Endocrinology Vol. 145, No. 4 1501-1502
Copyright © 2004 by The Endocrine Society
Obesity: The New Worldwide Epidemic Threat to General Health and Our Complete Lack of Effective Treatment
Tina Zimmermann-Belsing and
Ulla Feldt-Rasmussen
Department of Endocrinology, Rigshospitalet University of Copenhagen, DK-2100 Copenhagen, Denmark
Address all correspondence and requests for reprints to: Tina Zimmermann-Belsing, M.D., Ph.D., Department of Endocrinology P-2131, University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. E-mail: tzb{at}dadlnet.dk.
 |
Obesity and Treatment
|
|---|
Obesity has become a worldwide public health problem affecting millions of people. Obesity occurs through a long-standing imbalance between energy intake and energy expenditure, influenced by a complex biologic system that regulates appetite (1). Obesity is a chronic, stigmatized, and costly disease; it is rarely curable and is increasing in prevalence to a point today where we define obesity as an epidemic disease that outnumbers those suffering from hunger. Obesity causes hypertension, type 2 diabetes, dyslipidaemia, kidney disease, and heart disease (1). Until now, the available treatments, including drugs, are palliative and are effective only while the treatment is being actively used; but severe side effects have been registered (2, 3).
|
Leptin
|
|---|
The identification and sequencing of the ob gene and its product, leptin, in 1994 opened new approaches to the study of the mechanisms controlling body weight (4). Since its discovery, leptin has been the subject of enormous numbers of studies, especially within the fields of nutrition, metabolism, and endocrinology (5, 6, 7).
Ghrelin, a stomach-derived orexigenic peptide (8, 9), and leptin, a fat-derived anorexigenic hormone, act primarily in the hypothalamus to regulate energy homeostasis probably independently of each other (9).
|
Proopiomelanocortin (POMC)
|
|---|
POMC is the polypeptide precursor of ACTH hormone. It was first discovered in anterior pituitary corticotroph cells, is necessary for adrenal function and undergoes extensive posttranslational tissue-specific processing (10). POMC expressing neurons in brain are important for the control of pain and energy homeostasis and local production of POMC-derived peptides in skin may influence melanogenesis (10). Thus, POMC is a polypeptide precursor illustrating the many roles of a single gene and its various products in different locations.
The central melanocortin (MC) system is an important mediator of leptin control on energy homeostasis (11). POMC expression in the hypothalamic arcuate nucleus is induced by leptin (Fig. 1
). The precursor is processed by prohormone convertase 1 (PC1) and PC2 into 
MSH, the main agonist of the MC-3-receptor (MC3-R) and MC4-R (11). Disruption of this loop causes obesity in both humans and rodents. Mutations of MC4-R have been demonstrated in up to 5% of severely obese children (12). Overexpression of agouti-related transcript, a naturally occurring MC receptor antagonist acting mostly on MC4-R, results in hyperphagia and late-onset obesity (13). The two receptors are complementary to each other: MC4-R influences food intake and MC3-R regulates fat stores by an exclusively metabolic pathway (14).
The MC system also mediates other hormonal effects of leptin. During fasting, a marked reduction in circulating thyroid hormone and leptin levels is observed (10). MSH may also modulate the hypothalamo-pituitary-thyroid (HPT) axis response to leptin. MSH-producing neurons in the arcuate nucleus, are a target of leptin, and send monosynaptic projections to TRH neurons. Additionally, intraventricular infusion of MSH can completely restore fasting levels of pro-TRH mRNA in the paraventricular nucleus to normal-fed levels (15). On the other hand, alternative pathways to regulation of TRH must exist because MC4-R knockout mice, as wells as subjects with MC4-R deficiency, have normal thyroid function (10). Peripheral factors are also important for regulation of energy balance between the fed and fasting states including both leptin, insulin, thyroid hormones, uncoupling proteins, catecholamine, and heat production (16).
|
HPT Axis and Late-Onset Obesity
|
|---|
Leptin is accepted as an adiposity signal, believed to be involved in addition to thyroid hormones in the regulation of the switch from fed to starved states. It is not clear whether leptin and the MC pathways interact with the thyroid axis under physiologic conditions other than during starvation or in response to severe illness, both states in which the HPT axis may be severely suppressed (16). However, thyroid disease is a risk factor of adult-onset obesity (17). Over 40% of thyrotoxic Graves’ patients were overweight at diagnosis and after at least 6 months of treatment with antithyroid drug therapy 56.2% were overweight and 18.5% obese (17). Two independent variables identified as predicting weight gain were weight loss and a diagnosis of Graves’ disease and iatrogenic hypothyroidism during antithyroid drug treatment (17).
|
Neuronal Basic Helix-Loop-Helix Transcription Factor Family, Nhlh2
|
|---|
In this issue of Endocrinology, Jing et al. (18) studied Nhlh2 using Nhlh2 knockout animals as a model for adult-onset obesity. The phenotype of late-onset obesity in Nhlh2 knockout mice mimics adult-onset obesity in humans. Their results suggest that changes in energy balance either by leptin or other pathways (maybe thyrotoxicosis?) would signal through Nhlh2. In presence of Nhlh2, the increased transcription of PC1 and the increased POMC and prepro-TRH mRNA induced by food intake or circulating leptin, would stimulate processing of newly translated prohormones. Activation of both POMC and TRH signal transduction pathways would then balance energy expenditure with intake. Thus, the study demonstrated that the Nhlh2 transcription factor is expressed regionally in POMC neurons of the arcuate nucleus of the hypothalamus, but absence of Nhlh2 reduces expression of the PC1 and PC2 mRNA, and MSH peptides. In the paraventricular nucleus of the hypothalamus, PC1 and PC2 and both mRNA and peptide for TRH were reduced. Thus, regulation of body weight is linked to the action of Nhlh2 on prohormone convertase mRNA levels, supporting a direct role for transcriptional control of neuropeptide processing enzymes in the etiology of adult-onset obesity also seen in thyroid patients.
|
Perspective
|
|---|
Genes and neural pathways are likely to be important in genesis of human obesity, but they should not detract from the importance of environmental factors. The identification of major and minor genes involved in the etiology and pathogenesis of obesity remains critically important for the immediate future. The paper by Jing et al. (18) in this issue of Endocrinology is a step on the way to understand the complex etiology and pathology of obesity.
|
Footnotes
|
|---|
Abbreviations: HPT, Hypothalamo-pituitary-thyroid; MC, melanocortin; MC3-R and MC4-R, MC-3 and -4 receptor; Nhlhl2, neuronal basic helix-loop-helix transcription factor family; PC1 and PC2, prohormone convertase 1 and 2; POMC, proopiomelanocortin.
Received January 23, 2004.
Accepted for publication January 27, 2004.
|
References
|
|---|
- Kopelman PG 2000 Obesity as a medical problem. Nature 404:635–643[Medline]
- Bray GA, Tartaglia LA 2000 Medicinal strategies in the treatment of obesity. Nature 404:672–677[Medline]
- Proietto J, Thorburn AW 2003 The therapeutic potential of leptin. Expert Opin Investig Drugs 12:373–378[CrossRef][Medline]
- Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM 1994 Positional cloning of the mouse obese gene and its human homologue. Nature [Erratum (1995) 374:479] 372:425–432
- Fruhbeck G, Jebb SA, Prentice AM 1998 Leptin: physiology and pathophysiology. Clin Physiol 18:399–419[CrossRef][Medline]
- Mantzoros CS, Moschos SJ 1998 Leptin: in search of role(s) in human physiology and pathophysiology. Clin Endocrinol (Oxf) 49:551–567[CrossRef][Medline]
- Fruhbeck G 2001 A heliocentric view of leptin. Proc Nutr Soc 60:301–318[Medline]
- Chan JL, Bullen J, Lee JH, Yiannakouris N, Mantzoros CS 2004 Ghrelin levels are not regulated by recombinant leptin administration and/or three days of fasting in healthy subjects. J Clin Endocrinol Metab 89:335–343[Abstract/Free Full Text]
- Williams J, Mobarhan S 2003 A critical interaction: leptin and ghrelin. Nutr Rev 61:391–393[CrossRef][Medline]
- Raffin-Sanson ML, de Keyzer Y, Bertagna X 2003 Proopiomelanocortin, a polypeptide precursor with multiple functions: from physiology to pathological conditions. Eur J Endocrinol 149:79–90[Abstract]
- Cowley MA, Pronchuk N, Fan W, Dinulescu DM, Colmers WF, Cone RD 1999 Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat. Neuron 24:155–163[CrossRef][Medline]
- Vaisse C, Clement K, Durand E, Hercberg S, Guy-Grand B, Froguel P 2000 Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J Clin Invest 106:253–262[Medline]
- Nijenhuis WA, Oosterom J, Adan RA 2001 AgRP(83–132) acts as an inverse agonist on the human-melanocortin-4 receptor. Mol Endocrinol 15:164–171[Abstract/Free Full Text]
- Chen AS, Marsh DJ, Trumbauer ME, Frazier EG, Guan XM, Yu H, Rosenblum CI, Vongs A, Feng Y, Cao L, Metzger JM, Strack AM, Camacho RE, Mellin TN, Nunes CN, Min W, Fisher J, Gopal-Truter S, MacIntyre DE, Chen HY, Van der Ploeg LH 2000 Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nat Genet 26:97–102[CrossRef][Medline]
- Fekete C, Sarkar S, Rand WM, Harney JW, Emerson CH, Bianco AC, Lechan RM 2002 Agouti-related protein (AGRP) has a central inhibitory action on the hypothalamic-pituitary-thyroid (HPT) axis; comparisons between the effect of AGRP and neuropeptide Y on energy homeostasis and the HPT axis. Endocrinology 143:3846–3853[Abstract/Free Full Text]
- Zimmermann-Belsing T, Brabant G, Holst JJ, Feldt-Rasmussen U 2003 Circulating leptin and thyroid dysfunction. Eur J Endocrinol 149:257–271[Abstract]
- Dale J, Daykin J, Holder R, Sheppard MC, Franklyn JA 2001 Weight gain following treatment of hyperthyroidism. Clin Endocrinol (Oxf) 55:233–239[CrossRef][Medline]
- Jing E, Nillni EA, Sanchez VC, Stuart RC, Good DJ 2004 Deletion of the Nhlh2 transcription factor decreases the levels of the anorexigenic peptides of melanocyte-stimulating hormone and thyrotropin-releasing hormone and implicates prohormone convertases I and II in obesity. Endocrinology 145:1503–1513[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
M. Chen, M. Cai, C. J. Aprahamian, K. E. Georgeson, V. Hruby, C. M. Harmon, and Y. Yang
Contribution of the Conserved Amino Acids of the Melanocortin-4 Receptor in D-[Nle4,Phe7]-{alpha}-Melanocyte-stimulating Hormone Binding and Signaling
J. Biol. Chem.,
July 27, 2007;
282(30):
21712 - 21719.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Dey, A. A. Caro, and A. I. Cederbaum
S-adenosyl methionine protects ob/ob mice from CYP2E1-mediated liver injury
Am J Physiol Gastrointest Liver Physiol,
July 1, 2007;
293(1):
G91 - G103.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Yang, M. Chen, K. E. Georgeson, and C. M. Harmon
Mechanism of oleoylethanolamide on fatty acid uptake in small intestine after food intake and body weight reduction
Am J Physiol Regulatory Integrative Comp Physiol,
January 1, 2007;
292(1):
R235 - R241.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. R. Peluso
Flavonoids Attenuate Cardiovascular Disease, Inhibit Phosphodiesterase, and Modulate Lipid Homeostasis in Adipose Tissue and Liver
Experimental Biology and Medicine,
September 1, 2006;
231(8):
1287 - 1299.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Hosaka, T. Watanabe, Y. Sakai, T. Kato, and T. Takeuchi
Interaction between secretogranin III and carboxypeptidase E facilitates prohormone sorting within secretory granules
J. Cell Sci.,
October 15, 2005;
118(20):
4785 - 4795.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Obesity and Treatment
Leptin
