Endocrine Abstracts

Fat-derived adipokine genes that modulate metabolic and inflammatory responses, such as resistin (rstn) and fasting-induced adipose factor (fiaf), are also expressed in mouse brain and pituitary gland. We, and others, reported that central fiaf and rstn mRNA levels were increased following a brain injury-induced inflammatory response, and central injection of resistin reduced food intake and increased hepatic glucose production. Since LPS-induced endotoxinemia also provokes an anorectic response via a hypothalamic-dependent mechanism we hypothesized that LPS would modulate hypothalamic adipokine gene expression. Challenging CD-1 mice (male; 32 days old) with LPS (5 mg/kg; sc) reduced body weights (24 h; P<0.001) and realtime RT-PCR revealed time- and tissue-dependent increases in rstn, fiaf and suppressor of cytokine signaling-3 (socs-3) mRNA levels in hypothalamic, pituitary, cortical and adipose tissues. Gene expression in the hypothalamus and whole pituitary gland was rapidly and significantly increased (3–6 h; 64–440%) but returned to normal within 24 h. In contrast, though rstn mRNA was unaffected in fat, mRNA levels for all three genes were still significantly elevated at 24 h in cortex (40–140%) and fiaf and socs-3 expression remained elevated in visceral fat (137–400%; 24 h). In additional experiments, we examined the direct effect of LPS on N-1 hypothalamic neurons in vitro. LPS (25 μg/ml; 30 min) had no effect on rstn mRNA, but significantly increased fiaf (10-fold; P<0.001) and socs-3 (40%; P<0.001) gene expression. Blockade of the LPS receptor using toll-like receptor 4 antagonists significantly reduced, but did not prevent, the increases in fiaf and socs-3 mRNA. This result suggests that non-NFkB pathways also contribute to LPS-induced fiaf and socs-3 stimulation. We conclude that LPS treatment elevates central adipokine mRNA levels, which might then exert downstream consequences on hypothalamic control of appetite and energy metabolism.

Financial support was obtained from the IWK Health Centre, UIMRF/Capital Health and NSHRF.