|Budget Amount *help
¥3,500,000 (Direct Cost : ¥3,500,000)
Fiscal Year 2003 : ¥1,600,000 (Direct Cost : ¥1,600,000)
Fiscal Year 2002 : ¥1,900,000 (Direct Cost : ¥1,900,000)
Leptin is known to be an important circulating signal for regulation of food intake and body weight. These effects were suggested to be mediated through the hypothalamic center via the Ob-Rb receptor. We found that peripherally applied leptin increased Interleukin (IL)-1b transcripts in many regions of the brain. Although leptin did not induce STAT3 activation or suppressor of cytokine signaling3 (SOCS3) expression in the hypothalamus of the db/db mice, which lack a functional Ob-Rb receptor, leptin increased the IL-1b levels to similar extents as normal mice. Therefore, a novel function of leptin is suggested as the induction of IL-1b expression in many regions of the brain via STAT3-independent mechanisms.
Although leptin receptors exist in many regions of the brain, there have been few in vivo functional studies of leptin's target site other than the hypothalamus. We demonstrated that peripherally applied leptin increased STAT3 phosphorylation not only in the hypothalamus but also in
the brainstem as assessed by Western blotting and. Immunohistochemistry. These findings represent physiologically functional leptin Ob-Rb receptor in the brainstem as well as in the hypothalamus.
Glucocorticoids were suggested to play a physiological role in the feedback inhibition of immune/inflammatory responses Pretreatment with dexamethasone dose dependently inhibited leptin-induced IL-1b expression in the hypothalamus. Moreover, dexamethasone inhibited leptin-induced IL-1b expression in the primary cultured glial cells. In contrast, pretreatment with dexamethasone did not inhibit leptin-induced STAT3 phosphorylation in the hypothalamus. Therefore, it is suggested that glucocorticoid negatively regulates leptin-induced IL-1b expression in the brain.
We investigated role of double-stranded RNA-activated protein kinase (PKR) as a possible signaling pathway of leptin. 2-aminopurine, an inhibitor of PKR inhibited leptin-induced intracellular signaling. However, we observed that leptin did not activate PK, and found the site of action of 2-aminopurine to inhibit leptin signaling was Janus kinase. Less