Since the discovery of leptin, understanding of the mechanisms that control energy balance has rapidly advanced. Unfortunately, except for leptin replacement therapy in a handful of leptin deficient individuals, there is yet to emerge any interventions that effectively prevent or treat obesity in the general population. Both insulin and leptin are secreted in proportion to body fatness and serve as adiposity signals, acting on the same neurons of the hypothalamic arcuate nucleus to regulate energy homeostasis. Ghrelin, which is secreted by the stomach and duodenum, serves as a hunger signal at the hypothalamus and brainstem, while other peptides secreted by the GI tract, including PYY, act as satiation signals. The ligands leptin,120 POMC, 121,122 CART,123 and BDNF,91,124 the receptors for leptin, 125,126 melanocortins,127–130 and BDNF,131 and the enzyme PC1132,133 have been found to have function-altering mutations associated with obesity in children. Mutations in the ligands and receptors for NPY,134 AGRP,135 CPE,136,137 and MCH138 have been found to alter energy balance in rodents, but have not been as convincingly shown to be associated with human obesity. Lines with arrowheads indicate stimulatory action. Lines ending with a perpendicular end-block indicate inhibitory action. Abbreviations: GI, gastrointestinal; PYY, peptide YY, IR, insulin receptor; LR, leptin receptor, NPY, neuropeptide Y; AGRP, agouti-related protein; POMC, pro-opiomelanocortin; CART, cocaine-amphetamine related transcript; PC1, prohormone convertase 1; CPE, carboxypeptidase E; MSH, melanocyte stimulating hormone; TRH, thyrotropin-releasing hormone; MCH, melanin concentrating hormone; GABA, gamma amino butyric acid; BDNF, brain-derived neurotrophic factor; TrkB, tyrosine kinase receptor B.

The clinical history and examination of the patient should guide the care provider in forming a differential diagnosis. Onset of marked obesity during early infancy raises the suspicion for function-altering genetic mutations affecting the leptin signalling pathway, but these are exceedingly rare conditions, with the most common, melanocortin-4 receptor defects, comprising <5% of children with early-onset obesity.130 When evaluating new onset of excessive weight gain, potential side effect from a recently initiated medication should be taken into consideration, as weight gain may be associated with administration of insulin or insulin secretagogues, glucocorticoids, hormonal contraceptives (e.g., depot medroxyprogesterone acetate), psychotropic medications (including atypical antipsychotics (e.g., clozapine, olanzapine, risperidone), mood stabilizers (e.g. lithium), tricyclic antidepressants (e.g., amitriptyline, imipramine, and nortriptyline), and anticonvulsants (e.g., valproic acid, gabapentin, and carbamazepine)), antihypertensives (e.g., propranolol and clonidine), and antihistamines.139 In patients with decreased growth velocity despite continued weight gain, an endocrinopathy should be considered; measurement of TSH and free T4, and referral to a paediatric endocrinologist are recommended. All patients, regardless of the aetiology of obesity, should be assessed for modifiable lifestyle factors, including physical activity and diet, and screened for complications of obesity, including measurement of fasting lipids, fasting glucose, and alanine amino transferase. If fasting glucose is 100 – 126 mg/dL, an oral glucose tolerance test is recommended. Screening for vitamin D and iron deficiency should also be considered.

Image obtained by dual energy X-ray absorptiometry from a teenage girl with BMI 38 kg/m². Conditions that are of high prevalence and are well-established in their association with childhood obesity are shown in larger font size.

(A) Roux-en-Y gastric bypass, (B) Adjustable gastric band. (Reprinted from Inge TH, Zeller MH, Lawson ML, Daniels SR. A critical appraisal of evidence supporting a bariatric surgical approach to weight management for adolescents. J Pediatr 2005;147(1):10-9 with permission from Elsevier Limited.)140