Paradigm shift: the primary function of the “Adiponectin Receptors” is to regulate cell membrane composition

Abstract

The ADIPOR1 and ADIPOR2 proteins (ADIPORs) are generally considered as adiponectin receptors with anti-diabetic properties. However, studies on the yeast and C. elegans homologs of the mammalian ADIPORs, and of the ADIPORs themselves in various mammalian cell models, support an updated/different view. Based on findings in these experimental models, the ADIPORs are now emerging as evolutionarily conserved regulators of membrane homeostasis that do not require adiponectin to act as membrane fluidity sensors and regulate phospholipid composition. More specifically, membrane rigidification activates ADIPOR signaling to promote fatty acid desaturation and incorporation of polyunsaturated fatty acids into membrane phospholipids until fluidity is restored. The present review summarizes the evidence supporting this new view of the ADIPORs, and briefly examines physiological consequences.

Role of Perivascular Adipose Tissue-Derived Adiponectin in Vascular Homeostasis

“…Similarities were also iden-tified in Caenorhabditis elegans, where two AdipoRs homologs exist, and their disruption leads to membrane rigidification as a result of the accumulation of saturated fatty acids in plasma membranes [41]. This suggests that AdipoRs have an enzymatic activity that is independent of adiponectin, since C. elegans lacks adiponectin homolog [42]. Indeed, studies utilizing human cell lines showed that depletion of AdipoRs resulted in a higher accumulation of saturated fatty acids (SFAs) in plasma membranes, resulting in their rigidification [43].…”

“…In addition, upon palmitate treatment, cells showed mitochondrial respiratory defects and poor viability [44]. Intriguingly, supplementation with mono-or polyunsaturated fatty acids, which are known to increase membrane fluidity, was able to revoke detrimental effects of AdipoR2 silencing [42,44]. These findings suggest that the primary function of AdipoRs may not be adiponectin binding but the regulation of membrane homeostasis.…”

“…These findings suggest that the primary function of AdipoRs may not be adiponectin binding but the regulation of membrane homeostasis. This implies that future studies on AdipoRs should be more focused on their adiponectin-independent activity, possibly by using in vivo models [42].…”

Palmitic acid causes increased dihydroceramide levels when desaturase expression is directly silenced or indirectly lowered by silencing AdipoR2

“…AdipoR1 and AdipoR2 are members of the PAQR (Progestin and AdipoQ Receptors) protein family that are emerging as regulators of fatty acid desaturation and membrane homeostasis [ 12 ]. These proteins have seven transmembrane domains with a cytosolic N-terminus and their C-terminus pointing towards the extracellular space [ 13 ].…”

“…These proteins have seven transmembrane domains with a cytosolic N-terminus and their C-terminus pointing towards the extracellular space [ 13 ]. The AdipoRs were initially identified as adiponectin receptors [ 14 ], but recent experimental evidence based on studying the yeast [ 15 – 19 ] and C. elegans [ 20 – 28 ] homologs, and the AdipoRs themselves [ 23 – 27 , 29 , 30 ], suggests that their primary cellular function is in membrane homeostasis and is independent of adiponectin (reviewed in [ 12 ]). In particular, the AdipoRs react to membrane rigidification, e.g.…”