Role of hypoxia-inducible factor-1α in regulating oxidative stress and hypothalamic neuropeptides-mediated appetite control.

ABSTRACT

Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator responding to hypoxia. Amphetamine (AMPH), however, can activate HIF-1 under normoxic conditions, which is associated with the co-activation of oxidative stress. Hypothalamic neuropeptides and anti-oxidative enzymes have been found to participate in amphetamine (AMPH)-mediated appetite control. The present study examined whether HIF-1 was involved in the oxidative stress and anorectic action of AMPH. Rats were daily treated with AMPH for 4 days, and expression levels of HIF-1α, superoxide dismutase (SOD), catalase, neuropeptide Y (NPY), proopiomelanocortin (POMC), phosphatidylinositol 3-kinase (PI3K), and nuclear factor-kappaB (NF-κB) were assessed and compared. Results revealed that feeding behavior and NPY decreased, whereas HIF-1α/DNA binding activity and SOD, POMC, PI3K, and NF-κB expression levels increased in AMPH-treated rats. Further experiment revealed that intracerebroventricular (i.c.v.) pretreatment with HIF-1α inhibitor modified feeding behavior and expression levels of hypothalamic protein assessed. Another experiment revealed that pretreatment (i.c.v.) with reactive oxygen species scavenger modulated HIF-1α, NPY, POMC, PI3K, and NF-κB expression levels in AMPH-treated rats. It is suggested that HIF-1α plays a functional role in the increase of oxidative stress and the modulation of NFκB/NPY/POMC-mediated appetite control in AMPH-treated rats. These findings advance the knowledge of HIF-1α in the regulation of central dopamine agonist-mediated appetite control.