A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction

Abstract

The adipocyte-specific hormone leptin, the product of the obese (ob) gene, regulates adipose-tissue mass through hypothalamic effects on satiety and energy expenditure. Leptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine-receptor family. In rodents, homozygous mutations in genes encoding leptin or the leptin receptor cause early-onset morbid obesity, hyperphagia and reduced energy expenditure. These rodents also show hypercortisolaemia, alterations in glucose homeostasis, dyslipidaemia, and infertility due to hypogonadotropic hypogonadisms. In humans, leptin deficiency due to a mutation in the leptin gene is associated with early-onset obesity. Here we describe a homozygous mutation in the human leptin receptor gene that results in a truncated leptin receptor lacking both the transmembrane and the intracellular domains. In addition to their early-onset morbid obesity, patients homozygous for this mutation have no pubertal development and their secretion of growth hormone and thyrotropin is reduced. These results indicate that leptin is an important physiological regulator of several endocrine functions in humans.

Caloric restriction: Impact upon pituitary function and reproduction

“…Acute dietary fasting also profoundly suppresses serum leptin levels and attenuates the leptin pulse area and incremental pulse amplitude (Bergendahl et al, 2000). In humans, as in mice, congenital absence of leptin or functional leptin receptor causes severe obesity accompanied by neuroendocrine abnormalities (Montague et al, 1997;Strobel et al, 1998;Ozata et al, 1999;Clement et al, 1998). Interestingly, the neuroendocrine defects that are present in leptin-deficient rodents and in leptin-resistant humans differ from each other, which indicates that the role of leptin in mediating the neuroendocrine response to starvation may be different in humans versus rodents (Montague et al, 1997;Strobel et al, 1998;Ozata et al, 1999;Clement et al, 1998).…”

“…In humans, as in mice, congenital absence of leptin or functional leptin receptor causes severe obesity accompanied by neuroendocrine abnormalities (Montague et al, 1997;Strobel et al, 1998;Ozata et al, 1999;Clement et al, 1998). Interestingly, the neuroendocrine defects that are present in leptin-deficient rodents and in leptin-resistant humans differ from each other, which indicates that the role of leptin in mediating the neuroendocrine response to starvation may be different in humans versus rodents (Montague et al, 1997;Strobel et al, 1998;Ozata et al, 1999;Clement et al, 1998). Data from Chan et al (2003) has suggested that a reduction of circulating leptin levels in lean men regulates the acute fasting-induced changes that occur in the HPG axis and, in part, the changes that occur in the hypothalamic-pituitarythyroid (HPT) axis and in IGF-1-binding capacity, but it is not responsible for changes in the HPA, rennin-aldosterone, and GH-IGF-1 axes associated with acute fasting (Chan et al, 2003).…”

New advances in the genetics of early onset obesity

“…14 Hypothalamic hypothyroidism is seen at a young age with a subsequent failure to undergo pubertal development due to hypogonadotropic hypogonadism. Mutations in the leptin receptor result in a comparable phenotype, 15 although are not necessarily associated with elevated serum leptin concentrations (personal communication). Although leptin deficiency appears to be rare, it is entirely treatable with daily subcutaneous injections of recombinant human leptin with beneficial effects on appetite, fat mass and hyperinsulinaemia, reversal of the immune defects and infection risk and allowing the appropriate development of puberty 14 (Figure 1).…”

Body weight is regulated by the brain: a link between feeding and emotion

“…[53][54][55] Mutations in the human Ob-Rb also produce morbid obesity. 56 Importantly, the gene expression of the Ob-Rb is evident in the mediobasal hypothalamic sites including the arcuate nucleus. [57][58][59][60] The leptin receptor has also been identified in the human brain.…”