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Leptin‐induced neuroinflammatory effects in the hypothalamic neurons: role of Sirt1 and FoxO1

Accumulated evidence indicates that central nervous system signaling pathways may contribute to the etiology and pathogenesis of obesity‐induced hypertension. Hypothalamic leptin‐mediated signaling may contribute to the exaggerated sympathoexcitation in obesity. Leptin can influence food intake, energy expenditure and sympathetic nerve activity via hypothalamic pro‐opiomelanocortin (POMC) neurons in the arcuate nucleus (ARCN) of hypothalamus. The aim of the study was to determine the effects of leptin on the neuroinflammation‐mediated high sympathetic nerve activity in obesity. We used hypothalamic neuronal cell mHypoA‐POMC (CLU500) and microglial cell (SIM‐A9) to observe pro‐inflammatory and anti‐inflammatory cytokines levels after 24 hours leptin treatment. We found that leptin incubation increased the levels of pro‐inflammatory cytokines interleukin 6 (IL‐6), interleukin 1β (IL‐1β), and tumor necrosis factor alpha (TNFα) in both POMC and microglial cells. Leptin treatment also reduced the level of lipoxin A4, a potent anti‐inflammatory bioactive lipid formed from arachidonic acid in both cells. Knockdown nutrient‐sensing enzyme sirtuin 1 (Sirt1) by siRNASirt1 significantly attenuated the levels of leptin‐induced pro‐inflammatory cytokines in the POMC and microglial cells. On the contrary, knockdown transcription factor forkhead box protein O1 (FoxO1) by siRNAFoxO1 significantly enhanced leptin‐induced pro‐inflammatory cytokines. Further, in vivo study, we found significant increased protein expressions of IL‐6, IL‐1β and TNFα in the ARCN in 12 weeks high fat induced obese rats. siRNASirt1 reduced leptin‐mediated renal sympathetic nerve activity in obese rats. The study suggests that enhanced leptin‐mediated sympathetic activation in obesity may via hypothalamic neuroinflammatory pathway. We propose Sirt1 and FoxO1 in hypothalamus are key regulators of leptin signaling pathway contributed to the over sympathetic activation in obesity.