| dc.description | Obesity is a complex health care issue in industrialized societies and is implicated in the development of diabetes and cardiovascular disease. Fat-derived adipokines, including leptin, resistin, and fasting-induced adipose factor (FIAF), are key obesity hormones that modulate bodyweight and energy homeostasis via hypothalamic-dependent mechanisms. Although they are predominantly derived from adipose tissue, their expression was also detected in the brain and pituitary gland. I hypothesized that adipokines expressed in the central nervous system would impact energy homeostasis and brain function, via paracrine or intracrine-dependent mechanisms. RNA interference (RNAi) was used to silence adipokine expression in several models to investigate their potential roles. Proof-of-principle studies in C6 glioblastoma cells confirmed the effectiveness of using RNAi to silence the expression of brain leptin, and this knockdown increased cell death. RNAi also silenced leptin expression in the rat brain, which induced tissue-dependent changes in resistin (rstn) expression. In additional in vitro experiments rstn was silenced in mouse N-1 hypothalamic neurons. Rstn silencing concomitantly induced the expression of fiaf and suppressor of cytokine signaling-3 (socs-3), an intracellular inhibitor of leptin signaling, but decreased the activation of AMP-activated protein kinase (AMPK), an enzyme implicated in the control of energy metabolism. Parallel studies revealed that adipokine expression was modified in N-1 neurons and 3T3-L1 adipocytes, and in mice, following treatment with valproic acid (VPA), all-trans retinoic acid (ATRA), and rosiglitazone (ROSI), compounds known to induce either weight gain or insulin sensitization. The expression of brain adipokines was also induced by inflammatory stimuli and by two models of brain injury; cerebral hypoxia/ischemia (H/I) and traumatic brain injury (TBI), suggesting their involvement in the pathology of brain injury. In conclusion, these studies implicate centrally-derived adipokines (cephalokines) in the control of brain cell survival, signaling, and metabolism. Therefore brain adipokines might be part of a fine 'tuning' mechanism that regulates hypothalamic pathways implicated in the control of bodyweight and appetite, or impact brain repair and function following injury. | en_US |
