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Endocrinology Vol. 147, No. 6 2631-2633
Copyright © 2006 by The Endocrine Society

Diabetic Hyperphagia—Ghrelin in the Driver’s Seat

Richard W. Gelling

Department of Animal Physiology Metabolex, Inc. Hayward, California 94545

Address all correspondence and requests for reprints to: Richard W Gelling, Ph.D., Scientist II, Metabolex, Inc., 3876 Bay Center Place, Hayward, California 94545. E-mail: rgelling{at}metabolex.com.


   Introduction
Top
 Introduction
Is Ghrelin the Orexigenic...
 References
 
Uncontrolled, streptozotocin-induced diabetes mellitus (STZ-DM) is a highly reproducible rodent model of diabetes mellitus that is characterized by hyperglycemia, weight loss, and markedly increased food intake (1). The adaptive increase in food intake induced by depletion of energy stores in these animals involves the coordinated regulation of multiple pathways within the hypothalamic arcuate nucleus (ARC), an area of the brain that acts as an integration center for peripheral signals of energy status (2). Under basal conditions, insulin and leptin are thought to inhibit ARC neurons that coexpress neuropeptide Y (NPY) and agouti gene-related protein (AgRP), peptides that potentially stimulate food intake. Conversely, basal insulin and leptin levels also activate an adjacent ARC neuronal population that expresses preproopiomelanocortin (POMC), which is processed and released as {alpha}-MSH, reducing food intake and increasing energy expenditure (Fig. 1AGo) (2). Therefore, the dramatic decrease in circulating levels of both insulin and leptin after STZ treatment has been proposed to underlie the observed increases of ARC NPY/AgRP and decreases of POMC mRNA expression and protein levels in rodents with STZ-DM (Fig. 1BGo), changes that are thought to reflect neuronal activity that drives the hyperphagic behavior (3, 4, 5). However, an important question concerning this model is whether loss of these inhibitory signals alone can account for the observed alterations in neuropeptide levels and the resulting hyperphagia, or whether an additional active orexigenic signal is also required (6). Support for such a model exists at the neuronal level, as mice lacking NPY (NPY–/–) do not develop diabetic hyperphagia when treated with STZ (7).


Figure 1
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  		FIG. 1. Ghrelin regulation of hypothalamic ARC and the neuropeptide responses observed under basal conditions (A), diabetic hyperphagia (B), diabetes and ghrelin deficiency (C), and diabetes in the presence of a ghrelin receptor antagonist (D). NPY/AgRP and POMC neurons relay signals from the periphery to second-order neurons within other hypothalamic areas that regulate feeding behavior and energy expenditure.

 
The acylated 28-amino-acid enteric peptide, ghrelin, was originally identified as the endogenous ligand for the orphaned GH secretagogue receptor (GHSR) (8, 9). It was subsequently demonstrated to be an orexigenic hormone that potently increases food intake, body weight, and adiposity (10, 11) via its activation of ARC NPY/AgRP neurons (12, 13, 14). A number of observations have led us and others to hypothesize that increased ghrelin signaling may also contribute to the neuronal responses that underlie the diabetic hyperphagia. First, ghrelin activates ARC NPY/AgRP neurons (12, 13, 14); second, similar to diabetic hyperphagia, ghrelin-induced feeding is attenuated in NPY knockout mice (15); third, the recent observation that ghrelin levels are increased in rodents with STZ-DM (16); and, finally, our observation that this increase occurs before the onset of the overeating (6). These observations are consistent with ghrelin contributing to diabetic hyperphagia. However, conclusive studies to determine whether ghrelin plays a causative role in the pathogenesis of diabetic hyperphagia have had to wait for the availability of an efficacious GHSR antagonist and/or ghrelin knockout mice.

In this issue, Dong et al. (17) describe the results of such experiments. The authors examined the effect of genetic deletion of ghrelin or blocking ghrelin signaling with a GHSR antagonist in wild-type mice to determine whether ghrelin action plays a causative role in the increased food intake associated with uncontrolled insulin-deficient diabetes. Both these experimental approaches provide evidence that ghrelin signaling contributes to the central neuronal responses that underlie diabetic hyperphagia. In addition, the data highlight the highly adaptive and protective nature of the pathways that regulate energy homeostasis. Moreover, the study illustrates how, at least for ghrelin, there may be many challenges ahead in the development of therapies based on these pathways.


   Is Ghrelin the Orexigenic Signal in Diabetic Hyperphagia?
Top
 Introduction
 Is Ghrelin the Orexigenic...
References
 
Is ghrelin required for mice to exhibit diabetic hyperphagia? In the case of ghrelin–/– mice, the answer appears to be a qualified yes. Dong et al. (17) report that STZ-treated ghrelin–/– mice exhibit both a delayed and reduced maximal increase in food intake compared with diabetic controls. The time course of the developing hyperphagia was interesting in that ghrelin–/– mice displayed a greater initial suppression of food intake, which then gradually increased until diabetic ghrelin–/– mice become as hyperphagic as diabetic control mice. This suggests that increased ghrelin signaling is required for the more rapid recovery of food intake and onset of hyperphagia seen in diabetic control animals. Our observation that peak increases in ghrelin levels in rats with STZ-DM are seen 1 d after the induction of diabetes and are gradually suppressed by the developing hyperphagia is consistent with such a role (6). In addition, ghrelin appears to play a role in sustaining the hyperphagia associated with STZ-DM, as daily administration of GHSR antagonist to wild-type diabetic mice with established hyperphagia reduced food intake significantly (by ~24%) and was still effective 10 d after diabetes was induced (17).

What mechanism can explain this late-onset hyperphagia? One possible explanation is that the increased weight loss seen in diabetic ghrelin–/– mice compared with diabetic controls may have initiated other compensatory mechanism(s) in attempt to maintain body weight. This appears plausible, as the authors point out, because diabetes dramatically lowered {alpha}-MSH levels in ghrelin–/– mice from those seen in nondiabetic ghrelin–/– mice (Fig. 1CGo). Furthermore, although ARC NPY protein levels of diabetic ghrelin–/– mice were reduced compared with diabetic controls, there was an approximate 2-fold increase in NPY-staining cell bodies compared with that of nondiabetic ghrelin–/– and control animals (although not statistically significant). These changes were observed when the animals were hyperphagic; they are consistent with induction of such an overlapping anabolic pathway (18, 19) and may reflect the greater importance of dynamic regulation of {alpha}-MSH in the presence of a tonic baseline signal by NPY in diabetic ghrelin–/– mice. That diabetes does not cause hyperphagia or decrease POMC mRNA levels in NPY–/– mice (7) supports such a role for {alpha}-MSH signaling in the absence of NPY. Alternatively, a yet-unidentified factor or pathway involved in the regulation of food intake may be responsible for the late-onset of hyperphagia (Fig. 1CGo). Further studies to determine the time course of the changes in neuronal activation (including regulation of AgRP) in diabetic ghrelin–/– mice are required to fully understand the progression and mechanism(s) responsible for the hyperphagia.

The different responses of ghrelin–/– and NPY–/– mice to STZ-DM imply that the compensatory mechanisms that allow these animals to exhibit apparently normal regulation of energy balance are not the same. The fact that NPY–/– mice do not develop hyperphagia yet do not lose any more weight than diabetic controls would appear to indicate these mice are better able to compensate for the reduced food intake in the face of energy depletion. Indeed, the ability to compensate for compromised NPY/AgRP neuron function is impressive. For example, when NPY expression is knocked down in adult mice, the animals appear to be able to compensate for the loss of NPY (~80%) within the 14 d it takes the peptide levels to decrease significantly (20). Furthermore, studies that used a genetic strategy that allowed the targeted ablation of ARC NPY/AgRP-expressing neurons in adult animals resulted in animals that exhibited reduced food intake (or even starvation) and body weight (21, 22), whereas a similar degree of ablation of NPY-expressing neurons in newborn pups did not affect food intake and only decreased the body weight by ~10% (22). This indicates that compensation for loss of NPY/AgRP, GABA, and possibly other unknown signaling molecules can be compensated early in life, but not in the adult animal. In contrast to diabetic NPY–/– mice, diabetic ghrelin–/– mice eat less initially and lose more weight than diabetic controls (17), suggesting that compensation for the loss of ghrelin is not as effective as that for loss of NPY. A possible explanation is whereas NPY–/– mice completely lack NPY, ghrelin–/– mice still express the peptide at levels that should provide some basal orexigenic signal. It is tempting to hypothesize that the developmental changes that occur to compensate for the complete loss of NPY would be greater than for a situation in which there is some residual NPY signaling. The above-mentioned temporal knockout mouse models will be useful in testing this hypothesis.

Although blocking ghrelin signaling in wild-type mice with established diabetic hyperphagia required 4 d of treatment with a GHSR antagonist to significantly reduce 24-h food intake, a single dose of the antagonist was able to suppress early light-cycle food intake (a time when rodents do not normally eat) to levels near that seen in nondiabetic controls. Dong et al. (17) propose that this reflects the ability of elevated ghrelin to initiate a meal at an inappropriate time. It may also indicate an increase in the sensitivity of ARC neurons to ghrelin and its feeding effects in the absence of the inhibitory signals from insulin and leptin (6). Antagonism of the ghrelin signaling in the diabetic state results in a normalization of ARC NPY neuron activation and prevents the suppression of {alpha}-MSH neurons (Fig. 1DGo) (17). The latter observation and the fact that nondiabetic ghrelin–/– mice displayed a significant increase in basal staining of ARC {alpha}-MSH neurons is consistent with, and may indicate the importance of, ghrelin’s regulation of POMC neurons, which is thought to be mediated via inhibitory inputs from NPY/AgRP neurons that release NPY and/or GABA within the ARC directly (Fig. 1BGo) (23). One interesting yet worrisome effect of GHSR antagonist treatment of nondiabetic control animals was that it resulted in increases in both ghrelin plasma levels and immunoreactivity within the stomach, which the authors hypothesize may occur if ghrelin normally inhibits it own release via interactions with the GHSR on gastric ghrelin cells (24). If this proves true, then therapeutic approaches that neutralize ghrelin and/or antagonize the receptor may be ineffective simply because they increase circulating ghrelin to levels that can compete with the blockade.

The main implications of the studies presented by Dong et al. (17), are as follows: 1) elevation in ghrelin and its action at the level of the ARC are required for the "normal" pathogenic alterations in ARC neuropeptides and food intake; 2) even in the absence of ghrelin, mice still develop hyperphagia, likely through increased activation or recruitment of additional compensatory anabolic pathways; 3) and, finally, the dynamic ability of the ghrelin/NPY axis to compensate for loss of ghrelin signaling (25, 26, 27) is a substantial technical hurdle for therapeutic strategies that target the ghrelin signaling pathway. More generally, the observations here add to the growing body of evidence that indicates that ghrelin does play a physiological role in the regulation of energy homeostasis. This includes the two recent studies that demonstrate young (4–6 wk of age) mice lacking ghrelin (28) or the GHSR (29) do not develop obesity when fed a high-fat diet, data that suggest that compensatory pathways activated in adult ghrelin–/– and GHSR–/– mice (who do develop obesity when fed a high-fat diet) have not completely developed or have not been initiated in the younger animal (28, 29, 30). A more clinically relevant example is the identification of two separate, naturally occurring mutations of the ghrelin receptor gene that result in a syndrome characterized by both short stature and obesity (31, 32, 33). These observations, along with the present study by Dong et al. (17), underscore the fact that we have much to learn in regard to the intricacies of the physiological role of ghrelin.


   Acknowledgments
 
I thank Drs. Gordon L. Rintoul, Michael W. Schwartz, and David E. Cummings for their thoughtful discussion and advice on the manuscript.


   Footnotes
 
R.W.G. has nothing to declare.

Abbreviations: AgRP, Agouti gene-related protein; ARC, arcuate nucleus; GHSR, GH secretagogue receptor; NPY, neuropeptide Y; POMC, preproopiomelanocortin; STZ-DM, streptozotocin-induced diabetes mellitus.

Received March 7, 2006.

Accepted for publication March 20, 2006.


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