- Email: [email protected]
AgRP in energy balance: Will the real AgRP please stand up?
AgRP in energy balance: Will the real AgRP please stand up?
Minireview
Jeffrey S. Flier1,* 1
Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215 *Correspondence: [email protected]
The neuropeptide AgRP promotes food intake and weight gain by antagonizing signaling at melanocortin 3 and 4 receptors in the brain, but the limited phenotype of mice lacking AgRP raised questions about its importance. Four recent studies addressed this by creating mice in which AgRP neurons, which also express NPY and GABA, are ablated postnatally, and although details vary, they suggest that AgRP neurons are more essential to feeding and weight gain than is AgRP itself. A recent paper in Cell Metabolism (Wortley et al., 2005) indicates that AgRP itself is important for feeding and weight gain, but only as mice age, and the mechanism may involve dysfunction of the thyroid axis.
In complex physiologic systems, the true role of a regulatory molecule may sometimes be difficult to ascertain, with different experimental paradigms suggesting different views of the molecule’s position in physiology and disease. This may vary even within a specific circuit, where the role of individual components may be defined with different degrees of clarity. This is well illustrated within the melanocortin circuit for regulation of energy homeostasis. Melanocortin 4 receptor (MC4R) signaling plays an unambiguous role in determining anorexigenic and catabolic physiology, as revealed by both genetics and pharmacology, using both gain- and loss-of-function approaches (Huszar et al., 1997; Cone, 1999). In contrast, the precise physiologic role of the neuropeptide AgRP, which antagonizes signaling at both the MC4R and MC3R, has been more difficult to define. MC4Rs on hypothalamic neurons receive both agonistic and antagonistic signals. a-melanocyte-stimulating hormone (aMSH) derived from the POMC gene product stimulates these receptors and suppresses food intake and induces weight loss (Fan et al., 1997). In contrast, AgRP is an endogenous antagonist of the MC4R produced in neurons that coexpress NPY, and it promotes food intake and positive energy balance (Ollmann et al., 1997; Rossi et al., 1998). This anabolic role is demonstrated by central administration of AgRP or genetic overexpression, which reduce the MC4R signal and thereby induce hyperphagia, anabolism, and obesity. It was therefore a surprise to many in the field that loss of function of AgRP via knockout of the AgRP gene in mice produced a bland metabolic phenotype, with normal body weight, adiposity, and food intake, raising the possibility that this neuropeptide was not as essential for energy homeostasis as initially suspected (Qian et al., 2002). A series of recent papers have been published, one in the December issue of Cell Metabolism (Wortley et al., 2005), that address this question and provide several promising avenues for future research. When genetic loss of function produces a phenotype that differs from pharmacology, a number of possible explanations must be considered. Prominent among these is that gene ablation in early development promotes compensatory mechanisms that override the loss of the gene in question. Although much invoked, the specifics of such putative mechanisms have rarely been defined with precision. Four papers published recently
have taken the approach of genetically ablating not the AgRP peptide but the neurons that normally make the peptide and conclude that loss of AgRP neurons produces a more robust phenotype than loss of AgRP alone, with hypophagia and leanness and a variety of other features (Figure 1). Three different approaches were used to selectively target AgRP neurons for death, all using genetic approaches permitting faithful expression of specific molecules in this restricted group of cells. These approaches involved (1) transgenic expression of the neurotoxic CAG expanded repeat form of ataxin-3, which induces cell death (Bewick et al., 2005); (2) cre-mediated deletion of the mitochondrial transcription factor A (Tfam), which results in progressive postnatal cell death (Xu et al., 2005); and (3) expression of the receptor for diphtheria toxin in AgRP neurons, permitting temporally controlled ablation of these neurons after administration of diphtheria toxin (Gropp et al., 2005; Luquet et al., 2005). In one study (Bewick et al., 2005), mice with reduced numbers of AgRP neurons (which also express NPY) have reduced body weight, body fat, and food intake. In another (Xu et al., 2005), the reduction in body weight was more modest, and only evident in females. Whether the differences in these phenotypes results from differing neuronal loss, or other factors, is not yet apparent. In two studies in which loss of AgRP neurons was selectively induced postnatally via injection of diphtheria toxin (Gropp et al., 2005; Luquet et al., 2005), hypophagia and weight loss were seen, but the implications of the two studies are somewhat different. In both studies postnatal ablation of the AgRP neurons caused acute suppression of feeding over several days, in one case leading to impending starvation (Luquet et al., 2005). The study of Luquet et al. has an additional important dimension, by examining the effect of cell ablation at two different ages (Luquet et al., 2005). Ablation of AgRP neurons in the early postnatal period was equally effective at ablating the neurons as was the toxin administration in adults, but neonatal ablation was entirely without effect on feeding or body weight, indicating that some form of compensation was operating that was possible only at young ages (Luquet et al., 2005). The nature of this compensation is as yet unknown. The above studies permit several conclusions to be drawn. First, we are reminded that the function of a neuron expressing
CELL METABOLISM 3, 83–85, FEBRUARY 2006 ª2006 ELSEVIER INC.
DOI 10.1016/j.cmet.2006.01.003
83
M I N I R E V I E W
Figure 1. The consequences of loss of AgRP or AgRP neurons A) Hypothalamic neurons expressing MC4Rs receive antagonistic signals that act on this receptor the agonist a-MSH arises from POMC neurons, and the antagonist AgRP arises from neurons coexpressing AgRP and NPY. Stimulation of MC4Rs evokes catabolic signals that reduce appetite and promote weight loss. In prior studies, gene knockout of AgRP produced a minimal phenotype. Genetic ablation of AgRP neurons, however, produces a phenotype of leanness, which could be a consequence of loss of NPY, GABA, or some as yet undiscovered product of this neuron, as well as loss of AgRP. When these neurons are ablated in very young mice, an unknown compensation occurs that permits animals to feed and regulate weight normally. B) When older mice with AgRP (peptide) knockout are studied, they are lean, due not to reduced feeding but to increased thyroid hormones, which increase metabolic rate. Prior studies demonstrated that melanocortin signaling regulates activity of TRH neurons in the paraventricular nucleus that control the thyroid axis. AgRP suppresses the thyroid axis by antagonizing melanocortin signals on the TRH neuron, and removal of AgRP is hypothesized to activate the axis. Why this occurs only in older animals is unknown.
a specific neuropeptide such as AgRP is not limited to the release of that neuropeptide. For example, hypothalamic AgRP neurons also express NPY and the neurotransmitter GABA (Backberg et al., 2003), and potentially other undiscovered molecules, whose actions may be critical to the function of the neuron in a physiologic circuit. For this reason, the consequences of deleting a neuron may be quite different in magnitude (or even direction) from the consequences of deleting the specific neuropeptide. Second, the apparent capacity of the immature brain to respond to neuronal loss with a network-wide compensation is truly impressive. Identification of the signals that initiate the compensation and the cellular targets that effect it will likely produce exciting new insights into the mechanisms for brain plasticity, as well as potential new mediators of energy balance regulation. An additional aspect of the ‘‘normal phenotype’’ of AgRP knockout mice is revealed in the paper by Wortley et al. (Wortley et al., 2005). Unlike the above studies, it did not employ fancy genetic approaches to ablating AgRP neurons as an approach to this question. Rather, these investigators studied AgRP knockout mice more extensively than earlier studies, including an assessment of the effects of AgRP loss in older animals. Their younger mice had minimal phenotypes largely concordant with the earlier studies. One exception was their observation of reduced compensatory feeding after starvation, a subtle but important finding also made in mice with deletion of NPY (SegalLieberman et al., 2003). However, overt leanness, which was absent in younger mice, was observed in older mice (6 months). Interestingly, this leanness was not ascribed to reduced food intake but rather to increased energy expenditure, apparently associated with increased activity of the thyroid axis (Figure 1). Although the lack of hypophagia as an explanation may be surprising, the overactivity of the thyroid axis with loss of AgRP is not entirely unexpected.
84
Suppression of the thyroid axis in response to food restriction has been well studied (Ahima et al., 1996; Legradi et al., 1997; Kim et al., 2000; Flier et al., 2000; Fekete et al., 2002; Lechan and Fekete, 2005), and roles for both falling leptin and the melanocortin axis are well described as bringing this about. AgRP, which increases with starvation, has been shown to suppress expression of the neuropeptide TRH in the paraventricular nucleus, which then suppresses pituitary TSH and thyroid hormones. Removal of AgRP (and subsequent increased MC4R tone) might then be expected to derepress TRH, driving TSH and thyroid hormones to increased levels. If this sequence is true, it might imply that negative regulation of TRH by thyroid hormone, a dominant influence in this system, might be inhibited if MC4R tone is too high, a testable hypothesis. It may be tempting to speculate that the common development of obesity with aging is linked, via reduced MC4R tone, to subtle suppression of the thyroid axis, in addition to the expected stimulation of food intake and suppression of energy expenditure by reduced sympathetic activity. However much more data will be necessary before we can invoke melanocortin-regulated changes in thyroid thermogenesis as being important influences over energy balance and obesity with aging or other situations. So what can we say, in the light of all of these studies, about the ‘‘real role’’ of AgRP in energy balance? Excess AgRP is sufficient to cause obesity, as has been known since the initial discovery of this gene (Ollmann et al., 1997). In contrast, loss of AgRP, or AgRP neurons, in young animals is surprisingly benign, owing to compensatory mechanisms of uncertain nature that provide more than adequate protection for loss of AgRP and AgRP neuron-induced feeding and anabolism. Ablation of AgRP peptide promotes leanness, but this is seen primarily as mice age, at least in part through activation of the thyroid axis and consequent increases in energy expenditure. Finally, loss of AgRP neurons in adults is extremely poorly tolerated, causing
CELL METABOLISM : FEBRUARY 2006
M I N I R E V I E W
profound suppression of the capacity to feed, proving the essential role of these neurons in orexigenic drive (Figure 1). What remains to be determined is to what degree the hypophagia and leanness due to loss of these neurons in adults is due to loss of AgRP, as opposed to other factors released by these neurons, both known (NPY and GABA) and unknown. Until we have this information, the ‘‘real role’’ of AgRP, as opposed to the AgRP/NPY/GABA/?X neurons that expresses it, will remain a subject of continued investigation and speculation. And whether altered expression of AgRP, or altered numbers of AgRP neurons, are important contributors to the variations in body weight in human populations will likewise require further study.
Gropp, E., Shanabrough, M., Borok, E., Xu, A.W., Janoschek, R., Buch, T., Plum, L., Balthasar, N., Hampel, B., Waisman, A., et al. (2005). Nat. Neurosci. 8, 1289–1291. Huszar, D., Lynch, C.A., Fairchild-Huntress, V., Dunmore, J.H., Fang, Q., Berkemeier, L.R., Gu, W., Kesterson, R.A., Boston, B.A., Cone, R.D., et al. (1997). Cell 88, 131–141. Kim, M.S., Small, C.J., Stanley, S.A., Morgan, D.G., Seal, L.J., Kong, W.M., Edwards, C.M., Abusnana, S., Sunter, D., Ghatei, M.A., and Bloom, S.R. (2000). J. Clin. Invest. 105, 1005–1011. Lechan, R.M., and Fekete, C. (2005). Role of melanocortin signaling in the regulation of the hypothalamic-pituitary-thyroid (HPT) axis. Peptides. Published online November 22, 2005. doi: 10.1016/j.peptides.2005.01.033. Legradi, G., Emerson, C.H., Ahima, R.S., Flier, J.S., and Lechan, R.M. (1997). Endocrinology 138, 2569–2576. Luquet, S., Perez, F.A., Hnasko, T.S., and Palmiter, R.D. (2005). Science 310, 683–685.
Selected reading Ahima, R.S., Prabakaran, D., Mantzoros, C., Qu, D., Lowell, B., Maratos-Flier, E., and Flier, J.S. (1996). Nature 382, 250–252. Backberg, M., Collin, M., Ovesjo, M.L., and Meister, B. (2003). J. Neuroendocrinol. 15, 1–14. Bewick, G.A., Gardiner, J.V., Dhillo, W.S., Kent, A.S., White, N.E., Webster, Z., Ghatei, M.A., and Bloom, S.R. (2005). FASEB J. 19, 1680–1682. Cone, R.D. (1999). Trends Endocrinol. Metab. 10, 211–216. Fan, W., Boston, B.A., Kesterson, R.A., Hruby, V.J., and Cone, R.D. (1997). Nature 385, 165–168. Fekete, C., Sarkar, S., Rand, W.M., Harney, J.W., Emerson, C.H., Bianco, A.C., and Lechan, R.M. (2002). Endocrinology 143, 3846–3853. Flier, J.S., Harris, M., and Hollenberg, A.N. (2000). J. Clin. Invest. 105, 859– 861.
CELL METABOLISM : FEBRUARY 2006
Ollmann, M.M., Wilson, B.D., Yang, Y.K., Kerns, J.A., Chen, Y., Gantz, I., and Barsh, G.S. (1997). Science 278, 135–138. Qian, S., Chen, H., Weingarth, D., Trumbauer, M.E., Novi, D.E., Guan, X., Yu, H., Shen, Z., Feng, Y., Frazier, E., et al. (2002). Mol. Cell. Biol. 22, 5027–5035. Rossi, M., Kim, M.S., Morgan, D.G., Small, C.J., Edwards, C.M., Sunter, D., Abusnana, S., Goldstone, A.P., Russell, S.H., Stanley, S.A., et al. (1998). Endocrinology 139, 4428–4431. Segal-Lieberman, G., Trombly, D.J., Juthani, V., Wang, X., and Maratos-Flier, E. (2003). Am. J. Physiol. Endocrinol. Metab. 284, E1131–E1139. Wortley, K.E., Anderson, K.D., Yasenchak, J., Murphy, A., Valenzuela, D., Diano, S., Yancopoulos, G.D., Wiegand, S.J., and Sleeman, M.W. (2005). Cell Metab. 2, 421–427. Xu, A.W., Kaelin, C.B., Morton, G.J., Ogimoto, K., Stanhope, K., Graham, J., Baskin, D.G., Havel, P., Schwartz, M.W., and Barsh, G.S. (2005). PLoS Biol. 3, e415. 10.1371/journal.pbio.0030415.
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Minireview
Jeffrey S. Flier1,* 1
Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215 *Correspondence: [email protected]
The neuropeptide AgRP promotes food intake and weight gain by antagonizing signaling at melanocortin 3 and 4 receptors in the brain, but the limited phenotype of mice lacking AgRP raised questions about its importance. Four recent studies addressed this by creating mice in which AgRP neurons, which also express NPY and GABA, are ablated postnatally, and although details vary, they suggest that AgRP neurons are more essential to feeding and weight gain than is AgRP itself. A recent paper in Cell Metabolism (Wortley et al., 2005) indicates that AgRP itself is important for feeding and weight gain, but only as mice age, and the mechanism may involve dysfunction of the thyroid axis.
In complex physiologic systems, the true role of a regulatory molecule may sometimes be difficult to ascertain, with different experimental paradigms suggesting different views of the molecule’s position in physiology and disease. This may vary even within a specific circuit, where the role of individual components may be defined with different degrees of clarity. This is well illustrated within the melanocortin circuit for regulation of energy homeostasis. Melanocortin 4 receptor (MC4R) signaling plays an unambiguous role in determining anorexigenic and catabolic physiology, as revealed by both genetics and pharmacology, using both gain- and loss-of-function approaches (Huszar et al., 1997; Cone, 1999). In contrast, the precise physiologic role of the neuropeptide AgRP, which antagonizes signaling at both the MC4R and MC3R, has been more difficult to define. MC4Rs on hypothalamic neurons receive both agonistic and antagonistic signals. a-melanocyte-stimulating hormone (aMSH) derived from the POMC gene product stimulates these receptors and suppresses food intake and induces weight loss (Fan et al., 1997). In contrast, AgRP is an endogenous antagonist of the MC4R produced in neurons that coexpress NPY, and it promotes food intake and positive energy balance (Ollmann et al., 1997; Rossi et al., 1998). This anabolic role is demonstrated by central administration of AgRP or genetic overexpression, which reduce the MC4R signal and thereby induce hyperphagia, anabolism, and obesity. It was therefore a surprise to many in the field that loss of function of AgRP via knockout of the AgRP gene in mice produced a bland metabolic phenotype, with normal body weight, adiposity, and food intake, raising the possibility that this neuropeptide was not as essential for energy homeostasis as initially suspected (Qian et al., 2002). A series of recent papers have been published, one in the December issue of Cell Metabolism (Wortley et al., 2005), that address this question and provide several promising avenues for future research. When genetic loss of function produces a phenotype that differs from pharmacology, a number of possible explanations must be considered. Prominent among these is that gene ablation in early development promotes compensatory mechanisms that override the loss of the gene in question. Although much invoked, the specifics of such putative mechanisms have rarely been defined with precision. Four papers published recently
have taken the approach of genetically ablating not the AgRP peptide but the neurons that normally make the peptide and conclude that loss of AgRP neurons produces a more robust phenotype than loss of AgRP alone, with hypophagia and leanness and a variety of other features (Figure 1). Three different approaches were used to selectively target AgRP neurons for death, all using genetic approaches permitting faithful expression of specific molecules in this restricted group of cells. These approaches involved (1) transgenic expression of the neurotoxic CAG expanded repeat form of ataxin-3, which induces cell death (Bewick et al., 2005); (2) cre-mediated deletion of the mitochondrial transcription factor A (Tfam), which results in progressive postnatal cell death (Xu et al., 2005); and (3) expression of the receptor for diphtheria toxin in AgRP neurons, permitting temporally controlled ablation of these neurons after administration of diphtheria toxin (Gropp et al., 2005; Luquet et al., 2005). In one study (Bewick et al., 2005), mice with reduced numbers of AgRP neurons (which also express NPY) have reduced body weight, body fat, and food intake. In another (Xu et al., 2005), the reduction in body weight was more modest, and only evident in females. Whether the differences in these phenotypes results from differing neuronal loss, or other factors, is not yet apparent. In two studies in which loss of AgRP neurons was selectively induced postnatally via injection of diphtheria toxin (Gropp et al., 2005; Luquet et al., 2005), hypophagia and weight loss were seen, but the implications of the two studies are somewhat different. In both studies postnatal ablation of the AgRP neurons caused acute suppression of feeding over several days, in one case leading to impending starvation (Luquet et al., 2005). The study of Luquet et al. has an additional important dimension, by examining the effect of cell ablation at two different ages (Luquet et al., 2005). Ablation of AgRP neurons in the early postnatal period was equally effective at ablating the neurons as was the toxin administration in adults, but neonatal ablation was entirely without effect on feeding or body weight, indicating that some form of compensation was operating that was possible only at young ages (Luquet et al., 2005). The nature of this compensation is as yet unknown. The above studies permit several conclusions to be drawn. First, we are reminded that the function of a neuron expressing
CELL METABOLISM 3, 83–85, FEBRUARY 2006 ª2006 ELSEVIER INC.
DOI 10.1016/j.cmet.2006.01.003
83
M I N I R E V I E W
Figure 1. The consequences of loss of AgRP or AgRP neurons A) Hypothalamic neurons expressing MC4Rs receive antagonistic signals that act on this receptor the agonist a-MSH arises from POMC neurons, and the antagonist AgRP arises from neurons coexpressing AgRP and NPY. Stimulation of MC4Rs evokes catabolic signals that reduce appetite and promote weight loss. In prior studies, gene knockout of AgRP produced a minimal phenotype. Genetic ablation of AgRP neurons, however, produces a phenotype of leanness, which could be a consequence of loss of NPY, GABA, or some as yet undiscovered product of this neuron, as well as loss of AgRP. When these neurons are ablated in very young mice, an unknown compensation occurs that permits animals to feed and regulate weight normally. B) When older mice with AgRP (peptide) knockout are studied, they are lean, due not to reduced feeding but to increased thyroid hormones, which increase metabolic rate. Prior studies demonstrated that melanocortin signaling regulates activity of TRH neurons in the paraventricular nucleus that control the thyroid axis. AgRP suppresses the thyroid axis by antagonizing melanocortin signals on the TRH neuron, and removal of AgRP is hypothesized to activate the axis. Why this occurs only in older animals is unknown.
a specific neuropeptide such as AgRP is not limited to the release of that neuropeptide. For example, hypothalamic AgRP neurons also express NPY and the neurotransmitter GABA (Backberg et al., 2003), and potentially other undiscovered molecules, whose actions may be critical to the function of the neuron in a physiologic circuit. For this reason, the consequences of deleting a neuron may be quite different in magnitude (or even direction) from the consequences of deleting the specific neuropeptide. Second, the apparent capacity of the immature brain to respond to neuronal loss with a network-wide compensation is truly impressive. Identification of the signals that initiate the compensation and the cellular targets that effect it will likely produce exciting new insights into the mechanisms for brain plasticity, as well as potential new mediators of energy balance regulation. An additional aspect of the ‘‘normal phenotype’’ of AgRP knockout mice is revealed in the paper by Wortley et al. (Wortley et al., 2005). Unlike the above studies, it did not employ fancy genetic approaches to ablating AgRP neurons as an approach to this question. Rather, these investigators studied AgRP knockout mice more extensively than earlier studies, including an assessment of the effects of AgRP loss in older animals. Their younger mice had minimal phenotypes largely concordant with the earlier studies. One exception was their observation of reduced compensatory feeding after starvation, a subtle but important finding also made in mice with deletion of NPY (SegalLieberman et al., 2003). However, overt leanness, which was absent in younger mice, was observed in older mice (6 months). Interestingly, this leanness was not ascribed to reduced food intake but rather to increased energy expenditure, apparently associated with increased activity of the thyroid axis (Figure 1). Although the lack of hypophagia as an explanation may be surprising, the overactivity of the thyroid axis with loss of AgRP is not entirely unexpected.
84
Suppression of the thyroid axis in response to food restriction has been well studied (Ahima et al., 1996; Legradi et al., 1997; Kim et al., 2000; Flier et al., 2000; Fekete et al., 2002; Lechan and Fekete, 2005), and roles for both falling leptin and the melanocortin axis are well described as bringing this about. AgRP, which increases with starvation, has been shown to suppress expression of the neuropeptide TRH in the paraventricular nucleus, which then suppresses pituitary TSH and thyroid hormones. Removal of AgRP (and subsequent increased MC4R tone) might then be expected to derepress TRH, driving TSH and thyroid hormones to increased levels. If this sequence is true, it might imply that negative regulation of TRH by thyroid hormone, a dominant influence in this system, might be inhibited if MC4R tone is too high, a testable hypothesis. It may be tempting to speculate that the common development of obesity with aging is linked, via reduced MC4R tone, to subtle suppression of the thyroid axis, in addition to the expected stimulation of food intake and suppression of energy expenditure by reduced sympathetic activity. However much more data will be necessary before we can invoke melanocortin-regulated changes in thyroid thermogenesis as being important influences over energy balance and obesity with aging or other situations. So what can we say, in the light of all of these studies, about the ‘‘real role’’ of AgRP in energy balance? Excess AgRP is sufficient to cause obesity, as has been known since the initial discovery of this gene (Ollmann et al., 1997). In contrast, loss of AgRP, or AgRP neurons, in young animals is surprisingly benign, owing to compensatory mechanisms of uncertain nature that provide more than adequate protection for loss of AgRP and AgRP neuron-induced feeding and anabolism. Ablation of AgRP peptide promotes leanness, but this is seen primarily as mice age, at least in part through activation of the thyroid axis and consequent increases in energy expenditure. Finally, loss of AgRP neurons in adults is extremely poorly tolerated, causing
CELL METABOLISM : FEBRUARY 2006
M I N I R E V I E W
profound suppression of the capacity to feed, proving the essential role of these neurons in orexigenic drive (Figure 1). What remains to be determined is to what degree the hypophagia and leanness due to loss of these neurons in adults is due to loss of AgRP, as opposed to other factors released by these neurons, both known (NPY and GABA) and unknown. Until we have this information, the ‘‘real role’’ of AgRP, as opposed to the AgRP/NPY/GABA/?X neurons that expresses it, will remain a subject of continued investigation and speculation. And whether altered expression of AgRP, or altered numbers of AgRP neurons, are important contributors to the variations in body weight in human populations will likewise require further study.
Gropp, E., Shanabrough, M., Borok, E., Xu, A.W., Janoschek, R., Buch, T., Plum, L., Balthasar, N., Hampel, B., Waisman, A., et al. (2005). Nat. Neurosci. 8, 1289–1291. Huszar, D., Lynch, C.A., Fairchild-Huntress, V., Dunmore, J.H., Fang, Q., Berkemeier, L.R., Gu, W., Kesterson, R.A., Boston, B.A., Cone, R.D., et al. (1997). Cell 88, 131–141. Kim, M.S., Small, C.J., Stanley, S.A., Morgan, D.G., Seal, L.J., Kong, W.M., Edwards, C.M., Abusnana, S., Sunter, D., Ghatei, M.A., and Bloom, S.R. (2000). J. Clin. Invest. 105, 1005–1011. Lechan, R.M., and Fekete, C. (2005). Role of melanocortin signaling in the regulation of the hypothalamic-pituitary-thyroid (HPT) axis. Peptides. Published online November 22, 2005. doi: 10.1016/j.peptides.2005.01.033. Legradi, G., Emerson, C.H., Ahima, R.S., Flier, J.S., and Lechan, R.M. (1997). Endocrinology 138, 2569–2576. Luquet, S., Perez, F.A., Hnasko, T.S., and Palmiter, R.D. (2005). Science 310, 683–685.
Selected reading Ahima, R.S., Prabakaran, D., Mantzoros, C., Qu, D., Lowell, B., Maratos-Flier, E., and Flier, J.S. (1996). Nature 382, 250–252. Backberg, M., Collin, M., Ovesjo, M.L., and Meister, B. (2003). J. Neuroendocrinol. 15, 1–14. Bewick, G.A., Gardiner, J.V., Dhillo, W.S., Kent, A.S., White, N.E., Webster, Z., Ghatei, M.A., and Bloom, S.R. (2005). FASEB J. 19, 1680–1682. Cone, R.D. (1999). Trends Endocrinol. Metab. 10, 211–216. Fan, W., Boston, B.A., Kesterson, R.A., Hruby, V.J., and Cone, R.D. (1997). Nature 385, 165–168. Fekete, C., Sarkar, S., Rand, W.M., Harney, J.W., Emerson, C.H., Bianco, A.C., and Lechan, R.M. (2002). Endocrinology 143, 3846–3853. Flier, J.S., Harris, M., and Hollenberg, A.N. (2000). J. Clin. Invest. 105, 859– 861.
CELL METABOLISM : FEBRUARY 2006
Ollmann, M.M., Wilson, B.D., Yang, Y.K., Kerns, J.A., Chen, Y., Gantz, I., and Barsh, G.S. (1997). Science 278, 135–138. Qian, S., Chen, H., Weingarth, D., Trumbauer, M.E., Novi, D.E., Guan, X., Yu, H., Shen, Z., Feng, Y., Frazier, E., et al. (2002). Mol. Cell. Biol. 22, 5027–5035. Rossi, M., Kim, M.S., Morgan, D.G., Small, C.J., Edwards, C.M., Sunter, D., Abusnana, S., Goldstone, A.P., Russell, S.H., Stanley, S.A., et al. (1998). Endocrinology 139, 4428–4431. Segal-Lieberman, G., Trombly, D.J., Juthani, V., Wang, X., and Maratos-Flier, E. (2003). Am. J. Physiol. Endocrinol. Metab. 284, E1131–E1139. Wortley, K.E., Anderson, K.D., Yasenchak, J., Murphy, A., Valenzuela, D., Diano, S., Yancopoulos, G.D., Wiegand, S.J., and Sleeman, M.W. (2005). Cell Metab. 2, 421–427. Xu, A.W., Kaelin, C.B., Morton, G.J., Ogimoto, K., Stanhope, K., Graham, J., Baskin, D.G., Havel, P., Schwartz, M.W., and Barsh, G.S. (2005). PLoS Biol. 3, e415. 10.1371/journal.pbio.0030415.
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