Macelignan is a neuroprotective lingan isolated from nutmeg (Myristica fragrans) that protects dopaminergic neurons from inflammatory degeneration. Macelignans have been shown to possess a broad range of pharmacological properties, including anti-bacterial, antiinflammatory, and anti-cancer activity. It has also been demonstrated that macelignans have anti-diabetes, hepatoprotective, and more importantly, neuroprotective properties. Apparently, the neuroprotective effect of macelignan is mediated by PPARγ activation and arginase-1 expression. Macelignan inhibits LPS induced production of NO as well and inflammatory cytokines including TNF and IL- 1β in primary cultures of microglia. Macelignan reduced serum glucose, insulin, triglycerides, free fatty acid levels, and triglycerides levels in the skeletal muscle and liver of db/db mice. Furthermore, macelignan significantly improved glucose and insulin tolerance in these mice, and without altering food intake, their body weights were slightly reduced while weights of troglitazone-treated mice increased. Macelignan increased adiponectin expression in adipose tissue and serum, whereas the expression and serum levels of tumor necrosis factor-alpha and interleukin-6 decreased. Macelignan downregulated inflammatory gene expression in the liver and increased AMP-activated protein kinase activation in the skeletal muscle of db/db mice. Strikingly, macelignan reduced endoplasmic reticulum (ER) stress and c-Jun NH2-terminal kinase activation in the liver and adipose tissue of db/db mice and subsequently increased insulin signaling.