The 5-HT(1A) agonist 8-hydroxy-2 (di-n-propylamino) tetralin (8-OH-DPAT) causes inhibition of caspase-3 and apoptosis via the extracellular signal-regulated kinases (ERK1/2) in hippocampal HN2-5 cells. Two 5-HT(1A) agonists, Repinotan hydrochloride (BAY x 3702) and 8-OH-DPAT, block caspase-3 activation and apoptosis caused by anoxia/reoxygenation and H(2)O(2) treatment. This is reversed upon transient expression of dominant negative Ras (N17Ras) and Raf-1 (Raf301), confirming the involvement of Ras and Raf-1 in this 5-HT(1A)-R-->ERK1/2-->caspase-3 pathway. A selective inhibitor of phospholipase Cbeta (PLCbeta) (U73122) but not a general protein kinase C (PKC) inhibitor (GFX) reversed the 5-HT(1A)-R-mediated ERK1/2 stimulation. However, both GFX and the PKCalpha and PKCbeta(1) inhibitor Gö6976 reversed the ERK1/2-mediated inhibition of caspase-3. ERK-dependent activation of only PKCalpha was observed in immunoprecipitates obtained from 5-HT(1A) agonist-treated HN2-5 cells. Finally, transient expression of kinase-negative PKCalpha eliminated the 8-OH-DPAT-evoked block on the H(2)O(2)-triggered caspase-3 stimulation, establishing PKCalpha as a link between ERK and caspase-3 (5-HT(1A)-R-->PLC-->ERK1/2-->PKCalpha-->caspase-3). Our results elucidate a novel yet general, neuroprotective pathway through which G protein-coupled receptors could cause inhibition of effector caspases, such as caspase-3.
Obesity, characterized by chronic activation of inflammatory pathways, is a critical factor contributing to insulin resistance (IR) and type 2 diabetes (T2D). Free fatty acids (FFAs) are increased in obesity and are implicated as proximate causes of IR and induction of inflammatory signaling in adipose, liver, muscle, and pancreas. Cells of the innate immune system produce cytokines, and other factors that affect insulin signaling and result in the development of IR. In the lean state, adipose tissue is populated by adipose tissue macrophage of the anti-inflammatory M2 type (ATM2) and natural killer (NK) cells; this maintains the insulin-sensitive phenotype because ATM2 cells secrete IL10. In contrast, obesity induces lipolysis and release of pro-inflammatory FFAs and factors, such as chemokine (C–C motif) ligand 2 (CCL2) and tumor necrosis factor alpha (TNF-α), which recruit blood monocytes in adipose tissue, where they are converted to macrophages of the highly pro-inflammatory M1-type (ATM1). Activated ATM1 produce large amounts of pro-inflammatory mediators such as TNF-α, interleukin-1β, IL-6, leukotriene B4, nitric oxide (NO), and resistin that work in a paracrine fashion and cause IR in adipose tissue. In the liver, both pro-inflammatory Kupffer cells (M1-KCs) and recruited hepatic macrophages (Ly6Chigh) contribute to decreased hepatic insulin sensitivity. The present mini-review will update the bidirectional interaction between the immune system and obesity-induced changes in metabolism in adipose tissue and liver and the metabolic consequences thereof.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.