Gastric GDF15 levels are regulated by age, sex, and nutritional status in rodents and humans.

AIM: Growth differentiation factor 15 (GDF15) is a stress response cytokine that has been proposed as a relevant metabolic hormone. Descriptive studies have shown that plasma GDF15 levels are regulated by short term changes in nutritional status, such as fasting, or in obesity. However, few data exist regarding how GDF15 levels are regulated in peripheral tissues. The aim of the present work was to study the variations on gastric levels of GDF15 and its precursor under different physiological conditions, such as short-term changes in nutritional status or overfeeding achieved by HFD. Moreover, we also address the sex- and age-dependent alterations in GDF15 physiology. METHODS: The levels of gastric and plasma GDF15 and its precursor were measured in lean and obese mice, rats and humans by western blot, RT-PCR, ELISA, immunohistochemistry and by an in vitro organ culture system. RESULTS: Our results show a robust regulation of gastric GDF15 production by fasting in rodents. In obesity an increase in GDF15 secretion from the stomach is reflected with an increase in circulating levels of GDF15 in rats and humans. Moreover, gastric GDF15 levels increase with age in both rats and humans. Finally, gastric GDF15 levels display sexual dimorphism, which could explain the difference in circulating GFD15 levels between males and females, observed in both humans and rodents. CONCLUSIONS: Our results provide clear evidence that gastric GDF15 is a critical contributor of circulating GDF15 levels and can explain some of the metabolic effects induced by GDF15.

Secreted factors derived from obese visceral adipose tissue regulate the expression of breast malignant transformation genes.

BACKGROUND/OBJECTIVES: Obese adipose tissue, especially the visceral depot, exhibits altered production of several molecules that could have a role on the initiation/promotion of breast cancer development. The aim of this work was to evaluate the effect of excess adipose tissue and its secreted factors on the expression of genes involved in the early steps of tumor promotion on the mammary gland. SUBJECTS AND METHODS: Carcinogenesis-related gene expression was evaluated in mammary gland tissue from female diet-induced obese (DIO) Sprague-Dawley rats and circulating leukocytes isolated from a group of breast cancer diagnosed and non-diagnosed obese women and compared with their normal weight counterparts. In addition, the human non-tumoral mammary epithelial cell line MCF10A was treated in vitro with the visceral (retroperitoneal adipose tissue (RPAT)) or subcutaneous adipose tissue (SAT) secretome and with rising concentrations of the lipid peroxidation by-product 4-hydroxynonenal (4-HNE). RESULTS: DIO rats were classified as susceptible to DIO (DIO-S) or partially resistant to DIO (DIO-R) according to the maximum fat mass gain of the lean group as a cut-off. As compared with lean and DIO-R, the DIO-S group showed a higher fat mass and lower lean mass. The anatomical characteristic of DIO-S was correlated with differential expression of cellular proliferation (ALDH3A1 and MYC) and antioxidant and DNA protection (GSTM2, SIRT1), and tumor suppression (TP53, PTEN, TGFB1) genes. Remarkably, this carcinogenesis-related gene expression pattern was reproduced in MCF10A treated with the RPAT secretome from DIO-S rats and with the lipid peroxidation by-product 4-HNE. Moreover, this pattern was also detected in leukocytes from obese women compared with normal weight women without evidence of breast cancer. CONCLUSIONS: Lipid peroxides secreted by the obese visceral adipose tissue could be among the relevant factors that promote changes involved in the early steps of tumor development in mammary gland. These changes can be detected even before histological alterations and in circulating leukocytes.

Uroguanylin levels in intestine and plasma are regulated by nutritional status in a leptin-dependent manner.

PURPOSE: Uroguanylin (UGN) is a 16 amino acid peptide produced mainly by intestinal epithelial cells. Nutrients intake increases circulating levels of prouroguanylin that is processed and converted to UGN to activate the guanylyl cyclase 2C receptor (GUCY2C). Given that the UGN-GUCY2C system has been proposed as a novel gut-brain endocrine axis regulating energy balance, the aim of the present study was to investigate the regulation of UGN protein levels in duodenum and circulating levels in lean and obese mice under different nutritional conditions and its potential interaction with leptin. METHODS: Swiss, C57BL/6 wild-type and ob/ob male adult mice under different nutritional conditions were used: fed ad libitum standard diet (control); 48 h fasting (fasted); 48 h fasting followed by 24 h of feeding (refed); and fed high-fat diet (45 %) during 10 weeks. In addition, peripheral leptin administration was performed. Intestinal uroguanylin expression was studied by Western blot analysis; plasma levels were measured by ELISA. RESULTS: Food deprivation significantly reduced plasma UGN levels, which were correlated with the lower protein levels of UGN in duodenum. These effects were reverted after refeeding and leptin challenge. Consistently, in ob/ob mice UGN expression was decreased, whereas leptin treatment up-regulated UGN levels in duodenum in these genetically modified mice compared to WT. Diet-induced obese mice displayed increased UGN levels in intestine and plasma in comparison with lean mice. CONCLUSIONS: Our findings suggest that UGN levels are correlated with energy balance status and that the regulation of UGN by nutritional status is leptin-dependent.

Age, sex, and lactating status regulate ghrelin secretion and GOAT mRNA levels from isolated rat stomach.

Ghrelin is a stomach derivate peptide involved in energy homeostasis regulation, and ghrelin O-acyltransferase (GOAT) is the enzyme responsible for ghrelin acylation. Puberty is a period characterized by profound changes in the metabolic requirements and notable variations of sexual hormone levels. On the other hand, the weaning process is a fundamental modification of the diet, which implicates several adaptations of the gastrointestinal tract physiology. Until now the direct secretion of ghrelin by the stomach in these conditions, without interferences from other organs, has never been studied. The main objective of this article was to investigate how the stomach modulates ghrelin production and secretion as well as GOAT expression on these periods of life. Gastric ghrelin secretion is regulated through postnatal life in an independent way of gastric expression and circulating levels of this hormone. The present work shows a strong regulation of gastric ghrelin secretion by estrogens. The weaning strongly regulates gastric ghrelin secretion. Animals subjected to delayed weaning present a lower body weight than the corresponding controls. For the first time, it is shown that a noticeable decrease in circulating levels of testosterone and estrogens is associated with delay of weaning. GOAT mRNA levels in the stomach are strongly regulated by age, breastfeeding, and testosterone. In conclusion, the stomach itself regulates ghrelin and GOAT production to adapt the organism to the metabolic requirements demanded through each stage of life.

Macronutrients act directly on the stomach to regulate gastric ghrelin release.

BACKGROUND: Ghrelin is a gastric secreted hormone deeply implicated in meal initiation and body weight regulation. This peptide is a peripheral orexigenic hormone with a nutritional status-dependent regulation showing a pre-pandrial rise and post-prandial fall pattern. A wide variety of studies have tested the effect of meal different nutrient composition over stomach mucosa ghrelin content and plasmatic ghrelin levels; nevertheless, few and non-conclusive data exist about the direct action of macronutrients on the stomach in order to regulate ghrelin secretion. The recent identification of taste receptors or chemoreceptors in the stomach mucosa would reinforce this paradigm. AIMS: To investigate the individual effect of different macronutrients (l-glutamine, lipids, and glucose) over gastric ghrelin secretion by using an in vitro gastric explants model. RESULTS: L-glutamine and intralipid emulsion act locally in the stomach decreasing ghrelin secretion, while no effect was found after glucose exposure. CONCLUSIONS: These results show for the first time that macronutrients, and specially amino acids and lipids, act directly in the stomach in order to regulate gastric ghrelin release. Consequently, the chemosensory capacity of the stomach, until now restricted to the oral cavity or intestine, is demonstrated.

Uroguanylin: a new actor in the energy balance movie.

Uroguanylin (UGN) is a potential target in the fight against obesity. The mature protein is released after enzymatic cleavage from its natural precursor, proUGN. UGN is mostly produced in the gut, and its production is regulated by nutritional status. However, UGN is also produced in other tissues such as the kidneys. In the past, UGN has been widely studied as a natriuretic peptide owing to its involvement in several different pathologies such as heart failure, cancer and gastrointestinal diseases. However, recent studies have suggested that UGN also acts as a regulator of body weight homeostasis because it modulates both food intake and energy expenditure. This ultimately results in a decrease in body weight. This action is mediated by the sympathetic nervous system. Future studies should be directed at the potential effects of UGN agonists in regulating body weight in human obesity.

Growth hormone and somatostatin directly inhibit gastric ghrelin secretion. An in vitro organ culture system.

Ghrelin is a 28-amino-acid hormone produced mainly by the stomach which strongly promotes food intake. It is the only known peripheral orexigenic hormone that induces the release of GH. Ghrelin has been proposed as a link between the enteric system and central regulation of energy balance and growth. Although it has recently been the focus of extensive study, the secretion mechanism is not yet well characterized. The aim of this study was to test the direct effect of hormones from the somatotropic axis on ghrelin release directly from the stomach. To this end, an organ culture model of gastric tissue explants from rat donors was used. These stomach explants were incubated in 6 well plates for 1, 2, and 3 h after treatment with either GH, GHRH, SS or IGF-I, all them at 10(-6) M. After incubation, the medium was collected and the amount of ghrelin secreted by the gastric tissue was measured by radioimmunoassay. It was observed that GH and SS significantly decreased gastric ghrelin secretion, while GHRH and IGF-1 had no effect on the present model. These results would confirm the capacity of GH and SS to act directly upon gastric level, inhibiting ghrelin secretion in vitro.

Central obestatin administration does not modify either spontaneous or ghrelin-induced food intake in rats.

The isolation of ghrelin unveiled a new system implicated in food intake regulation. The recently isolated hormone obestatin derives from the same precursor of ghrelin and seems to perform opposite actions. It could be part of a dual system connecting gut and brain to regulate energy homeostasis. The ability of intracerebroventricular administration of obestatin to modify food intake was evaluated. Obestatin had no effect on spontaneous food intake in both ad libitum and food restricted rats. The obestatin injection was not able to antagonize the ghrelin-stimulated increase in food intake either. In conclusion, the present work does not support a role for obestatin on the regulation of food intake in any model studied.

FNDC5 is produced in the stomach and associated to body composition.

The fibronectin type III domain-containing protein 5 (FNDC5) discovered in 2002 has recently gained attention due to its potential role in protecting against obesity. In rat, no data exist regarding FNDC5 production and regulation in the stomach. The aim of the present work was to determine the expression of FNDC5 in the rat stomach and its potential regulation by body composition. The present data shows FNDC5 gene expression in the gastric mucosa. Immunohistochemical studies found FNDC5 immunopositivity in chief cells of gastric tissue. By the use of three different antibodies FNDC5 was found expressed in gastric mucosa and secreted by the stomach. The rate of gastric FNDC5 secretion parallels the circulating levels of FNDC5. The body fat mass increase after intervention with high fat diet coincided with a decrease in the secretion of FNDC5 from the stomach and a diminution in the FNDC5 circulating levels. In summary, the present data shows, for the first time, the expression of FNDC5 in the stomach of rats and its regulation by body composition, suggesting a potential role of gastric FNDC5 in energy homeostasis.

Hypothalamic levels of NPY, MCH, and prepro-orexin mRNA during pregnancy and lactation in the rat: role of prolactin.

Pregnancy and lactation provide excellent models of physiological hyperphagia and hyperprolactinemia. To identify possible factors associated with the increased feeding in these situations, we measured hypothalamic mRNA levels of three orexigenic neuropeptides--NPY, MCH, and orexins--in nonpregnant, pregnant, and lactating rats by in situ hybridization. NPY mRNA content in the arcuate nucleus was significantly increased during pregnancy and lactation. However, MCH and prepro-orexin expression was decreased in both states. 48 or 72 h of fasting in pregnant and lactating rats further elevated NPY mRNA levels and increased the low MCH mRNA content. Surprisingly, no effect was observed in prepro-orexin mRNA levels. Finally, we investigated the possible effect of high PRL levels on these orexigenic signals using a model of hyperprolactinemia induced by pituitary graft. NPY mRNA content was unchanged, but MCH and prepro-orexin mRNA levels were significantly decreased. Our results suggest that the increased NPY expression might be partly responsible for the hyperphagia observed during pregnancy and lactation. MCH and prepro-orexin may be involved in the adaptation of other homeostatic mechanisms and their decreased levels in these physiological settings could be mediated by the elevated circulating PRL levels.

Cellular distribution and regulation of ghrelin messenger ribonucleic acid in the rat pituitary gland.

Ghrelin, a 28-amino-acid acylated peptide, strongly stimulates GH release and food intake. In the present study, we found that ghrelin is expressed in somatotrophs, lactotrophs, and thyrotrophs but not in corticotrophs or gonadotrophs of rat pituitary. Persistent expression of the ghrelin gene is found during postnatal development in male and female rats, although the levels significantly decrease in both cases from pituitaries of 20-d-old rats onward, but at 60 d old, the levels were higher in male than female rats. This sexually dimorphic pattern appears to be mediated by estrogens because ovariectomy, but not orchidectomy, increases pituitary ghrelin mRNA levels. Taking into account that somatotroph cell function is markedly influenced by thyroid hormones, glucocorticoids, GH, and metabolic status, we also assessed such influence. We found that ghrelin mRNA levels decrease in hypothyroid- and glucocorticoid-treated rats, increase in GH-deficient rats (dwarf rats), and remain unaffected by food deprivation. In conclusion, we have defined the specific cell types that express ghrelin in the rat anterior pituitary gland. These data provide direct morphological evidence that ghrelin may well be acting in a paracrine-like fashion in the regulation of anterior pituitary cell function. In addition, we clearly demonstrate that pituitary ghrelin mRNA levels are age and gender dependent. Finally, we show that pituitary ghrelin mRNA levels are influenced by alteration on thyroid hormone, glucocorticoids, and GH levels but not by fasting, which indicates that the regulation of ghrelin gene expression is tissue specific.

Influence of thyroid status and growth hormone deficiency on ghrelin.

OBJECTIVE: To assess whether some of the alterations in energy homeostasis present in thyroid function disorders and GH deficiency could be mediated by ghrelin. DESIGN: To assess the influence of thyroid status on ghrelin, adult male Sprague-Dawley rats were treated with vehicle (euthyroid), amino-triazole (hypothyroid) or l-thyroxine (hyperthyroid). The influence of GH on ghrelin was assessed in wild-type (control) and GH-deficient (dwarf) Lewis rats. Evaluation of gastric ghrelin mRNA expression in the stomach was carried out by Northern blot. Circulating levels of ghrelin were measured by radioimmunoassay. RESULTS: Hypothyroidism resulted in an increase in gastric ghrelin mRNA levels (euthyroid: 100+/-3.2% vs hypothyroid: 127.3+/-6.5%; P<0.01), being decreased in hyperthyroid rats (70+/-5.4%; P<0.01). In keeping with these results, circulating plasma ghrelin levels were increased in hypothyroid (euthyroid: 124+/-11 pg/ml vs hypothyroid: 262+/-39 pg/ml; P<0.01) and decreased in hyperthyroid rats (75+/-6 pg/ml; P<0.01). Using an experimental model of GH deficiency, namely the dwarf rat, we found a decrease in gastric ghrelin mRNA levels (controls: 100+/-6% vs dwarf: 66+/-5.5%; P<0.01) and circulating plasma ghrelin levels (controls: 124+/-12 pg/ml vs dwarf: 81+/-7 pg/ml; P<0.01). CONCLUSION: This study provides the first evidence that ghrelin gene expression is influenced by thyroid hormones and GH status and provides further evidence that ghrelin may play an important role in the alteration of energy homeostasis and body weight present in these pathophysiological states.

Ghrelin elicits a marked stimulatory effect on GH secretion in freely-moving rats.

Ghrelin is a growth hormone-releasing acylated peptide from stomach. The purified peptide consist of 28 amino acids in which the serine 3 residue is n-octanoylated. Ghrelin has been reported to increase in vitro GH secretion as well as in vivo plasma GH levels in pentobarbital anaesthetized rats. The aim of this work was to characterize the stimulatory effect of Ghrelin on in vivo GH secretion in freely-moving rats. Furthermore, we compare the effect of Ghrelin with GHRH. In addition to vehicle, we administered different doses of Ghrelin (3 nmol/Kg, 12 nmol/Kg and 60 nmol/Kg); GHRH (3 nmol/Kg and 12 nmol/kg). Plasma GH levels were measured in blood samples taken at 5, 10, 15, 20, 30 and 45 min after their administration as an i.v. bolus at 0 min. Administration of Ghrelin led to an increase in plasma GH levels at all time-points tested (5, 10, 15, 20 and 30 min, P<0.01; and 45 min, P<0.05) in comparison to control untreated rats. A maximal stimulatory effect on plasma GH was observed following administration of 12 nmol/Kg of Ghrelin, the effect being similar to the one obtained with 60 nmol/Kg in terms of both AUC and mean peak GH levels. At the dose of 3 nmol/Kg GHRH and Ghrelin exhibited a similar stimulatory effect in term of both, AUC and mean peak GH levels. However following administration of a dose of 12 nmol/Kg, the effect of Ghrelin was much greater than the same dose of GHRH in terms of both AUC and mean peak GH levels. In summary, this study provides the first evidences that Ghrelin exert a marked stimulatory effect in plasma GH levels in freely-moving rats and provides further evidences that Ghrelin may play an important role in the physiological control of GH secretion.

Leptin increases in vivo GH responses to GHRH and GH-releasing peptide-6 in food-deprived rats.

BACKGROUND: Leptin has recently been shown to have a stimulatory effect on basal GH secretion. However, the mechanisms by which leptin exert this effect are not yet clear. GHRH and GH-releasing peptide (GHRP)-6 are the two most potent GH secretagogues described to date. OBJECTIVE: To determine if leptin could also enhance in vivo GH responses to a maximal dose of GHRH. DESIGN: Leptin (10microg i.c.v.) or vehicle was administered at random before GHRH (10microg/kg i,v.) or GHRP-6 (50microg/kg i.v.), to freely-moving rats with food available ad libitum and to (48h) food-deprived rats. METHODS: Leptin and GH concentrations were measured by radioimmunoassay. Comparison between the different groups was assessed by the Mann-Whitney test. RESULTS: In comparison with fed rats, food-deprived rats showed a marked decrease in GH responses to GHRH as assessed by the area under the curve (5492+/-190ng/ml in fed rats and 1940+/-128ng/ml in fasted rats; P<0.05) and GHRP-6 (3695+/-450 in fed rats and 1432+/-229 in fasted rats; P<0.05). In comparison with its effects in vehicle-treated rats, leptin administered to food-deprived rats markedly increased GH responses to both GHRH (6625+/-613ng/ml; P<0.05) and GHRP-6 (5862+/-441ng/ml; P<0.05). CONCLUSIONS: These data suggest that the blunted GH response to GHRH and GHRP-6 in food-deprived rats is a functional and reversible state, and that the decreased leptin concentrations could be the primary defect responsible for the altered GH secretion in food-deprived rats.

Regulation of serum leptin levels by gonadal function in rats.

The aim of this study was to investigate the regulation of serum leptin levels by gender and gonadal steroid milieu. Thus, we measured serum leptin levels by radioimmunoassay in (a) intact male and female rats, (b) female rats at different stages of the estrous cycle and (c) ovariectomized or orchidectomized rats. Gonadectomized groups were or were not implanted with silastic capsules (10 or 30 mm in length, 1.519mm internal diameter; 3.06 mm external diameter) containing estradiol or testosterone and decapitated two weeks later. We found (i) intact female rats weighing 50 g, 250 g and 300 g exhibited higher serum leptin concentrations than intact male rats of similar body weight; (ii) leptin concentrations were not affected by the phase of the estrous cycle; (iii) two weeks after gonadectomy serum leptin concentrations increased in both male (from 4.47+/-1.87 to 8.76+/-1.24 ng/ml) and female (from 1.97+/-0.46 to 5.29+/-0.51 ng/ml) rats. The ovariectomy-induced increase in serum leptin levels was not dependent, at least completely, on changes in body weight since it could be observed when comparisons were made between ovariectomized rats and intact rats in estrus matched for body weight. In contrast the effect of orchidectomy on serum leptin levels appears to be dependent on changes in body weight since it was no longer observed when comparisons were made with a group of intact male rats matched for body weight. In conclusion, these results suggest that serum leptin concentrations are controlled by gonadal function either directly or as a consequence of changes in body weight.

Orexin A suppresses in vivo GH secretion.

BACKGROUND/AIMS: Orexins (OXs) are a newly described family of hypothalamic neuropeptides. Based on the distribution of OX neurons and their receptors in the brain, it has been postulated that they could play a role in the regulation of neuroendocrine function. GH secretion is markedly influenced by nutritional status and body weight. To investigate the role OX-A plays in the neuroregulation of GH secretion we have studied its effect on spontaneous GH secretion as well as GH responses to GHRH and ghrelin in freely moving rats. Finally, we also assessed the effect of OX-A on in vitro GH secretion. METHODS: We administered OX-A (10 microg, i.c.v.) or vehicle (10 microl, i.c.v.) to freely moving rats. Spontaneous GH secretion was assessed over 6 h with blood samples taken every 15 min. RESULTS: Administration of OX-A led to a decrease in spontaneous GH secretion in comparison with vehicle-treated rats, as assessed by mean GH levels (means+/-s.e.m. 4.2+/-1.7 ng/ml vs 9.4+/-2.2 ng/ml; P<0.05), mean GH amplitude (3.6+/-0.5 ng/ml vs 20.8+/-5.6 ng/ml; P<0.01) and area under the curve (848+/-379 ng/ml per 4 h vs 1957+/-458 ng/ml per 4 h; P<0.05). In contrast, OX-A failed to modify in vivo GH responses to GHRH (10 microg/kg, i.v.) although it markedly blunted GH responses to ghrelin (40 microg/kg, i.v.) (mean peak GH levels: 331+/-71 ng/ml, vehicle, vs 43+/-11 ng/ml in OX-A-treated rats; P<0.01). Finally, OX-A infusion (10(-7), 10(-8) or 10(-9) M) failed to modify in vitro basal GH secretion or GH responses to GHRH, ghrelin and KCl. CONCLUSIONS: These data indicate that OX-A plays an inhibitory role in GH secretion and may act as a bridge among the regulatory signals that are involved in the control of growth, nutritional status and sleep regulation.

Regulation of in vivo TSH secretion by leptin.

Leptin, the product of the ob gene, is a hormone secreted by adipocytes that regulates food intake and energy expenditure. The hypothalamus-pituitary-thyroid axis is markedly influenced by the metabolic status, being suppressed during food deprivation. The aim of the present study was to assess whether leptin can act as a metabolic signal connecting the adipose tissue with the pituitary-thyroid axis. We studied the effect of leptin administration (10 microg, i.c.v.) on spontaneous TSH secretion and TSH responses to TRH in euthyroid and hypothyroid food-deprived rats. Spontaneous TSH secretion was assessed over 6 h with samples taken every 7 min. Administration of leptin to food-deprived euthyroid rats led to a reversal of the inhibitory effect exerted by fasting on spontaneous TSH secretion. This stimulatory effect of leptin on spontaneous TSH appears to be dependent on the thyroid status since it could not be observed in hypothyroid rats. This data suggests that blunted spontaneous TSH secretion in food-deprived rats is a functional and reversible state, and that the decreased leptin concentrations could be the primary event responsible for the suppression of the hypothalamic-pituitary-thyroid-axis in food-deprived rats.

[Role of ghrelin in the pathophysiology of eating behaviour]. / Papel de la ghrelina en la fisiopatología del comportamiento alimentario.

Ghrelin, the endogenous ligand for GHS-R, was isolated from rat stomach, although other tissues exist expressing ghrelin, such as pituitary, hypothalamus, placent, ovary, testes, etc. It was showed that ghrelin is implicated in GH secretion, in vivo and in vitro. There are direct evidences that proof that ghrelin administration induces GH secretion. There are in vivo data, showing ghrelin as a most potent GH secretor than GHRH. Evidences exist of ghrelin actions in the regulation of food intake and energy homeostasis. Ghrelin has a clear role in the differents pathologies such as obesity, anorexia and bulimia.

The brain-stomach connection.

The stomach-brain connection has been revealed to be one of the most promising targets in treating obesity. The stomach plays a key role in the homeostatic mechanism implicating stomach-brain communication regulated under neural and hormonal control. The present review explores specific topics related to gut-brain interactions focus on the stomach-brain connection through the different known systems implied in energy balance control as ghrelin, and nesfatin. Moreover, novel mechanisms for energy balance regulation involving gastric-brain communication are described including the role of the gastric intracellular mTOR/S6K1 pathway mediating the interaction among ghrelin, nesfatin and endocannabinoid gastric systems to modulate metabolism.

Drug development strategies for the treatment of obesity: how to ensure efficacy, safety, and sustainable weight loss.

The prevalence of obesity has increased worldwide, and approximately 25%-35% of the adult population is obese in some countries. The excess of body fat is associated with adverse health consequences. Considering the limited efficacy of diet and exercise in the current obese population and the use of bariatric surgery only for morbid obesity, it appears that drug therapy is the only available method to address the problem on a large scale. Currently, pharmacological obesity treatment options are limited. However, new antiobesity drugs acting through central nervous system pathways or the peripheral adiposity signals and gastrointestinal tract are under clinical development. One of the most promising approaches is the use of peptides that influence the peripheral satiety signals and brain-gut axis such as GLP-1 analogs. However, considering that any antiobesity drug may affect one or several of the systems that control food intake and energy expenditure, it is unlikely that a single pharmacological agent will be effective as a striking obesity treatment. Thus, future strategies to treat obesity will need to be directed at sustainable weight loss to ensure maximal safety. This strategy will probably require the coadministration of medications that act through different mechanisms.