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REVIEW ARTICLE Roles of Gastrointestinal and in Childhood and Changes After Weight Loss Due to Lifestyle Intervention

Christian L. Roth, MD; Thomas Reinehr, MD

hildhood obesity is a global epidemic and associated with an increased risk of hyper- tension, mellitus, and coronary disease, in addition to psychological disorders. Interventions such as bariatric surgery are highly invasive and lifestyle modi- fications are often unsuccessful because of disturbed perceptions of satiety. New sig- nalingC peptides discovered in recent years that are produced in peripheral tissues such as the gut, adipose tissue, and communicate with centers of energy homeostasis, such as the and hindbrain. This review discusses the major known gut- and adipose tissue– derived involved in the regulation of food intake and energy homeostasis and their se- rum levels in childhood obesity before and after weight loss as well as their relationship to conse- quences of obesity. Since most of the changes of gastrointestinal hormones and normalize in weight loss, pharmacological interventions based on these hormones will likely not solve the obesity epidemic in childhood. However, a better understanding of the pathways of body weight– and food intake–regulating gut- and adipose tissue–derived hormones will help to find new strat- egies to treat obesity and its consequences. Arch Pediatr Adolesc Med. 2010;164(2):131-138

Research on energy homeostasis regula- complex, overlapping mechanisms of en- tion in children is increasingly important ergy intake and storage. These mecha- as obesity is the most important risk fac- nisms evolved during long periods of hun- tor for the development of the metabolic ger in the evolution of man to protect the syndrome and mellitus species from extinction. However, to- (T2DM) in youth, and the rise in child- day’s modern sedentary lifestyle has turned hood obesity and childhood T2DM are this evolutionary advantage of storing en- nearly statistically parallel.1 In 2006, the ergy as fat into a high risk of cardiovas- prevalence of obesity in US children cular morbidity and mortality. To com- reached 17%, and if current trends con- plicate matters, although body weight is tinue, childhood obesity may reach 20% precisely regulated, long-term nutrient ex- by 2010.2 Pediatric endocrinology is ex- cess may change set points of the body en- periencing a wave of newly identified sig- ergy balance including the gut-brain and naling peptides illuminating the gut- the adipose tissue–brain axes. In cases of brain axis regulating the body’s energy obesity, this appears to make it even more balance, or more thoroughly described as difficult to reduce overweight, as active the gut–central and peripheral nervous sys- species-protecting defense mechanisms tems–accessory organ (eg, pancreas, ) maintain an elevated level of body fat. axis. Gut hormones (enterokines) and adi- Understanding the changes that occur in pose tissue–derived signaling molecules the particular regulators of homeostasis— (adipokines) interact with brain centers in hormones and peptides—relative to the Author Affiliations: Seattle Children’s Research Institute, Seattle, Washington timing and method of weight reduction in (Dr Roth); and Vestische Hospital for Children and Adolescents Datteln, Institute overweight children is fundamental to un- for Pediatric Nutrition Medicine, University of Witten/Herdecke, Datteln, Germany derstanding pediatric obesity. We exam- (Dr Reinehr). ined these homeostatic regulators before and

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 after weight reduction in a 1-year lifestyle intervention deficiency in Prader-Willi syndrome may be re- “Obeldicks.”3,4 Briefly, this program is based on physical lated to dysregulation, as high circulating levels exercise (1 year), nutrition education and behavior therapy of ghrelin have been observed in this disorder.35 Less clear for children and parents separately (first 3 months), and is why serum ghrelin levels are decreased in nonsyn- individual psychological care of the child and his or her dromic simple obesity, which may be due to overfeed- family (months 4-9). The exercise therapy consists of sports, ing and a consequence of metabolic changes associated instruction in physical exercise as part of everyday life, and with obesity, such as resistance.12,13,36-38 reduction of the amount of time spent watching televi- Important clues about why some children and not oth- sion. The nutritional course is based on the prevention con- ers are successful in maintaining long-term weight loss cept of the “optimized mixed diet,” which is both fat and have been shown in recent studies. Specifically, in- reduced containing 30% energy intake fat, 15% en- creased ghrelin levels during weight reduction are con- ergy intake proteins, and 55% energy intake carbohy- sidered to be a compensatory mechanism responsible for drates including 5% energy intake sugar.4 This lifestyle in- making weight reduction unsustainable.39 Krohn et al11 tervention was effective to reduce overweight over a period showed that the increase of ghrelin levels after weight of at least 3 years after intervention and improved cardio- loss in obese children is correlated with an increase in vascular risk factors such as dyslipidemia, impaired glu- insulin sensitivity. In a Spanish study of obese children cose tolerance, and hypertension.3,4 Furthermore, the intima- on a calorie-restricted diet, ghrelin levels increased sig- media thickness5 as a predictor of early cardiovascular nificantly after 3 months of successful weight reduc- changes was reduced in children who participated in this tion.13 In the Obeldicks lifestyle intervention, we found intervention. All these findings proved the clinical rel- no significant changes in ghrelin levels in the children evance of the achieved weight loss. who achieved substantial weight reduction.12 A slow re- This article will discuss the major known gut- and adi- duction of weight that does not cause an immediate com- pose tissue–derived peptides involved in the regulation pensatory increase of ghrelin may help stabilize and main- of food intake and energy homeostasis, including changes tain a lower body weight and prevent a fast regain of in some of these signaling molecules observed during weight due to an increase of ghrelin. These are encour- weight gain and loss in obese children participating in aging results because ghrelin is the only known circu- lifestyle interventions, and describe clues that may be help- lating .7,33,34 ful in both short-term and long-term management and is a recently identified derived from treatment of childhood obesity. the same (preproghrelin) as ghrelin and has the op- posite effect on weight status, inhibiting food intake and MODULATORS OF HUNGER AND SATIETY gastrointestinal motility. Obestatin is postulated to antago- FROM THE PERIPHERY (GASTROINTESTINAL nize ghrelin’s actions on homeostasis and gastrointestinal TRACT AND ADIPOSE TISSUE) function.40 Because obestatin and ghrelin are both derived from the same gene,40 one study hypothesized a possible The discovery of the adipose tissue–derived hormone lep- cause of obesity to be an imbalance of circulating obestatin tin in 1994 elucidated an important negative feedback and ghrelin levels.41 Preprandial ghrelin to obestatin ra- mechanism of energy balance and how information about tios were elevated in obese subjects compared with con- energy stores is conveyed to the central nervous system. trols, suggesting that a higher ratio may be involved in the This and other feedback mechanisms of energy metabo- etiology and pathophysiology of obesity; however, results lism have been intensively studied in rodent models. They from other studies are not conclusive.42-44 demonstrate that peptides produced in the periphery, such A short-term summer camp weight reduction study as adipose tissue hormones (, , adiponec- of 46 obese children demonstrated increased ghrelin and tin, visfatin, retinol-binding protein 4) and appetite- obestatin levels and ghrelin to obestatin ratios after weight restraining hormones from the gastrointestinal tract (pep- reduction.42 In Obeldicks, obestatin levels increased sig- tide tyrosine-tyrosine [PYY], -like peptide 1 nificantly after weight reduction while ghrelin levels did [GLP-1], , ) and pan- not change significantly, a pattern that may be impor- creas (insulin, [PP], ), as tant to stabilize the lower body weight and prevent re- well as the hunger-mediating hormone ghrelin, are im- currence of weight gain.38 portant afferent signals that bind to receptors in the hy- Peptide YY is a 36– peptide originally isolated pothalamus and hindbrain (Figure).6-9 and characterized in 198045 (Table). There are 2 endogenous forms, PYY1-36 and PYY3-36, abundant in humans. Peptide YY Gastrointestinal Peptides is a gut-derived hormone released postprandially by the L cells of the lower intestine that inhibits gastric acid secre- Ghrelin is a peptide containing 28 amino acids and was tion and motility through neural pathways.46-50 Peptide YY identified in 1999 as a ligand for the of growth belongs to the family of peptides that includes neuropep- hormone secretagogue receptor10 (Table). Ghrelin is pro- tide Y and PP, which mediate their effects via G protein– duced principally by the and, to a lesser extent, coupled Y2, Y4, Y5, and Y6 receptors and dis- 32 51 the and is the only known circulating orexi- play different tissue distributions and functions. PYY1-36 gen. Endogenous levels of ghrelin increase before meals bindstoallknownYreceptorsubtypes,whereasPYY3-36 shows and decrease after food intake, suggesting its role in both affinity for the Y1 and Y5 subtypes and high affin- 7,33,34 meal initiation and weight gain. It has been postu- ity for the inhibitory Y2 receptor subtype. PYY3-36 binding lated that both the hyperphagia and potentially the growth to the Y2 receptor subtype inhibits the orexigenic neuropep-

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Behavior, food reward: - Higher cortical regions - Midbrain/limbic system Hormonal and metabolic signals: - Hypothalamus - Hindbrain

Sympathetic Leptin

PP Amylin Ghrelin Insulin

Adipose tissue Vagus nerve Long-term signals PYY CCK GLP-1 OXM Pancreas GI tract Short-term signals

Figure. Peripheral regulators and important brain areas of energy homeostasis. Long-term regulators are adipose tissue–derived food intake–inhibiting hormones leptin and adiponectin, whereas hormones produced in the gastrointestinal (GI) tract and pancreas are short-term food intake–inhibiting (peptide tyrosine-tyrosine [PYY], glucagon-like peptide 1 [GLP-1], oxyntomodulin [OXM], cholecystokinin [CCK], pancreatic polypeptide [PP], amylin) or stimulating (ghrelin) signals. Intact lines connect to the hypothalamus (pink); dashed lines, to the hindbrain (blue, solitary tract nucleus).

tide Y in the hypothalamus, causing short-term inhibition Glucagon-like peptide 1 is a gut hormone synthe- of food intake, especially high-fat meals.8,52-54 Studies in ro- sized from enteroendocrine L cells of the small and large dents identified the hypothalamus, vagus, and brainstem intestine and secreted in 2 major molecular forms, 55 regions as sites of action. Functional magnetic resonance GLP-17-36 amide and GLP-17-37, with equipotent biologi- imaging of normal-weight humans infused with PYY3-36 to cal activity (Table). Glucagon-like peptide 1 binds re- circulating concentrations similar to those observed post- ceptors in key appetite-related sites in the hypothala- prandially showed modulated neuronal activity within the mus (eg, arcuate and dorsomedial nuclei) and the hypothalamus, brainstem, and midbrain regions involved brainstem (specifically the nucleus of the solitary 56 15,61,62 in food reward processing. This suggests that PYY3-36 af- tract). It is the most potent insulin-stimulating hor- fects feeding by action on homeostatic and hedonic brain mone known to date, it suppresses glucagon secretion, circuits. Peptide YY may also affect energy expenditure.57 and it inhibits gastric emptying and acid secretion. In obese Among other studies confirming this effect,58,59 peripheral children, an attenuated GLP-1 response may contribute 61-63 infusion of PYY3-36 in humans showed increased energy ex- to impaired insulin response, leading to T2DM. Glu- penditure and fat oxidation rates.60 cagon-like peptide 1 may also reduce energy intake and In obese children, levels of the anorexigenic hormone enhance satiety, likely through the aforementioned de- PYY are low. After efficient weight loss in Obeldicks, PYY lay of gastric emptying and specific GLP-1 receptors in levels significantly increased, reaching levels comparable the central nervous system. Its role in childhood obesity with normal-weight individuals.14 Once effective weight loss is poorly understood, with contradictory post–weight loss has been achieved, the effect of PYY may help sta- level changes reported in the literature.15-18,61-68 bilize weight and thereby prevent later weight gain in pa- Obese children participating in Obeldicks showed sig- tients whose PYY levels increased to normal levels. nificant decreases in GLP-1 levels. At baseline, GLP-1 lev-

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Table. Effects of Different Gut and Adipose Tissue Hormones on Food Intake and Their Changes in Childhood Obesity and After Weight Loss

Postmeal Changes in Childhood Changes Effect on Changes Obesity (Serum Levels After Weight Source Hormone Food Intake vs Fasting Compared With Lean) Loss Reference GI tract Ghrelin Orexigen Decreased Decreased Increase or Krohn et al,11 Reinehr et al,12 and stable Soriano-Guille´n et al13 PYY Anorexigen, meal Increased Decreased Increase Roth et al14 termination GLP-1 Anorexigen, insulin Increased Unchanged Controversial Bloom et al,15 Reinehr et al,16 stimulating Verdich et al,17 and Adam et al18 OXM Anorexigen Increased NA NA Cohen et al19 and Murphy et al20 CCK Anorexigen, meal Increased NA NA Smith and Gibbs21 termination, inhibition of gastric emptying Pancreas Insulin Anorexigen, Increased Increased Decrease Savoye et al,22 Reinehr et al,23 and homeostasis Lustig et al24 PP Anorexigen Increased Decreased Increase Reinehr et al25 Amylin Anorexigen, inhibition NA Increased Decrease Reinehr et al26 and Kahn et al27 of gastric emptying, reduction of meal size Adipose Leptin Anorexigen Increased (after Increased Decrease Lustig et al,24 Laimer et al,28 and tissue hours) Reinehr et al29 Adiponectin Anorexigen NA Decreased Increase Reinehr et al30 and Jeffery et al31

Abbreviations: CCK, cholecystokinin; GI, gastrointestinal; GLP-1, glucagon-like peptide 1; NA, not available; OXM, oxyntomodulin; PP, pancreatic polypeptide; PYY, peptide tyrosine-tyrosine.

els did not differ significantly between obese and lean chil- dents, it was proven that insulin administered intracere- dren. The glucose levels remained static and the decreases broventricularly inhibits food intake by activation of the in GLP-1 levels were significantly correlated with de- substrate–phosphatidylinositol 3-kinase creases in insulin levels and index scores.16 (IRS-PI3K) pathway in ventromedial neurons of the hy- Oxyntomodulin is a 37–amino acid peptide that, like pothalamus.69,70 Numerous insulin knockout models show GLP-1, is a product of the preproglucagon gene (Table). that decreased central insulin effect leads to the obese phe- It is released into the circulation system postprandially notype. Most recent research results show that central in- and when administered either centrally or peripherally sulin resistance can be caused by hypothalamic inflamma- in rodent models or peripherally in humans reduces food tion due to nutrient excess,71 causing reduced IRS-PI3K intake.19 Oxyntomodulin is equally effective as GLP-1 at signaling, which thereby contributes to increased appetite inhibiting food intake even though it is thought to do so and the maintenance of elevated body weight.72 In child- through a different pathway. hood obesity, increased insulin levels indicate pe- Cholecystokinin was the first gut hormone impli- ripheral and central insulin resistance. Successful reduc- cated in the control of appetite by reducing food in- tion of overweight leads to reduction of take.21 Cholecystokinin is a meal termination signal re- and improved insulin sensitivity.22,23 leased postprandially from the gastrointestinal tract Pancreatic polypeptide is a 36–amino acid peptide pro- (mostly upper small intestine), reducing both meal size duced under vagal control by peripheral cells of the en- and meal duration. After eating, cholecystokinin levels docrine , and to a lesser extent in the exo- remain elevated up to 5 hours and stimulate gall blad- crine pancreas, colon, and rectum, in response to a meal der contraction, pancreatic enzyme release, and intesti- and insulin-induced hypoglycemia (Table).47,73 Admin- nal motility, which in turn affect gastric emptying. The istration of pharmacological doses of PP in humans de- 74 alimentary , CCKA, is present on creases food intake for 24 hours and inhibits the gas- the vagus nerve, enteric neurons, brainstem, and dorso- tric emptying rate, exocrine pancreatic secretion, and medial nucleus of the hypothalamus. Cholecystokinin gallbladder motility.75 likely mediates its effect on appetite regulation by cross- Changes in PP levels and their relation to the anorexi- ing the blood-brain barrier where it acts on receptors in genic hormones insulin and leptin were studied in Obel- the dorsomedial nucleus of the hypothalamus to reduce dicks.25 At baseline, obese subjects had lower PP con- levels of , a potent appetite-stimulating centrations compared with lean controls.25 Following peptide. However, studies in children are missing so far. lifestyle intervention, PP concentrations significantly in- creased and tended to normalize in the children who Pancreatic Hormones and Peptides achieved substantial weight loss in comparison with chil- dren who did not lose weight.25 Yet, the changes in PP Insulin plays an extremely important role in energy ho- concentrations did not significantly correlate to changes meostasis (Table). Insulin receptors are expressed in dif- of insulin and leptin concentrations.25 ferent hypothalamic nuclei. After passing the blood-brain Amylin is a 37–amino acid polypeptide synthesized and barrier, insulin exerts appetite-inhibiting effects. In ro- released together with insulin by the pancreatic beta cells

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 in response to nutritional input and contributes to glyce- soluble receptor concentrations in obese children in- mic and appetite control (Table).26,76 Amylin is a satiety pep- crease after weight loss.29 tide, causing a reduction of the meal size and inhibition of Adiponectin is synthesized and secreted exclusively by gastric emptying. In addition, depositions that have adipose tissue (Table). It exerts anti-inflammatory effects been detected in pancreatic islets of T2DM play a central and appetite-restraining effects and counters insulin resis- role in the development of beta-cell failure in T2DM.27 tance, thereby offering protective mechanisms against the In obese children, amylin levels were significantly higher development of both T2DM and cardiovascular disease.82 as compared with lean controls.26 Substantial weight loss Adiponectin also affects thermogenesis and adiponectin re- in Obeldicks led to a significant decrease of amylin con- ceptors are expressed in various peripheral tissues, includ- centrations.26 Moreover, the increase of amylin levels in ing muscle, liver, and hypothalamus.85,86 The central ap- childhood was related to hypersecretion of insulin.26 petite-adjusting mechanisms of adiponectin are not yet fully understood. Interestingly, adiponectin levels are reduced Hormones Secreted by Adipose Tissue and Cytokines in states of obesity and T2DM.30,31 Adiponectin has anti- inflammatory properties and negatively correlates with cyto- Adipose tissue is not only important in energy storage, but kine levels and insulin resistance. Low adiponectin levels it is also very active in producing hormones and cytokines might play a role in the development of the metabolic syn- (adipokines), which play a role in the pathogenesis of obe- drome and cardiovascular disease.30,31 sity-associated illnesses. Proinflammatory adipokines pro- In Obeldicks, adiponectin levels significantly in- duced in adipose tissue are leptin, resistin, plasminogen ac- creased and insulin resistance significantly improved in tivator inhibitor-1, , and a parallel manner in the children who lost weight.30 In ␣. Several studies demonstrated higher levels of inflam- an even more recent study, Jeffery et al31 also studied this matory markers in obese children than in normal-weight negative correlation of adiponectin levels in obese chil- children77-81 and some of these could be normalized by life- dren and its role in mediating cardiovascular disease in style intervention.77 Adipokines are a possible link be- children. They found clear links between adiponectin and tween insulin resistance and adiposity. The production of features of the . interleukin 6 leads to the increase of C-reactive protein, Resistin is another hormone secreted by adipose tis- which represents a cardiovascular risk factor.82 sue and is involved in insulin sensitivity. It has been shown Leptin is a 167–amino acid peptide formed in adipose to modulate both glucose tolerance and lipid metabo- tissue, forwarding information regarding energy supply and lism in vivo and in vitro.87 Although some data are con- peripheral energy storage in adipose tissue to the brain, spe- tradictory, it seems that insulin might inhibit resistin se- cifically the hypothalamus (Table). Leptin production is cretion; however, recent animal models show that insulin stimulated by insulin and glucocorticoids. The leptin re- is not the major regulator of resistin.88 ceptor is a single-transmembrane domain receptor of the Two longitudinal adult analyses reported serum resistin family, which activates Januskinase2 in changes to be positively correlated with changes in fat mass the signal transduction pathway and like insulin, acti- or weight loss,89,90 yet other adult studies reported no vates IRS-PI3K in neurons of the ventromedial hypothala- correlations.91-93 Resistin serum levels were studied in obese mus, whereby it induces central appetite inhibition and childrenafter1yearofweightloss.94 Girlsdemonstratedhigher stimulates energy expenditure by increasing the central sym- resistin concentrations than boys, but there were no differ- pathetic tone. A high density of leptin receptors was found ences of resistin levels between lean and obese children, and in the hypothalamic arcuate nucleus and the ventrome- there were no significant changes after weight loss.94 dial hypothalamus nucleus.20,83 Leptin has a soluble recep- Retinol-binding protein 4 (RBP4) is a recently iden- tor that represents the main binding site for leptin in blood tified secreted primarily from adipose tissue and may be a negative regulator of free leptin.84 with some secretion by the liver. It is a proposed link be- Leptin’s homeostatic effect is anorexigenic, invoking sa- tween obesity and insulin resistance.95 In normal mice, tiety and ceasing nutritional intake. Leptin levels circulat- elevated RBP4 levels caused insulin resistance in muscle ing in the blood correlate with the amount of adiposal tis- and increased hepatic , whereas RBP4 sue mass. Although it would seem that increased levels of gene knockout mice had increased insulin sensitivity.95 leptin in overweight individuals would lead to appetite sup- In adults96,97 and children79,98,99 with obesity and T2DM, pression and lower food intake, this does not occur be- elevated RBP4 levels have been correlated with insulin cause increased fat mass also leads to leptin resistance and resistance. Two recent studies showed that lifestyle inter- decreased leptin signaling in the brain.72 This resistance then vention almost reversed elevated RBP4 levels in obese chil- may lead to ineffective appetite inhibition and changes the dren.79,99 In our lifestyle intervention,99 children with sub- set point of energy homeostasis, resulting in a defense of a stantial weight loss demonstrated a significant decrease of higher level of body fat. Leptin deficiency in obese indi- RBP4 levels in a parallel manner to blood pressure and tri- viduals is very rare and is caused by a homozygous ob gene glycerides and insulin levels. These data suggest a link be- mutation. Only a few patients and families have been re- tweenRBP4,obesity,andmarkersofthemetabolicsyndrome. ported in the literature. In these individuals, leptin levels Visfatin/NAMPT is a recently identified adipocyto- are low and leptin therapy has been proven to be a causal kine from visceral fat that was found in higher concen- treatment of obesity.24 In most obese individuals, how- trations in obese than in nonobese children.100 Visfatin, ever, serum leptin levels are upregulated because of the in- originally named pre–B cell colony-enhancing factor, is creased fat mass and leptin resistance, and leptin levels fall from the same gene that encodes nicotinamide 5-phos- after successful weight loss,28,29 while decreased serum phoribosyl-1-pyrophosphate transferase (NAMPT), an en-

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 zyme important in mammalian nicotinamide adenine di- ing energy homeostasis in obese children have at least nucleotide (NADϩ) biosynthesis.101 The relationship as much to do with the endocrine phenomena that are between visfatin/NAMPT and the parameters of glucose involved in the communication between peripheral tis- and insulin resistance is uncertain because sues (gut, adipose tissue) and the brain as they have to of contradicting data102-107 potentially attributed to dif- do with genetics and sociocultural and lifestyle factors. ferences in immunoassay specificity.108 Recent evidence This implies that the solutions to this serious, ever- indicates haplodeficiency and chemical inhibition of escalating threat to both the life span and life quality of NAMPT may cause defects in NADϩ biosynthesis.101 Al- our children are also embedded in a better understand- terations in NAD levels could alter activities of impor- ing of the endocrine status of the obese child. The ma- tant enzymes in metabolic pathways such as glycolysis jority of the changes of gut hormones and adipokines ob- or oxidation in pancreatic beta cells.101,109 served in obese children are reversible after weight loss, and therefore, pharmacological interventions based on SOME EXAMPLES OF these hormones will likely not solve the obesity epi- PHARMACOLOGICAL APPROACHES demic in childhood. However, successful solutions have much to do with the length and thoroughness of inter- After the appetite-inhibiting effect of leptin had been dis- ventions; there are no simple, quick-fix pharmaceutical covered, it was hoped that administration of leptin might solutions to sustainable weight loss. Understanding the beacureforobesity.Theattemptsweredisappointing,mostly pathways of body weight– and food intake–regulating because simple obesity results in leptin resistance. Only in gut- and adipose tissue–derived hormones will help to very rare patients with congenital leptin deficiency does lep- find better answers that can effectively combat both child- tin treatment lead to a strong long-term reduction of over- hood obesity as well as the plethora of pathologies that weight.24 Someoftheguthormones,suchasGLP-1andCCK, it either causes or exacerbates. have a very short half-life of a few minutes in the circula- tion because of rapid degradation, thus limiting their use Accepted for Publication: October 6, 2009. as antiobesity drugs. However, exendin-4 is a long-acting Correspondence: Christian L. Roth, MD, Division of En- GLP-1 receptor that has recently been approved by docrinology, Seattle Children’s Hospital Research Insti- the US Food and Drug Administration for the treatment of tute, 1900 Ninth Ave, Seattle, WA 98101 (christian.roth T2DM and has also been associated with weight loss.110 Pre- @seattlechildrens.org). liminary data from rat models suggest that oxyntomodu- Author Contributions: Study concept and design: Roth. linmaybeusefulintreatingobesity.111 Onesuchrodentstudy Analysis and interpretation of data: Roth and Reinehr. Draft- suggested that oxyntomodulin exerts its anorectic effect ing of the manuscript: Roth. Critical revision of the manu- through the GLP-1 receptor, as it was ineffective in GLP-1 script for important intellectual content: Roth and Reinehr. receptor knockout mice.112 In a recent 4-day human study, Statistical analysis: Roth. Obtained funding: Reinehr. Ad- oxyntomodulinnotonlypromotedweightlossbutincreased ministrative, technical, and material support: Roth. Study energy expenditure by more than 25%.113 supervision: Roth and Reinehr. GLP-1 and the amylin analogue appear Financial Disclosure: None reported. to decrease weight in patients with T2DM, which is an important secondary goal in treating these patients.114 Pharmaceutical studies have recently been performed to REFERENCES explore amylin’s therapeutic potential for treating both obesity and diabetes.114-116 Traditional pharmacothera- 1. Fagot-Campagna A, Pettitt DJ, Engelgau MM, et al. Type 2 diabetes among North American children and adolescents: an epidemiologic review and a public health pies to treat T2DM often exacerbate obesity, undermin- perspective. J Pediatr. 2000;136(5):664-672. ing any benefits of improved glycemic control as well as 2. Koplan JP, ed. Progress in Preventing Childhood Obesity: How Do We Mea- patients’ compliance with the treatment. 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