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• W2022705537 abstract "Mechanisms by which the hypothalamus senses nutritional status are important for many metabolic diseases, including obesity and diabetes. Now, Coppola et al., 2007Coppola A. Liu Z.-W. Andrews Z.B. Paradis E. Roy M.-C. Friedman J.M. Ricquier D. Richard D. Horvath T.L. Gao X.-B. Diano S. Cell Metab. 2007; 5 (this issue): 21-33Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar report that hypothalamic neurons sense nutritional deficit through a cascade of events involving leptin, corticosterone, and glial production of thyroid hormone, leading to neuronal induction of uncoupling protein. Mechanisms by which the hypothalamus senses nutritional status are important for many metabolic diseases, including obesity and diabetes. Now, Coppola et al., 2007Coppola A. Liu Z.-W. Andrews Z.B. Paradis E. Roy M.-C. Friedman J.M. Ricquier D. Richard D. Horvath T.L. Gao X.-B. Diano S. Cell Metab. 2007; 5 (this issue): 21-33Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar report that hypothalamic neurons sense nutritional deficit through a cascade of events involving leptin, corticosterone, and glial production of thyroid hormone, leading to neuronal induction of uncoupling protein. It all seemed so simple. A decrease in the levels of the fat-produced hormone leptin signals the hypothalamus that fat levels have fallen, and hypothalamic neurons activate a complex program, including hunger, to preserve energy and restore fat levels (Ahima et al., 1996Ahima R.S. Prabakaran D. Mantzoros C. Qu D. Lowell B. Maratos-Flier E. Flier J.S. Nature. 1996; 382: 250-252Crossref PubMed Scopus (2585) Google Scholar). Impairments in this mechanism, including deficiency in or insensitivity to leptin, would, by misleading the brain into underestimating available nutritional resources, then plausibly constitute a major cause of obesity and diabetes. If only. A series of studies, including those reported in this issue of Cell Metabolism by Coppola et al., 2007Coppola A. Liu Z.-W. Andrews Z.B. Paradis E. Roy M.-C. Friedman J.M. Ricquier D. Richard D. Horvath T.L. Gao X.-B. Diano S. Cell Metab. 2007; 5 (this issue): 21-33Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar, have now elegantly demonstrated that hypothalamic responses to food deprivation involve at least three hormones, two cell types, and an unexpected interlocutor, uncoupling protein 2 (UCP2). Even before the studies leading to this paper, it was clear that responses to fasting involved more hormones than leptin since, for example, elevated corticosterone mediates the induction of hypothalamic agouti-related peptide (AgRP) and neuropeptide Y (NPY) during fasting and diabetes (Makimura et al., 2003Makimura H. Mizuno T.M. Isoda F. Beasley J. Silverstein J.H. Mobbs C.V. BMC Physiol. 2003; 3: 5Crossref PubMed Google Scholar). Since many of the neuroendocrine responses to food deprivation, including elevation of plasma corticosterone, are reversed by elevating plasma leptin levels (Ahima et al., 1996Ahima R.S. Prabakaran D. Mantzoros C. Qu D. Lowell B. Maratos-Flier E. Flier J.S. Nature. 1996; 382: 250-252Crossref PubMed Scopus (2585) Google Scholar), these observations suggest that at least some of the effects of leptin deficiency are mediated indirectly via leptin's regulation of glucocorticoid secretion. Coppola et al., 2007Coppola A. Liu Z.-W. Andrews Z.B. Paradis E. Roy M.-C. Friedman J.M. Ricquier D. Richard D. Horvath T.L. Gao X.-B. Diano S. Cell Metab. 2007; 5 (this issue): 21-33Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar now make a strong case that effects of corticosterone on at least some neuroendocrine responses to fasting are also indirect and are mediated by yet another hormone, the thyroid hormone T3, produced by a surprising source, a specialized class of hypothalamic glia called tanycytes. In previous studies, the authors had demonstrated that tanycytes express the enzyme type 2 deiodinase (Diano et al., 2003aDiano S. Leonard J.L. Meli R. Esposito E. Schiavo L. Brain Res. 2003; 976: 130-134Crossref PubMed Scopus (42) Google Scholar), which locally converts a precursor to the active T3. The authors further demonstrated that the induction of type 2 deiodinase by fasting (as with AgRP and NPY [Makimura et al., 2003Makimura H. Mizuno T.M. Isoda F. Beasley J. Silverstein J.H. Mobbs C.V. BMC Physiol. 2003; 3: 5Crossref PubMed Google Scholar]) is mediated by fasting-induced elevation of glucocorticoid secretion (Coppola et al., 2005Coppola A. Meli R. Diano S. Endocrinology. 2005; 146: 2827-2833Crossref PubMed Scopus (68) Google Scholar). In the present study, Coppola et al., 2007Coppola A. Liu Z.-W. Andrews Z.B. Paradis E. Roy M.-C. Friedman J.M. Ricquier D. Richard D. Horvath T.L. Gao X.-B. Diano S. Cell Metab. 2007; 5 (this issue): 21-33Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar demonstrate the physiological significance of the induction of hypothalamic type 2 deiodinase by fasting. First, the authors showed that the tanycytes expressing type 2 deiodinase directly contact hypothalamic neurons expressing AgRP and NPY (the same neurons express both genes). As they had reported previously, fasting increased the expression of type 2 deiodinase and the local hypothalamic production of T3. In the periphery, T3 is known to induce the activity of uncoupling proteins (Collin et al., 2005Collin A. Cassy S. Buyse J. Decuypere E. Damon M. Domest. Anim. Endocrinol. 2005; 29: 78-87Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar); such proteins “uncouple” the transfer of protons down the mitochondrial proton gradient from the production of ATP, which, by reducing the efficiency of ATP production, produces heat, a mechanism accounting for the thermogenic (and antiobesity) effects of peripheral T3. The authors therefore examined whether the fasting-induced increase in hypothalamic T3 production was associated with an induction of hypothalamic UCP2, and they observed that this was indeed the case. It is also known that the expression of uncoupling protein in the periphery is associated with increased numbers of mitochondria, and the authors also observed that this was the case in hypothalamic neurons expressing NPY and AgRP. Finally, and most importantly, the authors demonstrated that blocking the production of T3 blocked the induction of fasting-induced UCP2 and that ablation of UCP2 diminished the activating effects of fasting on NPY/AgRP neurons. These observations led to the conclusion that fasting reduces plasma leptin, which through hypothalamic action leads to the elevation of peripheral corticosterone, which then acts on hypothalamic tanycytes to increase local production of T3, which then stimulates UCP2 in NPY/AgRP neurons, leading to an increase in number of mitochondria and activity of these neurons (Figure 1). Why bother with such a Rube Goldberg mechanism? One interesting possibility is that fasting-induced hypothalamic UCP2 mediates the robust energy-conserving drop in core body temperature that occurs during fasting (Conti et al., 2006Conti B. Sanchez-Alavez M. Winsky-Sommerer R. Morale M.C. Lucero J. Brownell S. Fabre V. Huitron-Resendiz S. Henriksen S. Zorrilla E.P. et al.Science. 2006; 314: 825-828Crossref PubMed Scopus (269) Google Scholar). The authors also speculate that one function of the mechanism is, by increasing mitochondrial number, to increase the bioenergetic capacity of the NPY/AgRP neurons that are chronically activated by fasting. This hypothesis is supported by the observation that UCP2 transgenic mice exhibit elevated ATP levels in the hippocampus (Diano et al., 2003bDiano S. Matthews R.T. Patrylo P. Yang L. Beal M.F. Barnstable C.J. Horvath T.L. Endocrinology. 2003; 144: 5014-5021Crossref PubMed Scopus (145) Google Scholar). On the other hand, such a mechanism would be somewhat paradoxical in that the increased mitochondrial number appears to be secondary to induction of UCP2, which actually reduces mitochondrial efficiency. For example, overexpression of UCP2 in pancreatic β cells reduces ATP synthesis and sensitivity to glucose, whereas ablation of UCP2 in pancreatic β cells increases ATP synthesis and sensitivity to glucose (Zhang et al., 2001Zhang C.Y. Baffy G. Perret P. Krauss S. Peroni O. Grujic D. Hagen T. Vidal-Puig A.J. Boss O. Kim Y.B. et al.Cell. 2001; 105: 745-755Abstract Full Text Full Text PDF PubMed Scopus (793) Google Scholar). It is not clear why elevated UCP2 expression should produce the same energetic effect in NPY/AgRP neurons as ablating UCP2 expression produces in pancreatic β cells. Furthermore, since NPY/AgRP neurons are inhibited by both leptin and glucose (Mountjoy et al., 2006Mountjoy P.D. Bailey S.J. Rutter G.A. Diabetologia. 2006; (Published online November 9, 2006)https://doi.org/10.1007/s00125-006-0473-3Crossref PubMed Scopus (96) Google Scholar), and since inhibition of neuronal activity is mediated through glucose metabolism (Yang et al., 2004Yang X.J. Kow L.M. Pfaff D.W. Mobbs C.V. Diabetes. 2004; 53: 67-73Crossref PubMed Scopus (76) Google Scholar), an increase in metabolic capacity during fasting would increase the sensitivity of these neurons to glucose and thus, if anything, would be expected to silence, rather than activate, these neurons. It is perhaps more plausible that UCP2 produces the same effect in NPY/AgRP neurons as it does in pancreatic β cells, viz., reduction of metabolic efficiency and, thus, sensitivity to glucose (Zhang et al., 2001Zhang C.Y. Baffy G. Perret P. Krauss S. Peroni O. Grujic D. Hagen T. Vidal-Puig A.J. Boss O. Kim Y.B. et al.Cell. 2001; 105: 745-755Abstract Full Text Full Text PDF PubMed Scopus (793) Google Scholar). In fact, reducing metabolic efficiency by reducing the inhibitory effect of glucose activates these glucose-inhibited neurons. Such a mechanism could optimize the integration of the signal for long-term energy availability, leptin, with the signal for short-term energy availability, glucose. It should be noted, however, that reducing neuroendocrine sensitivity to glucose is not necessarily inconsistent with increased metabolic capacity. A key result of decreasing metabolic capacity is an increase in the number of NADH molecules required to produce one ATP molecule, which would be expected to reduce the ratio of cytoplasmic NADH to ATP molecules. Several lines of evidence suggest that molecular effects of glucose may be mediated through NADH rather than ATP (Yang et al., 2004Yang X.J. Kow L.M. Pfaff D.W. Mobbs C.V. Diabetes. 2004; 53: 67-73Crossref PubMed Scopus (76) Google Scholar), so UCP2 expression could reduce glucose sensitivity of NPY/AgRP neurons while still maintaining ATP production. Since cytoplasmic NADH is also produced by lactate metabolism, this mechanism also suggests that hypothalamic glial cells, which are well placed to monitor blood glucose and supply lactate to NPY/AGPR neurons to support elevated neuronal activity (Magistretti et al., 1999Magistretti P.J. Pellerin L. Rothman D.L. Shulman R.G. Science. 1999; 283: 496-497Crossref PubMed Scopus (964) Google Scholar), are particularly suitable to coordinate these metabolic signals. Thus, the studies by Coppola et al., 2007Coppola A. Liu Z.-W. Andrews Z.B. Paradis E. Roy M.-C. Friedman J.M. Ricquier D. Richard D. Horvath T.L. Gao X.-B. Diano S. Cell Metab. 2007; 5 (this issue): 21-33Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar raise many fascinating questions for future analysis." @default.
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• W2022705537 title "The “Domino Theory” of Hunger: The Hypothalamus Is Hot" @default.
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