Adipose tissue as an endocrine organ regulating growth, puberty, and other physiological functions.
There are reports on some patients with clearly manifested specific features of genotype and phenotype similar to those of ob/ob and db/db mice. Three patients from Turkey were described who had a homozygous mutation in the gene of leptin identical to the mutation in C57BL6J ob/ob mice. This mutation is a C --> T substitution in codon 105 of the amino acid sequence of leptin. In mice this mutation generates a stop-codon; in humans it substitutes Arg-105 with Trp. The mutant human leptin cannot be secreted by the cells and thus has no effect on the hypothalamus. Patients with a homozygous mutation of the leptin receptor resulting in the G --> T substitution in the splice donor site of exon 16 were studied in a family of Kabilian origin. Exon 16 was not included in the mature mRNA molecule, and a truncated leptin receptor was synthesized which lacked the transmembrane and intracellular domains; this receptor was unable to transduce the hormonal signal. Both groups of patients suffered from obesity, delayed linear growth, infertility, increased blood insulin level, and other disorders. Leptin influences lipid metabolism by stimulating the expression of the proopiomelanocortin (POMC) gene in melanocortinergic neurons of the hypothalamus. POMC is the precursor of alpha-melanocyte-stimulating hormone (alpha-MSH), which binds to the melanocortin receptor MC4-R in the brain, decreases appetite, and activates lipid metabolism. Patients with mutations in MC4-R suffered only from obesity, but their growth and puberty were not affected. Thus, leptin apparently stimulates growth and puberty not through its binding to the receptors on melanocortinergic neurons, but through its binding to receptors on other hypothalamic neurons; this effect of leptin is not affected by mutations in the MC4-R gene.
Pankov
Y A
YA
Endocrinology Research Center, Russian Academy of Medical Sciences, Moscow, 115478, Russia. yuri-pankov@mtu-net.ru
D000273:Adipose Tissue / Q000502:physiology*; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology; D004703:Endocrine System / Q000502:physiology*; D006128:Growth / Q000502:physiology*; D006801:Humans; D020738:Leptin; D051379:Mice; D008954:Models, Biological; D011506:Proteins / Q000502:physiology; D011627:Puberty / Q000502:physiology*; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin
D002352:Carrier Proteins; D020738:Leptin; D011506:Proteins; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin