| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Mount Sinai School of Medicine Neurobiology of Aging Laboratories New York, New York 10029
Address all correspondence and requests for reprints to: Dr. Charles V. Mobbs, Mount Sinai School of Medicine, Neurobiology of Aging Laboratories, Box 1639, 1425 Madison Avenue, New York, New York 10029. E-mail: charles.mobbs{at}mssm.edu.
Hormones are increasingly understood to produce pleiotropic effects, especially in the brain, on functions well outside those they have been traditionally thought to regulate. For example, although effects of estrogen in the brain were thought formerly to be limited to those hypothalamic neurons associated with reproductive function, it is now clear that estrogen robustly influences cognitive functions and even synaptic connections in areas of the brain, such as the hippocampus, that play little or no role in reproduction (1).
So it now is with leptin. Although for a hormone so recently discovered it may be a stretch to refer to "traditional" views, leptin is generally understood to function mainly as a signal of fat stores to hypothalamic neurons controlling energy balance (2). On the other hand, even before the discovery of leptin, many impairments in ob/ob mice, which are massively obese due to a lack of leptin, were not so easily understood in terms of impairments in energy balance. For example, it has long been known that the brains of ob/ob mice weigh less than the brains of wild-type mice with evidence of general reduction in neuron size (3). Since the discovery of leptin, several studies have corroborated that leptin can enhance brain growth (4, 5). In particular, Ahima et al. (5) demonstrated that the brains of leptin-deficient mice exhibit an immature profile of gene expression, in that the expression of markers of neuronal and glial specialization is reduced in leptin-deficient mice, whereas the expression of growth associated protein-43, a marker of neuronal outgrowth, is increased. This study was also notable in demonstrating that the reduced brain growth in leptin-deficient mice was not due to the obese phenotype itself, as another form of genetic obesity did not exhibit reduced brain growth. However, the mechanisms by which leptin stimulates brain growth have not been examined in any detail.
The studies by Udagawa et al. (6), published in this issue of Endocrinology, address these mechanisms in elegant and thorough detail. Udagawa et al. assessed the effects of leptin on maintenance, proliferation, and differentiation of neuronal precursor cells, focusing on the cerebral cortex because they had previously observed cortical expression of the leptin receptor earlier during development than hypothalamic expression (7). Using the bromodeoxyuridine method to mark dividing cells, the authors observed that significantly fewer cells had arisen from cell division in the cortex of ob/ob mice at embryonic d 14 and 16, suggesting that leptin stimulates cell division during this critical period of brain development. In an in vitro preparation of neuronal precursor cells, leptin did not directly stimulate proliferation, but instead appeared to enhance the proliferative response to epidermal growth factor. Furthermore, leptin stimulated the expression of Hes1, a transcription factor that blocks neurogenesis and increases the proportion of dividing progenitors. On the other hand, leptin also stimulated the transcription factor Ngn1, which is expressed in newly committed neuronal progenitors and immature neurons and promotes neurogenesis. These observations suggest that leptin increases the final number of neurons by stimulating the proliferation of precursor cells committed to neuronal differentiation, then also promoting the terminal differentiation process. Leptin may have similar effects on astrocyte differentiation, but this effect is highly sensitive to precise dosing in vitro, so the significance of the effect is unclear at present.
The studies by Udagawa et al. have two main implications. First, although previous investigators had shown an effect of leptin on brain growth (4, 5), the detailed studies now presented are likely to convince developmental biologists of the robustness of the effects and the unique opportunity to study mechanisms of neuronal development using this highly tractable system. Thus, it is now clear that leptin given postnatally to ob/ob mice will produce at least some of the maturational effects normally only observed during normal embryonic development. This provides an experimental system to temporally dissociate specific maturational processes and thus a unique paradigm for assessing mechanisms underlying these processes. Second, the proposed studies provide a mechanism to explain the well-established relationship between malnutrition during development and subsequent cognitive impairments (8), a major concern especially in developing countries that experience famine. Because at least some effects of leptin deficiency during pregnancy can be reversed by postnatal treatment with leptin, it is possible that postnatal leptin administration to children malnourished during development might improve cognitive function in adulthood.
Finally, as is so often the case with leptin, the present studies raise the issue of whether the effects of leptin deficiency on brain growth are purely pathological or whether they indicate a normal physiological function. It is generally accepted that a key physiological function of leptin is to signal adequacy of adipose stores; a reduction in leptin levels caused by undernutrition triggers a neuroendocrine response to protect nutritional resources at the expense of longer-term but temporarily expendable functions such as reproduction and growth (2). In this context, what would be the physiological significance of reducing brain size during fetal malnutrition through what appears to be a highly regulated mechanism? One possibility is that such a phenomenon would be part of a general developmental mechanism to reduce final body size when there is a likelihood that nutritional resources will be limited in adulthood. In any case, the studies by Udagawa et al. have firmly laid the foundation for further analysis of the mechanisms by which leptin influences brain development.
Received November 17, 2005.
Accepted for publication November 21, 2005.
 |
References |
|---|
 Top References |
|---|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
