Reflections on STAT3, STAT5, and STAT6 as fat STATs.

The current issue of the Proceedings contains an article entitled "Defective STAT signaling by the leptin receptor in diabetic mice" by Ghilardi et al. (1). The reported results suggest how leptin, the recently discovered weight control hormone (2), may signal cells through its cognate receptor by activation of STATs, proteins that serve the dual function of signal transducers and activators of transcription in cells exposed to signaling polypeptides (3, 4). Mice that produce no leptin (obese or ob mutants) weigh up to 60 g instead of the usual 15-20 g for a normal mouse. The human protein is virtually identical to mouse leptin, suggesting that the control of body weight in humans may also be regulated by this hormone (2). The effect of leptin on ob mice is to control food intake, so that weight loss ensues (5-7). In addition, the mice exhibit increased "mouse-like" exploratory activity. Thus, the description of the first molecule in the weight control pathway opens up the chance to explore in molecular detail the control of a complex behavior. The Ghilardi et al. paper (1) reports confirmatory results showing the presence in cells of widely scattered tissues, including the hypothalamus, the putative control center for feeding behavior, of a "long" and "short" leptin receptor (8-10). The leptin receptor has considerable sequence similarity to the gp130 transmembrane receptor chain that pairs as the signaling molecule with a number of other transmembrane proteins to constitute the receptor for many ligands including interleukin (IL)-6, ciliary neurotrophic factor, leukemiainhibitory factor (11, 12). The leptin receptor appears not to function normally in the mouse mutant termed diabetes (db) because of a base change in an intron that leads to a frequent aberrant splice choice; the resulting mRNA retains a translation stop codon producing a truncated protein lacking approximately 270 amino acids of the cytoplasmic domain of the transmembrane receptor (9). The omission of these amino acids was hypothesized to prevent intracellular signaling occasioned by leptin binding to its cell surface receptor. Based on the homology between the leptin receptor and the gp130 transmembrane protein (8-12), the pathway through which the leptin receptor seemed likely to signal is the recently recognized JAK/STAT pathway (3, 4). All of the known receptors that contain gp130 have JAK kinases (tyrosine kinases) bound to their intracellular tails (11). After ligand-mediated receptor assembly, the JAKs become phosphorylated on tyrosine and thereby activated as tyrosine kinases. The intracellular tail of one or more receptor chains is then phosphorylated on one or more tyrosine residues (13-15), offering binding sites to the Src homology 2 groups of latent cytoplasmic proteins called STATs (15). The attached STATs become phosphorylated on tyrosine by the activated Jak kinases. The STATs then dimerize, translocate to the nucleus, and participate in transcriptional regulation by binding to specific DNA sites. In the mutant db receptor both the putative STAT-binding sites and the JAK-binding sites are missing. There are six mouse and human STATs known at present (seven if the duplicated STAT5A and STAT5B genes are considered as two) and at least STATI, STAT3, and STAT5 exhibit differentially spliced forms. Over 30 different polypeptides have been recorded that cause STAT activation in various mammalian cells (3, 4, 11). The most potent activation of STATs through the gp130-containing receptors is of STAT3 (15-18) and by sequence comparison the wild-type leptin receptor has potential docking sites for STAT3 molecules. Ghilardi et al. (1) now report success in showing STAT activation dependent on the long form of the leptin receptor. In a comprehensive set of experiments they cotransfected COS cells with either the long or short versions of the leptin receptor together with, individually, each of six mouse or human STAT proteins. Leptin treatment of the cells transfected with the long but not the short receptor resulted in activation of DNAbinding complexes containing, individually, STAT3, STAT5, or STAT6; STATI, STAT2, and STAT4 were not detectably activated. It will now be crucial to show whether the same set of STATs is activated by leptin in the hypothalamus, which is hypothesized to be the center for weight control in the Coleman model (19). In this model the ob gene product, a circulating hormone, would operate by binding to a hypothalamic receptor, the db gene product, to regulate feeding.