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COMMENTARY |
Division of Nutrition and Metabolic Diseases, Department of Internal Medicine and the Center for Human Nutrition, The University of Texas Southwestern Medical Center at Dallas and Veterans Affairs North Texas Health Care System, Dallas, Texas 75390-9052
Address all correspondence and requests for reprints to: Abhimanyu Garg, M.D., The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9052. E-mail: Abhimanyu.garg{at}utsouthwestern.edu.
Posttranslational processing of preproghrelin encoded by the ghrelin (GHRL) gene is predicted to yield two peptides, ghrelin and obestatin, which have been proposed to have opposite actions on feeding behavior (1, 2). Although ghrelin increases food intake (1), obestatin has been shown to suppress it (2). This commentary focuses on the recent controversy about the role of obestatin as a hormone.
The GHRL gene is predominantly expressed in the stomach in X/A-like cells (specialized oxyntic gland cells) but also at low levels in the duodenum, and the rest of the bowel, pancreas, pituitary, hypothalamus, kidney, and placenta (1, 3). The GHRL gene encodes a polypeptide containing 117 residues, called preproghrelin, which undergoes stepwise processing, including proteolysis and acylation, to form ghrelin (Fig. 1
) (1, 4, 5).
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). Purification of the immunoreactive obestatin from the rat stomach extract revealed the sequence to be consistent with the obestatin sequence deduced from rat preproghrelin cDNA. The investigators reported that synthetic obestatin, when injected ip (12.5–1000 nmol/kg) or intracerebroventricularly (8 nmol/kg), acutely suppressed food intake over 5 h in adult male mice in a dose-dependent fashion. Obestatin reduced gastric emptying and inhibited jejunal contractions acutely. In adult male rats, obestatin suppressed body weight gain over a 7-d period. The hormone was reported to bind to G protein-coupled receptor-39 (GPR39) (2). As often happens in highly competitive areas of science, many original findings have been challenged. First, three groups were unable to confirm the binding of obestatin to GPR39 (6, 7, 8). Second, the original investigators themselves could not reproduce the binding of obestatin to tissue homogenates or recombinant GPR39 (9). Thus, the receptor involved in action of obestatin remains unknown. Third, obestatin lacks specific binding at the blood-brain barrier and undergoes rapid degradation (10).
Furthermore, many other laboratories failed to observe any significant effects of obestatin on food intake in animal models. In doses ranging from 12–1000 nmol/kg body weight ip or approximately 1.2–12 nmol/kg intracerebroventricularly, obestatin did not reduce food intake in adult mice or rats over 1–24 h or over 7–9 d (6, 11, 12, 13, 14, 15, 16, 17). In defense of their original findings, Zhang et al. (9) reported that obestatin, 750 nmol/kg ip, reduced food intake in mice when animals had access to food at precisely 15 min after injection. Recently, Lagaud et al. (18) also observed a mild, but significant reduction in food intake with 10–300 nmol/kg obestatin given ip to mice and rats; however, higher doses were ineffective. These authors also reported reduction in food intake and weight gain over a 7-d period with three times daily obestatin injections in mice (18). Nonetheless, in the hands of most of the investigators, obestatin has shown no effects on body weight.
Obestatin does not affect secretion of any pituitary hormone or corticosterone in rat (17, 19); other investigators (20) have found little or no effects of obestatin on gastric or jejunal motility. Whether obestatin reduces thirst (16), promotes sleep (21), or affects memory and anxiety (22) remains to be confirmed.
Serum obestatin levels did not change upon fasting or feeding in rats (2); but in mice, a slight reduction was seen upon fasting (14). In humans also no postprandial changes in serum obestatin levels have been noted (23). For a hormone proposed to affect food intake acutely, this lack of change in circulating concentrations postprandially is surprising.
The intriguing feature of the preproghrelin protein is its proteolytic cleavage, such that during one processing step ghrelin is released, and with another, obestatin is released. Studies of animals lacking various prohormone convertases (PCs) suggest that PC1 is involved in processing of proghrelin to ghrelin as well as obestatin, although direct processing of proghrelin to obestatin was not evaluated (4). A recent study suggests that PC7 and furin may also be involved in ghrelin processing (5). These proteases recognize di-basic residues K-R or R-R and cleave the peptide bond carboxy terminal to the dibasic pair (24). They may also recognize monobasic residue cleavage sites, but the rules of engagement may be different or inefficient. Although the release of ghrelin after the initial removal of signal peptide involves a single cleavage, the release of obestatin requires cleavage at both the amino- and carboxy-terminus. The efficiency with which these two cleavages might occur is not clear because the proposed cleavage sites lack the more efficient dibasic residues. Interestingly, in vitro digestion of proghrelin using several convertases failed to yield obestatin (5). Thus, whether production of obestatin requires other proteases, which work in a different microenvironment, remains unclear. If PCs are involved, do they assume a relaxed specificity to become more active for these monobasic cleavage sites? Furthermore, the fact that monkeys and baboons have glutamine instead of arginine at position 75 suggests that these species do not produce obestatin. Skipping of these primates from evolutionary conservation argues against any vital role of obestatin. Certainly, the hard evidence for production of obestatin from proghrelin in vivo is still lacking. The relative efficiencies for processing of proghrelin into ghrelin, or obestatin in the stomach or other tissues under a variety of conditions are also still not clear.
With such controversy related to the effect of obestatin and the lack of mechanistic insight about its formation and action, what can be learned by measuring serum levels of obestatin in humans? First, it is not clear what is being measured in plasma, whether it is obestatin, preproghrelin, proghrelin, or some intermediary carboxy-terminal peptide derived during ghrelin production containing the epitope against which the antiserum was raised. Purification of the immunoreactive obestatin from serum and its sequencing has not been reported. A few investigators have measured serum obestatin in humans under different conditions. For example, similar or slightly higher serum obestatin levels have been reported in patients with Prader-Willi syndrome compared with matched obese controls (23, 25). Guo et al. (26) observed lower levels of serum obestatin and ghrelin but an increased ghrelin-to-obestatin ratio in obese subjects. Haider et al. (27) reported increases in both serum total ghrelin and obestatin after weight loss following bariatric surgery in severely obese patients. The obese subjects had much lower serum obestatin levels (mean ± SD; 131 ± 52 pg/ml) compared with the controls (649 ± 154 pg/ml) (27). However, using the same RIA kit, Qi et al. (28) reported much lower mean levels in healthy subjects (44 pg/ml). This suggests a lack of standardization of the assay.
Hormones are classically defined as chemical mediators that are released in the circulation to incite action away from their site of origin. Furthermore, the synthesis of hormones is regulated by feedback mechanisms, and they act on cells through their specific receptors. In recent years, this definition has become blurred. Hormones are now known to be secreted by tissues other than classical endocrine organs, such as the central nervous system, gastrointestinal tract, and adipose tissue. Hormones have been shown to cause paracrine and local effects as well. Even considering this broader definition of a hormone, controversies about obestatin and its action indicate that the weight of evidence does not support its designation as a hormone until more conclusive data emerge.
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Acknowledgments |
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Footnotes |
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Disclosure Summary: The author has nothing to declare.
Abbreviations: GHRL, Ghrelin (gene); GPR39, G protein-coupled receptor-39; PC, prohormone convertase.
Received May 3, 2007.
Accepted June 19, 2007.
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-amidating monooxygenase (PAM). Furthermore, the relative formation of ghrelin and obestatin in the stomach under various feeding conditions and in other tissues expressing the GHRL gene remains to be studied. Numbers above the bars represent the position of amino acids in preproghrelin.