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Vollum Institute, Oregon Health Sciences University, Portland, Oregon 97201
Address all correspondence and requests for reprints to: Roger D. Cone, Vollum Institute L-474, Oregon Health Sciences University, 3181 S. W. Sam Jackson Park Road, Portland, Oregon 97201. E-mail: cone{at}ohsu.edu
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Introduction |
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Because the absence of leptin in the obese mouse leads to uncontrolled hypertrophy of the adipose tissues, it was assumed by many that the natural role for leptin was to limit the amount of energy stored in adipose tissue. Indeed, the first reports of leptin administration, performed simultaneously by three groups using the leptin deficient obese mouse (2, 3, 4), demonstrated that leptin rapidly "melted the fat off" these animals. These findings led to the expectation that common obesity might result from leptin deficiency, and that leptin replacement might be a rapid and effective weight reducing treatment; however, subsequent experiments in both rodents and humans have shown this is not the case. Serum leptin levels increase proportionately with adipose mass, and organisms appear to adapt to these elevated levels (5, 6). Both diet-induced obesity as well as several genetic models of obesity appear to produce resistance to the anorexic effects of elevated leptin (7, 8). Thus, while the experimental elevation of leptin within normal physiological levels produces a transient decrease in food intake and weight loss (8, 9) the normal physiological context in which leptin acts as a negative adipostatic signal, limiting weight gain in times of nutritional excess, remains to be defined.
In a now classic paper, however, Ahima and colleagues demonstrated that decreased leptin levels have a critical role in the starvation response, the complex neuroendocrine response to nutritional deficiency that involves decreased thyroid hormone, decreased reproductive hormones, and elevated glucocorticoids (10). In this study, leptin replacement was shown to blunt much of the reduction in thyroid hormone and testosterone caused by starvation, indicating that reduction in serum leptin is necessary for the initiation of the complex behavioral and endocrine response to nutritional deficiency.
Is leptin’s physiological role to constrain food intake and prevent excess energy storage, to initiate the starvation response, or both? The dissection of the complex neural pathways upon which leptin acts may help resolve these issues, and a paper in this issue of Endocrinology from Ahima and colleagues (9) demonstrates that some neuropeptide messenger RNA (mRNA) levels are bidirectionally regulated from baseline by raising or lowering serum leptin levels within physiological bounds while other neuropeptides are only sensitive to decreases in leptin below baseline.
Neuropeptide Y (NPY) was implicated in central leptin action even
before cloning of the gene by virtue of the fact that arcuate nucleus
NPY mRNA and protein levels were demonstrated to be significantly
up-regulated in the obese mouse. Significant attenuation of
the obesity in the obese mouse (
40%) resulting from
absence of the NPY gene demonstrated a role for elevated arcuate NPY
gene expression in mediating a component of the obesity resulting from
leptin deficiency (11). Ahima et al. (9) show in this issue
that maintaining constant leptin levels by chronic administration via
osmotic minipump (4 µg/h) prevents the 40–50% increase in arcuate
NPY mRNA normally seen following a 70-h fast in the rat. Leptin
infusion in fed rats (2–4 µg/h), producing a maximal 2-fold increase
in serum leptin, resulted in a 25–50% reduction in arcuate NPY mRNA
levels. Thus, arcuate nucleus NPY mRNA levels are bidirectionally
regulated by leptin and may be involved in both the starvation response
as well as the anorexic effects of elevated leptin.
Two findings implicated the arcuate POMC neurons as an important anorexic pathway, acting to tonically inhibit food intake and energy storage. Central administration of melanocortin agonists and antagonists were demonstrated to inhibit and stimulate food intake, respectively (12), and deletion of the gene encoding the melanocortin-4 receptor (MC4-R), the primary downstream target for neural melanocortin peptides, produced an obesity syndrome in mice (13). These findings, along with identification of high levels of leptin receptor expression in arcuate NPY and POMC neurons (14), led investigators to propose that while the NPY pathway mediated a significant component of the orexigenic effects of decreased leptin, the melanocortin neurons must mediate the anorexic effects of elevated leptin (15, 16). The experimental evidence is complex. On the one hand, MC4-RKO mice, and Ay mice overexpressing the MC4-R antagonist, agouti, are profoundly leptin resistant, implicating the MC4-R in mediating leptin’s anorexic effects. However, this conclusion is contradicted by the observations that Ay mice in which the leptin gene has been deleted remain fully responsive to elevated leptin (17), and young lean MC4-RKO mice with normal serum leptin levels are also leptin responsive (18). Additional work demonstrates that central administration of the melanocortin antagonist SHU9119 blocks the anorexigenic effect of leptin administration (19). Curiously, CRH and GLP-1 antagonists have the same effect (20, 21). Thus, antagonism of any of the anorexigenic neuropeptides appears to block the effect of supraphysiological doses of leptin.
Ahima and colleagues also examined CRH, POMC, and CART mRNA levels in these studies. The majority of arcuate POMC neurons also express the CART (cocaine- and amphetamine-regulated peptide), which has also been demonstrated to inhibit feeding behavior in rodents (22). Leptin replacement in the fasted rats was found to block the 20–25% decrease in POMC mRNA normally seen after the 70-h fast. Thus, POMC may be involved in a component of the starvation response. POMC is unlikely to be the dominant pathway involved in regulation of the thyroid or gonadal hormone axes in starvation, however, because, unlike obese mice, MC4-RKO mice are fertile and euthyroid. Perhaps the POMC pathway is important in changes in feeding behavior seen in leptin deficiency.
Previously, large doses of leptin administered to normal animals or to obese mice had been demonstrated to increase levels of POMC and CART mRNA (19, 23). Remarkably, the 1.5- to 2-fold elevation in serum leptin delivered to ad-lib fed rats in this study from Ahima and colleagues (9) produced a significant reduction in nocturnal food intake (25%), and weight loss in rats, but had no detectable effect on CRH, POMC or CART mRNA levels. The implications of this finding are that these anorexigenic peptide pathways are unidirectionally responsive to leptin, only detecting changes in leptin below baseline and signaling information specifically related to nutritional deficiency. These pathways may not be involved in mediating the effects of physiologically relevant increases in leptin above baseline levels.
While this work implies a unidirectional response to leptin by these anorexigenic peptide pathways, additional work will be needed to prove the case. First, the work of Ahima and colleagues only examines neuropeptide mRNA levels, and it is quite possible that increased leptin could alter POMC, CART, or CRH peptide processing or release to send an anorexic signal through these pathways. Secondly, in the case of central POMC signaling, the majority of arcuate NPY neurons have been found to express the melanocortin antagonist, agouti-related protein (AGRP), and these fibers project to most of the same sites as POMC neurons (24, 25). Thus, an increased melanocortin signal could also be accomplished by decreased release of the antagonist, AGRP, and this study already shows that bidirectional regulation of the NPY gene by leptin can take place in the very same neurons expressing AGRP, the arcuate NPY/AGRP neurons. Nevertheless, the type of careful analysis of physiologically relevant changes in leptin levels presented in this issue by Ahima and colleagues is what is needed to better understand the ups and downs of leptin action.
Received August 27, 1999.
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This article has been cited by other articles:
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  D. L. Marks, N. Ling, and R. D. Cone Role of the Central Melanocortin System in Cachexia Cancer Res., February 1, 2001; 61(4): 1432 - 1438. [Abstract] [Full Text]
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