help button home button Endocrine Society Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Joseph-Bravo, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Joseph-Bravo, P.
Endocrinology Vol. 145, No. 11 4813-4815
Copyright © 2004 by The Endocrine Society

Hypophysiotropic Thyrotropin-Releasing Hormone Neurons as Transducers of Energy Homeostasis

Patricia Joseph-Bravo

Departamento de Genética del Desarrollo y Fisiología Molecular Instituto de Biotecnología Universidad Nacional Autónoma de México Cuernavaca, Morelos 62271, México

Address all correspondence and requests for reprints to: Patricia Joseph-Bravo, Instituto de Biotecnología, UNAM A.P. 510-3, Cuernavaca, Morelos 62271, México. E-mail: joseph{at}ibt.unam.mx.

Understanding the fine tuning of food intake and energy homeostasis has become an important area of research due to the worldwide increase in obesity. The hypothalamus has long been recognized as the integrator of neural and peripheral signals involved in hunger and satiety, and in the past decade, many of these have been identified as well as the neural circuits involved. Most of these signals are peptides or proteins; some are released by peripheral tissues (adipocytes, stomach, pancreas, gut), whereas others constitute the neuromodulators involved in neural communication between hypothalamic nuclei. Neurons expressing neuropeptide Y (NPY) and agouti-related peptide (AgRP), proopiomelanocortin (POMC)-derived peptides ({alpha}-MSH, ß-endorphin) and cocaine- and amphetamine-related transcript (CART), in the arcuate nucleus, constitute the primary sensors for the peripheral signals evoked by feeding or fasting. Central or peripheral administration of some of these peptides stimulate or decrease food intake (orexigenic or anorexigenic, respectively). The arcuate nucleus sends projections to the paraventricular nucleus (PVN) or, to the dorso- and ventromedial nuclei as well as to the lateral hypothalamus; in turn, these hypothalamic nuclei communicate with the PVN (Fig. 1Go). The PVN receives inputs from, and projects to, other brain areas such as brainstem and nucleus tractus solitarius, to name a few. In the PVN, hypophysiotropic neurons act as neuroendocrine transducers that, in response to stimuli, release peptides to the portal circulation, thus acting as hormones that reach the anterior pituitary. Two important neuronal types regulating energy metabolism are those synthesizing TRH, which controls the pituitary-thyroid axis and those that produce CRH that regulates the pituitary-adrenal axis (1, 2, 3, 4, 5). Nerve endings containing {alpha}-MSH, AgRP, CART, {gamma}-amino butyric acid (GABA), or NPY have been identified in close apposition to TRH cell bodies, and central administration of these peptides modulates TRH biosynthesis. {alpha}-MSH and CART (coexpressed in the same neurons in the arcuate nucleus: POMC/CART) increase TRH gene expression, whereas NPY and AgRP have the opposite effects (see Ref.6 and references therein).



View larger version (79K):
[in this window]
[in a new window]
  		FIG. 1. Schematic representation of most important signals involved in energy homeostasis. Orexigenic (brown) and anorexigenic (green) efferences from the arcuate nucleus (ARC) to the PVN, lateral hypothalamus (LH), ventromedial nucleus (VMN), and dorsomedial hypothalamus (DMH). ANS, Autonomic nervous system; BDNF, brain-derived neurotropic factor; CCK, cholecystokinin; gc, glucocorticoids; ME, median eminence; NE, norepinephrine; NTS, nucleus of solitary tract; Ob-Rb, leptin receptor; YY, peptide YY; 5HT, serotonin. Continuous lines represent well-characterized circuits; dashed lines, possible regulators (for reviews, see Refs.1 2 3 4 ; also see Ref.6 and references therein).

 
Fasting reduces leptin secretion from adipose tissue and induces considerable metabolic changes that lead to increased appetite and diminished metabolic rate, a response considered as a survival mechanism. Energy homeostasis is attained not only by regulating expression and release of hypothalamic peptides involved in control of food intake, but also by the integration of the autonomous and endocrine systems that regulate energy expenditure. Thyroid hormones are important modulators of energy homeostasis through their effect in thermogenesis, direct regulation of uncoupling proteins and stimulating lipolysis (7). Levels of thyroid hormones drop during fasting, and the normal feedback mechanism is inhibited because pro-TRH expression in the PVN and TSH serum levels are also diminished; injection of leptin restores pro-TRH mRNA levels despite continuation of fast (8). Leptin’s effect on TRH neurons can be mediated by activating POMC/CART or inhibiting NPY/AgRP neurons, but also directly on TRH PVN neurons (5, 8, 9).

How do hypophysiotropic TRH neurons integrate incoming signals? (Fig. 2Go). Do all hypophysiotropic neurons respond to metabolic signals, or are there specialized subpopulations? (See Ref.6 and references therein, and Ref.10 .) A key regulator seems to be {alpha}-MSH, which increases cAMP response element binding protein phosphorylation; this can be inhibited indirectly by NPY, or directly through antagonism of the {alpha}-MSH receptors melanocortin-3 and -4 receptors (MC3-R and MC4-R) by AgRP (see Ref.6 and references therein, and Ref.11). AgRP is involved in mediating the effects of leptin on appetite and satiety, but the specific contribution of MC3-R and MC4-R on TRH expression was uncertain. The work presented by Fekete et al. in this issue (6) provides conclusive evidence for the role of MC4-R as transducers of {alpha}-MSH/AgRP effects in TRH neurons. The authors compared the response to icv injections of AgRP on various parameters reflecting energy metabolism (food intake, body weight, epididymal white fat, brown adipose tissue, serum T4, and pro-TRH mRNA levels in PVN) in wild-type and MC4-R KO mice. Results showed that mutant mice did not respond to AgRP injections, thus proving MC4-R as the important receptor in modulating TRH expression. This complements Dr. Lechan’s group’s significant contributions on the detailed anatomical distribution and characterization of neural afferents impinging on TRH neurons in the PVN and their role in metabolic regulation (Figs. 1Go and 2Go).



View larger version (76K):
[in this window]
[in a new window]
  		FIG. 2. Known modulators of TRH expression in PVN. Signaling molecules known to increase pro-TRH mRNA levels are in black characters; in red, those that inhibit expression (see Ref.6 and references therein) and in blue, those which effects have only been characterized in vitro (14 15 16 17 ). Receptors identified in TRH neurons are in italics. BDNF, Brain-derived neurotropic factor; endocan, endocannabinoids; EGF, epidermal growth factor; gal, galanin; gc, glucocorticoids; GR, glucocorticoid receptor; NE, norepinephrine; P-CREB, phosphorylated cAMP response element binding protein; STAT, signal transducer and activator of transcription; TRß, thyroid hormone receptor ß.

 
The job, however, is not finished. Knockout mice have shown the redundancy of circuits involved in appetite and satiety. Modern societies are burdened not only with obesity but also with stress-related diseases. How do glucocorticoids affect the fine tuning of energy homeostasis? They are known to affect appetite and body weight (12), interact with leptin and insulin-signaling pathways (13), inhibit the thyroid axis, contrarrest the stimulatory effect of increased cAMP levels in TRH transcription (14, 15), and interact with cannabinoid receptors affecting TRH and CRH neurons in the PVN (18). Moreover, subtle changes due to daily stress or feeding times could affect thyroid function, momentarily altering energy expenditure. Furthermore, not only the hedonic aspects of food should be considered (19), but also its quality and the effect of particular micronutrients. For example, in a Mexican semirural population with very low income, more than 50% of women at 30 yr old are overweight, with high incidence of obesity as they get older; many consume at least 50% of daily caloric intake in tortillas that sometimes amount to almost 70% of protein intake (20). Corn is deficient in tryptophan, so the possibility of low serotonin (21) responsible for increased feeding (to achieve adequate levels) is worth considering.


   Footnotes
 
Abbreviations: AgRP, Agouti-related peptide; CART, cocaine- and amphetamine-related transcript; GABA, {gamma}-amino butyric acid; MC3-R and MC4-R, melanocortin-3 and -4 receptors; NPY, neuropeptide Y; POMC, proopiomelanocortin; PVN, paraventricular nucleus.

Received July 28, 2004.

Accepted for publication August 5, 2004.


   References
Top
 References
 

  1. Leibowitz SF, Wortley KE 2004 Hypothalamic control of energy balance: different peptides, different functions. Peptides 25:473–504[CrossRef][Medline]
  2. Sahu A 2004 A hypothalamic role in energy balance with special emphasis on leptin. Endocrinology 145:2613–2620[Abstract/Free Full Text]
  3. Zigman JM, Elmquist JK 2003 From anorexia to obesity—the Yin and Yang of body weight control. Endocrinology 144:3749–3756[Abstract/Free Full Text]
  4. Hillebrand JJG, de Wied D, Adan RAH 2002 Neuropeptides, food intake and body weight regulation: a hypothalamic focus. Peptides 23:2283–2306[CrossRef][Medline]
  5. Flier JS, Harris M, Hollenberg AN 2000 Leptin, nutrition, and the thyroid: the why, the wherefore, and the wiring. J Clin Invest 105:859–861[Medline]
  6. Fekete C, Marks D, Sarkar S, Emerson CH, Rand WH, Cone RD, Lechan R 2004 Effect of agouti-related protein in regulation of the hypothalamic-pituitary-thyroid (HPT) axis in the melanocortin 4 receptor knockout mouse. Endocrinology 145:4816–4821[Abstract/Free Full Text]
  7. Lanni A, Moreno M, Lombardi A, Goglia F 2003 Thyroid hormones and uncoupling proteins. FEBS Lett 543:5–10[CrossRef][Medline]
  8. Legradi G, Emerson CH, Ahima RS, Flier JS, Lechan RM 1997 Leptin prevents fasting-induced suppression of prothyrotropin-releasing hormone messenger ribonucleic acid in neurons of the hypothalamic paraventricular nucleus. Endocrinology 138:2569–2567[Abstract/Free Full Text]
  9. Guo F, Bakal K, Minokoshi Y, Hollenberg AN 2004 Leptin signaling targets the thyrotropin-releasing hormone gene promoter in vivo. Endocrinology 145:2221–2227[Abstract/Free Full Text]
  10. Sánchez E, Uribe RM, Corkidi G, Zoeller RT, Cisneros M, Zacharias M, Morales-Chapa C, Charli C, Joseph-Bravo P 2001 Differential responses of TRH neurons to cold exposure or suckling indicate functional heterogeneity of the TRH system in the PVN of rat hypothalamus. Neuroendocrinology 74:407–422[CrossRef][Medline]
  11. Cowley MA 2003 Hypothalamic melanocortin neurons integrate signals of energy state. Eur J Pharmacol 480:3–11[CrossRef][Medline]
  12. Chrousos GP 2000 The role of stress and the hypothalamic-pituitary-adrenal axis in the pathogenesis of the metabolic syndrome: neuroendocrine and target tissue-related causes. Int J Obes 24(Suppl 2):S50–S55
  13. Wilding JPH 2002 Neuropeptides and appetite control. Diabetes 19:619–627
  14. Pérez-Martínez L, Carreón-Rodríguez A, González-Alzati ME, Morales C, Charli JL, Joseph-Bravo P 1998 Dexamethasone rapidly regulates TRH mRNA levels in hypothalamic cell cultures. Interaction with the cAMP pathway. Neuroendocrinology 68:345–354[CrossRef][Medline]
  15. Cote-Vélez A, Pérez-Martínez L, Díaz-Gallardo MY, Pérez-Monter C, Charli JL, Joseph-Bravo P,Rapid transcriptional regulation of rat TRH gene by cAMP is repressed by dexamethasone in hypothalamic cells. Identification of a composite GRE and a non-canonical CRE in TRH promoter. J Mol Endocrinol, in press
  16. Guerra-Crespo M, Ubieta R, Joseph-Bravo P, Charli JL, Pérez-Martínez L 2001 BDNF increases the early expression of TRH mRNA in fetal TrkB+ hypothalamic neurons in primary culture. Eur J Neurosci 14:483–494[CrossRef][Medline]
  17. Ren Y, Satoh T, Yamada M, Hashimoto K, Konaka S, Iwasaki T, Mori M 1998 Stimulation of the thyrotropin-releasing hormone gene by epidermal growth factor. Endocrinology 139:195–203[Abstract/Free Full Text]
  18. Shi D, Malcher-Lopez, Halmos KC, Tasker JG 2003 Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: a fast feedback mechanism. J Neurosci 23:4850–4857[Abstract/Free Full Text]
  19. Berthoud HR 2004 Mind versus metabolism in the control of food intake and energy balance. Physiol Behav 81:781–793[CrossRef][Medline]
  20. Charli-Joseph L 2004 Análisis del estado nutricio y la conducta alimentaria de mujeres en edad fértil de Ixtenco, Tlaxcala. [Analysis of nutritional state and food behavior in women at reproductive age of Ixtenco, Tlaxcala.] B. Sc. Thesis in Biology, Facultad de Ciencias, Universidad National Autónoma de México
  21. Fernstrom JD 2000 Can nutrient supplements modify brain function? Am J Clin Nutr 71(Suppl):1669S–1673S



This article has been cited by other articles:


Home page
 EndocrinologyHome page
C. T. Phillips and R. D. Palmiter
Role of Agouti-Related Protein-Expressing Neurons in Lactation
Endocrinology, February 1, 2008; 149(2): 544 - 550.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Joseph-Bravo, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Joseph-Bravo, P.

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