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COMMENTARY

Ghrelin and growth : Story in reverse

Ralf M. Nass, Bruce D. Gaylinn, Alan D. Rogol, and Michael O. Thorner1 Department of Medicine, University of Virginia, Charlottesville, VA 22908

he current epidemic of + striction (40% of normal levels). They and in the face of show that is important for the a surfeit of calories contrasts maintenance of the blood– levels T - Pituitary + Ghrelin the natural selection to survive needed for survival during prolonged nu- famine that confronted our ancestors. IGF-I trient restriction. The depletion of fat re- The report in PNAS by Zhao et al. (1) GH serves after more than 3 days of nutri- Luminal MCFA shows that ghrelin is an important hor- + Preproghrelin tional restriction with feeding one time + GOAT mone in this process. By studying mice + per 24 h results in debilitating hypoglyce- Increased glucose mia at the end of the day in the GOAT under severe caloric restriction, they production show that knockout (KO) of the enzyme + KO mice but not wild-type mice. Thus ghrelin O-acyltransferase (GOAT), nec- a clear metabolic phenotype has been Reduced glucose demonstrated in the GOAT KO mouse. essary to convert ghrelin to its active Nutrient FAT uptake absorption - Thus, ghrelin is critical in the counter- form, manifests the first clear phenotype from gut seen in KO of ghrelin activity; ghrelin is regulatory ensemble of factors that maintains blood glucose (Fig. 1). This necessary for triggering the growth- + - - hormone (GH) response to nutritional repertoire includes catecholamines, glu- Supply Disposal deprivation that prevents cagon, , and GH. Earlier studies suggested that ghrelin might in- and death. MUSCLE crease resistance and impair insulin The road to ghrelin’s discovery started secretion (10). Zhao et al. (1) define with the observation that morphine GLUCOSE a physiological role for ghrelin; it orches- stimulates GH secretion, isolation of the BALANCE trates the enhanced GH secretion induced enkephalins, and development of enkeph- Fig. 1. Regulation of glucose balance by GH and by prolonged nutritional restriction. It alin analogs that selectively stimulate se- ghrelin. Glucose supply is controlled by absorption must be emphasized that these mice were cretion of GH [GH-secretagogues from the gut as well as hepatic glucose production and glucose disposal rate. Circulating ghrelin levels are calorie restricted but not fasted. This is (GHSs)] and orally active GHS. One such important, because the lipid group that is GHS, MK-0677, was used to expression regulated through acylation of preproghrelin by GOAT and depend on the presence of luminal medium-chain attached to preproghrelin by GOAT is clone the GHS (GHS-R) (2). fatty acids (MCFA). Ghrelin increases GH release. GH likely derived from free fatty acids (FFA) Using cell lines expressing this receptor, release from the pituitary is inhibited by IGF-I negative in the lumen of the gut rather than Kojima et al. (3) isolated and character- feedback. Ghrelin increases hepatic glucose production circulation (11). Indeed, with prolonged ized its endogenous ligand (ghrelin) from and decreases glucose uptakeinskeletalmuscleandfat (>37.5 h) in humans, ghrelin rat stomach extracts. They discovered cells. GH increases hepatic glucose production by in- levels are suppressed, whereas desacyl- that the third of ghrelin had an hibiting insulin action. GH decreases glucose disposal ghrelin is tonically secreted (12). If the to and possibly, fat tissue indirectly unexpectedly large mass; it was a serine FFA required for activation of ghrelin fi through and increase in FFA. During conditions residue modi ed by the attachment of of prolonged nutritional restriction when fat depots must come from the gut, then ghrelin will octanoate, a medium-chain . and hepatic glycogen content are depleted, GH levels be suppressed in wild-type mice during Removing the octanoate blocked ghrelin’s are elevated by decreased IGF-I and long-term fasting; this contrasts the in- ability to bind to or activate its receptor. increased ghrelin. Low portal insulin levels reduce he- creased levels described by Zhao et al. This acylation of a with a medium- patic GH receptor expression and reduce IGF-I secretion (1) during nutritional restriction. chain fatty acid is unique to ghrelin. despite high GH levels. In addition, the low insulin levels The evidence presented suggests that Although ghrelin was named for its lead to high ghrelin secretion, because insulin normally GH is pivotal in preserving normal GH-releasing activity, its pleiotropic inhibits ghrelin release. blood–glucose levels. This is supported effects, including increased appetite, al- by the lower levels of GH observed in tered gastrointestinal motility, and regu- , and Prader–Willi the GOAT KO mice and the rescue of lated lipid and glucose metabolism, syndrome (6, 7). blood glucose by infusion of GH or ghre- cardiac function, blood pressure, Recently, two groups independently lin. This emphasizes the physiological immune function, cell proliferation, , identified GOAT, which had been importance of direct effects of GH in anxiety, and even memory, soon became previously known as an orphan member the severely nutritionally restricted state, apparent (4). However, KO of ghrelin or of a family of membrane-bound O- a time when the levels of insulin-like GHS-R or the combined KO of both acyltransferase enzymes (MBOATs) growth factor I (IGF-I) are low. GH levels receptor and ligand had no distinctive (8, 9). GOAT is expressed in the ghrelin- are raised in starved infants (at a time when glucose may be low) with profoundly phenotype (5). The reason that no phe- producing cells of the stomach and small low IGF-I levels, and this reverses with notype was observed with these KO ani- intestine. GOAT is required for the at- mals is likely because previous studies tachment of octanoate to preproghrelin did not employ the prolonged (10 days) and has no other known activity (8, 9). Author contributions: R.M.N., B.D.G., A.D.R., and M.O.T. severe nutritional restriction (40% of The report by Zhao et al. (1) combines wrote the paper. normal levels) that is used in the study molecular biological approaches with an The authors declare no conflict of interest. of Zhao et al. (1). Ghrelin’s potent integrative biological experimental para- See companion article on page 7467 in issue 16 of volume orexigenic properties led a number of digm. They study a GOAT KO mouse 107. groups to suggest that ghrelin may be that, therefore, lacks acyl-ghrelin and 1To whom correspondence should be addressed. E-mail: important in the pathogenesis of obesity, expose it to prolonged nutritional re- [email protected].

www.pnas.org/cgi/doi/10.1073/pnas.1002941107 PNAS | May 11, 2010 | vol. 107 | no. 19 | 8501–8502 Downloaded by guest on September 25, 2021 refeeding. Thus, they are at least partially mouse, thereby protecting the mouse under fed conditions (17) and with the GH-resistant (13). from neuroglycopenia. Rabinowitz et al. administration of GHS-R antagonists (18). Under conditions of nutritional re- (15) showed in humans that GH increases Ghrelin has direct, GH-independent striction, GH levels are high, leading to lipolysis and release of FFA from fat cells, effects on glucose metabolism, such as mobilization of fat to provide the required and it inhibits glucose uptake in both increasing hepatic glucose production and calories. However, after prolonged nutri- muscle and fat; they posited that this decreasing the glucose disposal rate (10, tional restriction, as in this study, the fat process prevents neuroglycopenia in times 19). Zhou et al. (1) do not specifically depots are depleted, and this is shown by of famine. This is what Zhou et al. (1) address the question as to what extent both body-composition analysis and re- show, and additionally, they note that ghrelin and GH independently modulate duced levels of circulating FFA. In addi- this is a ghrelin-dependent process. An- glucose levels during caloric restriction. tion, the hepatic glycogen content is other critical step in this cascade is GH continues to exert its effects under depleted in both wild-type and KO mice portal insulin concentration regulation conditions of significant loss of body fat at the end of the study. Thus, the mecha- of the expression of GH-R to determine mass and low circulating FFA levels. Al- nism by which GH maintains blood glu- the GH sensitivity of the liver and its though the traditional concept in which cose must be caused by reducing the ability to produce IGF-I; IGF-I feeds GH acts on glucose metabolism and in- energy expenditure or glucose uptake in back to inhibit GH secretion. creases favors a role the peripheral tissues or increased gluco- for FFA (20), the data presented in this neogenesis (Fig. 1). paper strongly support direct effects of GH is considered to exert diabetogenic Ghrelin is critical in the GH on glucose , independent effects by increasing insulin resistance in counterregulatory of insulin, IGF-I, or FFA. peripheral tissues. Keller and Zapf (14) GH plays a fundamental role in main- showed that, in the absence of GH, glu- ensemble of factors that taining metabolic homeostasis and body cose transport in fat cells is maximal and composition. The critical role of ghrelin cannot be further increased by insulin. maintains blood glucose. However, when GH is present, glucose in regulating these processes is highlighted transport is inhibited, and insulin is able to in the study of Zhao et al. (1). The reverse this inhibition. The traditional In the presence of low portal insulin, as in has an obligatory requirement to concept that GH antagonizes insulin ac- calorie-restricted states, liver GH recep- metabolize glucose to meet its energy ’ tion may need to be reversed and tors are reduced, thus reducing IGF-I requirements. The body s response to substituted by insulin antagonizing the levels. Subsequent long-loop IGF-1 feed- hypoglycemia is to mount a stress re- GH-mediated tonic inhibition of glucose back to the pituitary is diminished result- sponse, including the release of cortico- transport. This framework fits with the ing in elevated GH secretion (16). tropin releasing hormone and GH experimental data that show that GH se- This model of GH tonically sup- releasing hormone from the hypothalamus cretion is enhanced in the GOAT KO pressing glucose transport into fat cells to stimulate corticotropin and GH that mouse in the nutritionally restricted state also explains why GH-deficient animals act to raise blood glucose. This study but not to the level attained in the wild- and humans are obese yet sensitive to in- (1) suggests that the ghrelin-producing type mouse under the same conditions. sulin. GH is the partitioning hormone that cell senses glucose to regulate ghrelin If glucose transport is inhibited in a dose- directs the use and storage of nutrients, release. Ghrelin is essential for main- dependent manner, the tonic inhibition of and ghrelin plays a role in its regulation. A taining the level of GH required in pre- glucose transport in fat, and possibly similar association between GH and vention of neuroglycopenia and thus, muscle, would be greater in the wild-type ghrelin has been shown in clinical studies preservation of life.

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