1 activation (23). Because a tissue-specific effect of LE administration on the AMPK pathway was observed, the impact of lipid oversupply on serum adiponectin and adiponectin receptor mRNA expression levels were also evaluated.…”