Abstract:Adiponectin receptors (ADIPORs) are integral membrane proteins that control glucose and lipid metabolism by mediating, at least in part, a cellular ceramidase activity that catalyses the hydrolysis of ceramide to produce sphingosine and a free fatty acid (FFA). The crystal structures of the two receptor subtypes, ADIPOR1 and ADIPOR2, show a similar overall seven-transmembrane-domain architecture with large unoccupied cavities and a zinc binding site within the seven transmembrane domain. However, the molecular… Show more
“…These in vitro and
in vivo studies revealed that both AdipoR1 and AdipoR2
exhibit ceramidase activity that is enhanced by adiponectin and reduces
cellular ceramide concentration (184, 185). Consistent with
these data, crystal structures of both AdipoR1 and AdipoR2 suggest they
possess intrinsic ceramidase activity (487). …”
Section: Adiposity and Insulin Resistancementioning
The objective of this comprehensive review is to summarize and discuss
the available evidence of how adipose tissue inflammation affects insulin
sensitivity and glucose tolerance. Low-grade, chronic adipose tissue
inflammation is characterized by infiltration of macrophages and other immune
cell populations into adipose tissue, and a shift towards more pro-inflammatory
subtypes of leukocytes. The infiltration of pro-inflammatory cells in adipose
tissue is associated with an increased production of key chemokines such as C-C
motif chemokine ligand 2, pro-inflammatory cytokines including tumor necrosis
factor α and interleukins 1β and 6, as well as reduced expression
of the key insulin sensitizing adipokine, adiponectin. In both rodent models and
humans, adipose tissue inflammation is consistently associated with excess fat
mass and insulin resistance. In humans, associations with insulin resistance are
stronger and more consistent for inflammation in visceral as opposed to
subcutaneous fat. Further, genetic alterations in mouse models of obesity that
reduce adipose tissue inflammation are – almost without exception -
associated with improved insulin sensitivity. However, a dissociation between
adipose tissue inflammation and insulin resistance can be observed in very few
rodent models of obesity as well as in humans following bariatric surgery- or
low-calorie diet-induced weight loss, illustrating that the etiology of insulin
resistance is multifactorial. Taken together, adipose tissue inflammation is a
key factor in the development of insulin resistance and type 2 diabetes in
obesity, along with other factors that likely include inflammation and fat
accumulation in other metabolically active tissues.
“…These in vitro and
in vivo studies revealed that both AdipoR1 and AdipoR2
exhibit ceramidase activity that is enhanced by adiponectin and reduces
cellular ceramide concentration (184, 185). Consistent with
these data, crystal structures of both AdipoR1 and AdipoR2 suggest they
possess intrinsic ceramidase activity (487). …”
Section: Adiposity and Insulin Resistancementioning
The objective of this comprehensive review is to summarize and discuss
the available evidence of how adipose tissue inflammation affects insulin
sensitivity and glucose tolerance. Low-grade, chronic adipose tissue
inflammation is characterized by infiltration of macrophages and other immune
cell populations into adipose tissue, and a shift towards more pro-inflammatory
subtypes of leukocytes. The infiltration of pro-inflammatory cells in adipose
tissue is associated with an increased production of key chemokines such as C-C
motif chemokine ligand 2, pro-inflammatory cytokines including tumor necrosis
factor α and interleukins 1β and 6, as well as reduced expression
of the key insulin sensitizing adipokine, adiponectin. In both rodent models and
humans, adipose tissue inflammation is consistently associated with excess fat
mass and insulin resistance. In humans, associations with insulin resistance are
stronger and more consistent for inflammation in visceral as opposed to
subcutaneous fat. Further, genetic alterations in mouse models of obesity that
reduce adipose tissue inflammation are – almost without exception -
associated with improved insulin sensitivity. However, a dissociation between
adipose tissue inflammation and insulin resistance can be observed in very few
rodent models of obesity as well as in humans following bariatric surgery- or
low-calorie diet-induced weight loss, illustrating that the etiology of insulin
resistance is multifactorial. Taken together, adipose tissue inflammation is a
key factor in the development of insulin resistance and type 2 diabetes in
obesity, along with other factors that likely include inflammation and fat
accumulation in other metabolically active tissues.
“…These effects of the receptors are strictly dependent on the presence of APN [7]. Furthermore, recent structural insights into the APN receptors point directly at a receptor-inherent ceramidase activity and further highlights the sphingolipid axis as a major primary mediator of APN effects [28, 29]. …”
Acute systemic removal of APN results in a much more negative metabolic phenotype compared with congenital knockout of Adipoq. Specifically, our data demonstrate that acute depletion of APN is especially detrimental to lipid homeostasis, both under basal and insulinopenic conditions. This suggests that compensatory mechanisms exist in congenital knockout mice that offset some of the metabolic actions covered by APN.
“…The effects of adiponectin appear to be dependent on receptor-mediated increases in ceramidase activity, resulting in decreased intracellular ceramide concentrations [29]. A very recent study [68] showed that adiponectin receptors themselves possess ceramidase activity.…”
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