Editorial: Further Insights into Leptin Action.

The genetically obese Zucker fatty rat (fa/fa) and its cousins the ob/ob and db/db mice were first described in the 1950s and 1960s. These animals have been the subjects of literally thousands of studies over the ensuing decades, but it is only in the past 5 yr that the ultimate mechanism for these syndromes has been given a firm molecular foundation. The elegant parabiosis studies of Coleman (1) had provided clear evidence for the lack of a humoral factor in ob/ob mice being responsible for their obesity, but the identity of that factor was not known until the product of the ob gene was positionally cloned by Friedman’s group in 1994 (2). The identification of the normal hormone product of the ob locus (leptin) and the cloning of its receptor (Ob-R, 3) followed in short order, and a whole new field (and industry) was born. The explosive growth of interest in leptin is illustrated by the number of oral and poster presentations– 105–on leptin biology at the recent Annual Meeting of The Endocrine Society and an ever increasing rate of submission of papers on leptin to this journal. In the current issue, da Silva et al. (4) have examined the expression and signaling properties of the mutant leptin receptors responsible for the obese phenotype of the Zucker fatty rat. Their thorough analysis reveals a number of functional abnormalities in the fa mutant leptin receptor that alter its level of expression, ligand binding, ligand processing properties, and ability to activate the JAK-STAT signal transduction pathway. The authors have analyzed the effect of the fa mutation (a missense mutation in the extracellular domain defined in 1996 by several groups) on the two major isoforms of the leptin receptor, Ob-Ra and -Rb. These are generated by alternative messenger RNA splicing, leading to forms with a full-length intracellular domain (Rb) or with a truncated intracellular domain (Ra). The significance of the existence of the two isoforms is unclear; however, the fact that obese db/db mice have a mutation that prevents Rb but allows Ra expression argues strongly that the cytoplasmic domain is required for signal transduction and normal energy homeostasis. Heavy expression of Ob-Ra (the short form of the leptin receptor) in the choroid plexus had initially suggested a possible role for the truncated receptor in hormone transport (3); consistent with this, Ob-Ra has been recently shown to be highly expressed in brain microvessels at the blood-brain barrier (5). The current study is the first to examine in detail the endocytotic itineraries of both the normal and mutant Ra. Because it has been suggested that human obesity may reflect a leptin-resistant state, the ability of leptin to reach its proper target(s) of action may be important in human pathology and will certainly be important in the potential pharmacological use of leptin agonists. Also significant in the current study is the lack of activation of the JAK-STAT signaling pathway by the fa mutant Ob-Rb. The homology of the leptin receptor with other members of the class 1 cytokine receptor family had led to the prediction that this pathway would be used by the leptin receptor, and that has been born out in a number of laboratories, although the MAP kinase and phosphatidylinositol-3-kinase signaling pathways have also been implicated in leptin action in some systems. The current study’s demonstration of defective JAK-STAT signaling by the mutant fa receptor complements and extends previous results by Tartaglia and co-workers (6) and also addresses one of the paradoxes noted by both groups, namely the constitutive activation of egr-1 transcription by mutant Ob-Rb in transfected cells. Activation of egr-1 is a common target of several cytokines and growth factors, and its apparent activation by Ob-Rbfa raised the possibility that this could lead to downregulation of signaling pathways and contribute to leptin resistance. The activation of egr-1 does require cotransfection of JAK2 into the host cell reporter system, and it is unknown whether the constitutive activation of egr-1 occurs in vivo under normal circumstances. The paper in this issue represents an important step in the elucidation of the molecular mechanism for leptin action at the cellular level. The discovery of a novel hormone system— and we wonder how many others will be revealed as more disease genes are cloned and as the human genome is sequenced—obviously opens the door to other questions. In the leptin field, these include: What is the full range of physiological effects of leptin? The importance of leptin for energy homeostasis, thermogenesis, and satiety sensing is clear from the ob/ob, db/db, and fa/fa phenotypes, but leptin may also play important roles in sexual maturation, fertility, and insulin action as well. How are leptin’s effects mediated? The leptin receptor is widely expressed in human tissues. Numerous pathways have already been tied to leptin action, including the hypothalamopituitary-adrenal axis, gonadal steroidogenesis, neuropeptide Y, the sympathetic nervous system, and the insulin secretion and signaling pathways. The appreciation that hormonal signaling pathways are networks of highly interactive and degenerate systems ensures that the ultimate consequences of leptin action will be widely felt throughout the organism. Leptin action in the CNS as well as in peripheral tissues—muscle, fat, gut, pancreas, and the liver—all need further definition. What is the relevance of leptin to human disease? Current evidence suggests that mutations in the coding sequences of leptin and its receptor are probably only rare causes of human obesity. However, to say that leptin is not a major player in human obesity would be analogous to saying that insulin is not a major player in diabetes because mutations of insulin and its receptor are rare. Obesity in larger populations may be linked to the Ob and Ob-R loci, and the possibility of more common obesity due to abnormal regulation of these proteins is still possible. The further definition of leptin resisReceived July 8, 1998. Address all correspondence and requests for reprints to: Don McClain, M.D., Ph.D., Division of Endocrinology, VA and University of Mississippi Medical Center, Jackson, Mississippi 39216. 0013-7227/98/$03.00/0 Vol. 139, No. 9 Endocrinology Printed in U.S.A. Copyright © 1998 by The Endocrine Society