EXPRESSION OF OB MESSENGER-RNA AND ITS ENCODED PROTEIN IN RODENTS - IMPACT OF NUTRITION AND OBESITY

The mutant gene responsible for obesity in the ob/ob mouse was recentl y identified by positional cloning (Zhang Y., R. Proenca, M. Maffel, M . Barone, L. Leopold, and J.M. Friedman, 1994, Nature (Lend.) 372:425) , The encoded protein was predicted to be an adipocyte-derived secrete d protein and to represent an ''adipostat'' signal reflecting the stat e of energy stores, We confirm that the adipocyte is the source of ob mRNA and that the predicted 16-kD ob protein is present in rodent seru m as detected by Western blot, To evaluate the hypothesis that it migh t represent an adipostat, we assessed serum levels of oh protein and e xpression of ob mRNA in adipose cells and tissue of rodents in respons e to a variety of perturbations which effect body fat mass, Both ob pr otein and ob mRNA. expression are markedly increased in obesity, The l evels of ob protein are similar to 5-10-fold elevated in serum of db/d b mice, in mice with hypothalamic lesions caused by neonatal administr ation of monosodium glutamate (MSG), and in mice with toxigene induced brown fat ablation, (UCP-DTA), Very parallel changes are observed in adipocyte ob mRNA expression in these models and in ob/ob mice, As pre dicted however, no serum ob protein could be detected in the ob/ob mic e, By contrast to obesity, starvation of normal rats and mice for 1-3 d markedly suppresses ob mRNA abundance, and this is reversed with ref eeding, Similarly, ob protein concentration in normal mice falls to un detectable levels with starvation, In the ob/ob, UCP-DTA and MSG model s, overexpression of ob mRNA is reversed by caloric restriction. These data support the hypothesis that expression of oh mRNA and protein ar e regulated as a function of energy stores, and that ob serves as a ci rculating feedback signal to sites involved in regulation of energy ho meostasis.