Obestatin inhibits dopamine release in rat hypothalamus.

We have investigated the effects of the gastric peptide obestatin injected into the arcuate nucleus of the rat hypothalamus on the hypothalamic mRNA expression of peptides which play master roles as feeding behavior modulators. We have also evaluated the effects of obestatin on dopamine, norepinephrine and serotonin release from rat hypothalamic synaptosomes in vitro. After 4 daily intrahypothalamic injections of obestatin (1 nmol/kg), we recorded a significant reduction of daily caloric intake and body weight gain. Gene expressions of either anorexigenic (cocaine- and amphetamine-regulated transcript, corticotropin releasing hormone, proopiomelanocortin) or orexigenic (agouti-related peptide, neuropeptide Y, orexin-A) peptide mRNAs in the hypothalamus, as evaluated by real-time quantitative PCR, were not different in respect to vehicle treated rats. Moreover, ghrelin/obestatin prepropeptide gene expression in the hypothalamus was not affected by obestatin treatment. In hypothalamic synaptosomes perfused with obestatin (1-100 nM), we found a dose-dependent inhibition of depolarization-induced dopamine release, while norepinephrine and serotonin releases were not modified by obestatin treatment. When ghrelin (1 nM) and obestatin (1 nM) were co-perfused, we observed that ghrelin reversed obestatin-induced inhibition of dopamine release, and obestatin was able to block ghrelin-induced inhibition of serotonin release. We can conclude that obestatin plays an anorectic role in the hypothalamus which could be partially mediated by the acute inhibition of dopamine release, with the possible involvement of antagonism of the hypothalamic serotonin inhibitory effects of ghrelin.