MECHANISMS IN ENDOCRINOLOGY: Ghrelin: the differences between acyl- and des-acyl ghrelin

Abstract

Des-acyl ghrelin (DAG) is one of the three preproghrelin gene-encoded peptides. Compared with ghrelin and obestatin, it has not received the attention it deserves. DAG has long been considered an inert degradation product of acyl ghrelin (AG). Recent evidence, however, indicates that DAG behaves like a separate hormone. DAG can act together with AG, can antagonize AG, and seems to have AG-independent effects. Therefore, it is believed that DAG must activate its own receptor and that it may also interact with AG at this receptor. Of potential clinical importance is that an increasing number of studies suggest that DAG might be a functional inhibitor of ghrelin and that DAG can suppress ghrelin levels in humans. Therefore, DAG or DAG analogs might be good candidates for future treatment of metabolic disorders or other conditions in which antagonism of AG actions could be beneficial, such as diabetes, obesity, and Prader-Willi syndrome.

Ghrelin and Insulin Secretion in Humans: Not a Tale of Two Hormones?

“…The Ser3-octanoylated ghrelin form (acylated ghrelin [AG]) also was soon recognized to act as a hypothalamic orexigenic signal (2) and to modulate tissue pathways and functions as a potential contributor to metabolic adaptation to low nutrient availability. Experimental AG administration commonly causes weight gain and hyperglycemia by enhancing food intake, fat deposition, and hepatic gluconeogenesis (3)(4)(5). A more comprehensive understanding of the metabolic impact of ghrelin has been recently allowed by the increasing appreciation of the independent, and generally more favorable, effects of its unacylated form (UAG), which does not increase food intake or circulating glucose in vivo (3,4,6).…”

“…Experimental AG administration commonly causes weight gain and hyperglycemia by enhancing food intake, fat deposition, and hepatic gluconeogenesis (3)(4)(5). A more comprehensive understanding of the metabolic impact of ghrelin has been recently allowed by the increasing appreciation of the independent, and generally more favorable, effects of its unacylated form (UAG), which does not increase food intake or circulating glucose in vivo (3,4,6). Although no specific UAG receptor has been yet identified, UAG coadministration may counteract the glucogenic effects of AG as well as AG-induced hyperglycemia (3,4,7), and positive or negative associations have been respectively reported in humans between AG or UAG and markers of whole-body insulin resistance (8).…”

“…A more comprehensive understanding of the metabolic impact of ghrelin has been recently allowed by the increasing appreciation of the independent, and generally more favorable, effects of its unacylated form (UAG), which does not increase food intake or circulating glucose in vivo (3,4,6). Although no specific UAG receptor has been yet identified, UAG coadministration may counteract the glucogenic effects of AG as well as AG-induced hyperglycemia (3,4,7), and positive or negative associations have been respectively reported in humans between AG or UAG and markers of whole-body insulin resistance (8). Modulating the AG-UAG balance by inhibiting the acylating enzyme ghrelin O-acyltransferase (9) or by exogenous hormone administration has therefore become an attractive therapeutic target to limit positive energy balance and altered glucose metabolism in obese and insulinresistant states.…”

“…In terms of physiologic relevance, it also will be important to assess the impact of ghrelin forms on insulin secretion following oral glucose ingestion, when incretins contribute to modulate gut signaling to the pancreas. Moreover, AG-UAG interactions should be systematically investigated in clinical conditions characterized by insulin resistance, when a decline in circulating UAG and higher AG-UAG ratios have been reported (3,4,8). Under these conditions, potential differential modulation by AG and UAG of additional regulators of insulin secretion should be also considered, including autonomic nervous signaling (13), circulating hormones such as growth hormone and cortisol (1,6,19), and dietary carbohydrate intake as shown by Tong et al (19).…”

Ghrelin: a new treatment for non-alcoholic fatty liver disease?

“…Both ghrelin and des-acyl ghrelin (DAG) appear to have many functions and effects that are much wider than the direct control over food intake [6].…”