agents, low insulin‐like growth factor‐I levels, and the presence of additional evidence of hypothalamic dysfunction support the presence of true GH deficiency (GHD) in many children with PWS. GH treatment in these children decreases body fat and increases linear growth, muscle mass, fat oxidation, and energy expenditure. In PWS children, therapy with GH significantly improves the rate of growth and final height. Long‐term studies show that the final height is in the average range for age, and GH is now licensed for use in PWS.
Prader–Willi syndrome is caused by deficiency of one or more paternally expressed imprinted transcripts within chromosome 15q11‐q13, a region that includes multiple small nucleolar RNAs (snoRNAs). The molecular pathophysiology of PWS remains unclear, although the expression of oxytocin and brain‐derived neurotrophic factor (BDNF) is reduced in the postmortem brains of PWS patients [15]. Microdeletions of the HBII‐85 snoRNAs in children with PWS provide strong evidence that deficiency of HBII‐85 snoRNAs plays a major role in the key characteristics of the PWS phenotype [16].
Albright hereditary osteodystrophy
Albright hereditary osteodystrophy (AHO) is an autosomal dominant disorder due to inactivating mutations in GNAS1, the gene encoding Gαs, the G protein that couples receptors to adenylyl cyclase leading to cAMP generation. Heterozygous loss‐of‐function mutations lead to AHO, a disease characterized by short stature, obesity, skeletal defects, and developmental delay. Maternal transmission of GNAS1 mutations leads to AHO plus resistance to several hormones (e.g. parathyroid hormone) that activate Gαs in their target tissues, while paternal transmission leads only to the AHO phenotype. Studies in both mice and humans demonstrate that GNAS1 is imprinted in a tissue‐specific manner, being expressed primarily from the maternal allele in some tissues and biallelically in most other tissues; thus, multihormone resistance occurs only when GNAS mutations are inherited maternally [17]. Patients can present with severe obesity alone; the other classical features can emerge over time in some but not all patients.
Bardet–Biedl syndrome
Bardet–Biedl syndrome (BBS) is a rare (prevalence <1/100,000) autosomal recessive disease characterized by obesity, learning difficulties, syndactyly, brachydactyly or polydactyly, retinal dystrophy or pigmentary retinopathy, hypogonadism, and renal abnormalities. The differential diagnosis includes Biemond syndrome II (iris coloboma, hypogenitalism, obesity, polydactyly, and mental retardation) and Alstrom syndrome (retinitis pigmentosa, obesity, diabetes mellitus, and deafness but without developmental delay). Bardet–Biedl syndrome is a genetically heterogeneous disorder, with over 16 genes involved in the structure and/or function of the basal body, a modified centriole which is essential for the function of non‐motile cilia [18].
Molecular mechanisms involved in energy homeostasis
The first description of hypothalamic injury associated with obesity was published by Mohr in 1840 [19] but remained unsupported until two landmark papers by Babinski in 1900 [20] and by Frohlich in 1901 [21] describing tumors in the region of the hypothalamus that were associated with obesity, gonadal atrophy, decreased vision and short stature. In 1940, Hetherington and Ranson demonstrated that electrolytic lesions in rodents involving, but not restricted to, the ventromedial region of the hypothalamus (VMH) were associated with hyperphagia (increased food intake), hyperinsulinemia and obesity [22]. However, the precise nature of these hypothalamic pathways and the nature of their inputs and outputs were only clarified with the identification and characterization of single‐gene defects in rodent models of obesity.
Rodent models of obesity
Since the early 1900s, a number of obese inbred strains of mice, both dominant (yellow, Ay/a) and recessive (ob/ob, db/db, fa/fa, tub/tub), have been studied. In the 1990s, the genes responsible for these syndromes were identified mostly by positional cloning techniques and these observations have given substantial insights into the physiologic disturbances that can lead to obesity, the metabolic and endocrine abnormalities associated with the obese phenotype, and the more detailed anatomic and neurochemical pathways that regulate energy intake and energy expenditure [23]. These studies provide the basic framework upon which the understanding of the more complex mechanisms in humans can be built.
Leptin–melanocortin pathway
The initial observations in this field were made as a result of positional cloning strategies in two strains of severely obese mice (ob/ob and db/db). Severely obese ob/ob mice were found to harbor mutations in the ob gene resulting in a complete lack of its protein product, leptin [24]. Administration of recombinant leptin reduced the food intake and body weight of leptin‐deficient ob/ob mice and corrected their neuroendocrine and metabolic abnormalities. The signaling form of the leptin receptor is deleted in db/db mice, which are consequently unresponsive to endogenous or exogenous leptin. The physiologic role of leptin in humans and rodents might be to act as a signal for starvation because as fat mass increases, further rises in leptin have a limited ability to suppress food intake and prevent obesity [25].
Considerable attention has focused on deciphering the hypothalamic pathways that coordinate the behavioral and metabolic effects downstream of leptin. The first‐order neuronal targets of leptin action in the brain are anorectic (reducing food intake) pro‐opiomelanocortin (POMC) and orexigenic (increasing food intake) neuropeptide‐Y/agouti‐related protein (NPY/AgRP) neurons in the hypothalamic arcuate nucleus, where the signaling isoform of the leptin receptor is highly expressed [26]. In the fed state, leptin stimulates POMC expression; POMC is sequentially cleaved by prohormone convertases to yield peptides, including α‐melanocyte‐stimulating hormone (MSH) which suppresses food intake by signaling through the melanocortin 4 receptor (MC4R). In fact, targeted disruption of MC4R in rodents leads to increased food intake, obesity, severe early hyperinsulinemia, and increased linear growth; heterozygotes have an intermediate phenotype compared to homozygotes and wild‐type mice [27].
Monogenic obesity syndromes affecting the leptin‐melanocortin pathway
Congenital leptin deficiency
In 1997, we reported two severely obese cousins from a highly consanguineous family of Pakistani origin [28]. Both children had undetectable levels of serum leptin and were found to be homozygous for a frameshift mutation in the ob gene, which resulted in a truncated protein that was not secreted. We and others have since identified other families with mutations in the leptin gene including some that result in proteins that are bioinactive [29]. All subjects in these families are characterized by severe early‐onset obesity and intense hyperphagia [30–32] with food‐seeking behavior and an inability to discriminate between appetizing and bland foods [33]. Although normal pubertal development did not occur, there was some evidence of a delayed but spontaneous pubertal development in one person [32].
We demonstrated that children with leptin deficiency had profound abnormalities of T cell number and function [30], consistent with high rates of childhood infection and a high reported rate of childhood mortality from infection in obese Turkish subjects. Most of these phenotypes closely parallel those seen in murine leptin deficiency. However, there are some phenotypes where the parallels between humans and mice are not as clear‐cut. The contribution of reduced energy expenditure to the obesity of the ob/ob mouse is well established [34]. In leptin‐deficient humans, we found no detectable changes in resting or free‐living energy expenditure [30]. Ozata et al. reported abnormalities of sympathetic nerve function in leptin‐deficient humans consistent with defects in the efferent sympathetic limb of thermogenesis [32].
Response to leptin therapy
In 2002 we reported the dramatic and beneficial effects of daily subcutaneous injections of leptin in reducing body weight and fat mass in three congenitally leptin‐deficient children [30]. All children showed a response to initial leptin doses designed to produce plasma