RAPID INHIBITION OF OB GENE-EXPRESSION AND CIRCULATING LEPTIN LEVELS IN LEAN MICE BY THE BETA-3-ADRENOCEPTOR AGONISTS BRL 35135A AND ZD2079

The acute effect of two selective beta 3-adrenoceptor agonists, BRL, 3 5135A and ZD2079, on the expression of the ob gene and plasma leptin l evels has been examined in mice. By 4-5 h after the administration of either beta 3-agonist to lean animals there was a major loss of ob mRN A from epididymal white adipose tissue. This was accompanied by a subs tantial fall in circulating leptin levels, as measured by an ELISA. Ev en 24 h after the first administration of beta 3-agonists, ob mRNA lev els and circulating leptin levels remained low. In contrast to lean an imals, treatment with BRL 35135A had only a minor effect on ob mRNA le vels in obese (ob/ob) mice. Regulation of leptin production appears to involve a negative feedback loop to white adipose tissue through the sympathetic nervous system suppressing ob gene transcription via beta 3-adrenoceptors; an impairment in this loop is evident in the ob/ob mu tant. (C) 1996 Academic Press, Inc.