Abstract
Despite being unable to activate the cognate ghrelin receptor (GHS-R), unacylated ghrelin (UAG) possesses a unique activity spectrum that includes promoting bone marrow adipogenesis. Since a receptor mediating this action has not been identified, we re-appraised the potential interaction of UAG with GHS-R in the regulation of bone marrow adiposity. Surprisingly, the adipogenic effects of intra-bone marrow (ibm)-infused acylated ghrelin (AG) and UAG were abolished in male GHS-R-null mice. Gas chromatography showed that isolated tibial marrow adipocytes contain the medium-chain fatty acids utilised in the acylation of UAG, including octanoic acid. Additionally, immunohistochemistry and immunogold electron microscopy revealed that tibial marrow adipocytes show prominent expression of the UAG-activating enzyme ghrelin O-acyl transferase (GOAT), which is located in the membranes of lipid trafficking vesicles and in the plasma membrane. Finally, the adipogenic effect of ibm-infused UAG was completely abolished in GOAT-KO mice. Thus, the adipogenic action of exogenous UAG in tibial marrow is dependent upon acylation by GOAT and activation of GHS-R. This suggests that UAG is subject to target cell-mediated activation – a novel mechanism for manipulating hormone activity.
Highlights
Since its discovery[1], the gastric hormone ghrelin has become established as a key player in the team of hormones co-ordinating central and peripheral processes with nutritional status[2,3,4]
This approach revealed that infusion of acylated ghrelin (AG) or unacylated ghrelin (UAG) had no significant effect on circulating ghrelin in either WT or GHS-R-null mice (Fig. 1A)
We have re-examined this phenomenon and the data we present here support the surprising hypothesis that the adipogenic action of UAG is dependent upon both GHS-R, the receptor to which it does not usually bind[8,11], and the acylating activity of ghrelin O-acyl transferase (GOAT)
Summary
Since its discovery[1], the gastric hormone ghrelin has become established as a key player in the team of hormones co-ordinating central and peripheral processes with nutritional status[2,3,4]. Ghrelin is structurally unique, requiring post-translational acylation of the third (serine) residue to enable it to bind to and activate its cognate receptor, the growth hormone secretagogue receptor, GHS-R1a1,8. This modification is accomplished by the action of ghrelin O-acyl transferase (GOAT), a member of the membrane-bound O-acyl transferase (MBOAT) family of enzymes[9,10]. Behaviour[14,16] or increase intra-abdominal fat mass[18] This evidence has led several groups to speculate that UAG may exert this unique profile of actions via a novel receptor[15,19,20], but no candidate receptors have emerged[21]. Our results suggest a novel endocrine mechanism of target cell-mediated transacylation
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