Jeong HW, Hsu KC, Lee J-W, Ham M, Huh JY, Shin HJ, Kim WS, Kim JB. Berberine suppresses proinflammatory responses through AMPK activation in macrophages. Am J Physiol Endocrinol Metab 296: E955-E964, 2009. First published February 10, 2009 doi:10.1152/ajpendo.90599.2008 has been shown to improve several metabolic disorders, such as obesity, type 2 diabetes, and dyslipidemia, by stimulating AMP-activated protein kinase (AMPK). However, the effects of BBR on proinflammatory responses in macrophages are poorly understood. Here we show that BBR represses proinflammatory responses through AMPK activation in macrophages. In adipose tissue of obese db/db mice, BBR treatment significantly downregulated the expression of proinflammatory genes such as TNF-␣, IL-1␤, IL-6, monocyte chemoattractant protein-1 (MCP-1), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Consistently, BBR inhibited LPS-induced expression of proinflammatory genes including IL-1␤, IL-6, iNOS, MCP-1, COX-2, and matrix metalloprotease-9 in peritoneal macrophages and RAW 264.7 cells. Upon various proinflammatory signals including LPS, free fatty acids, and hydrogen peroxide, BBR suppressed the phosphorylation of MAPKs, such as p38, ERK, and JNK, and the level of reactive oxygen species in macrophages. Moreover, these inhibitory effects of BBR on proinflammatory responses were abolished by AMPK inhibition via either compound C, an AMPK inhibitor, or dominant-negative AMPK, implying that BBR would downregulate proinflammatory responses in macrophages via AMPK stimulation.mitogen-activated protein kinase; adenosine 5Ј-monophosphate-activated protein kinase; reactive oxygen species INFLAMMATION IS AN IMPORTANT RESPONSE that protects host organisms against external injuries and pathogens. Nevertheless, many recent reports (19,42,49) have suggested that obesity is tightly associated with a chronic and low-grade inflammatory state. In obese subjects, macrophage infiltration is increased into the adipose tissue, which contributes to developing insulin resistance (16,43). Inflammation is also known to trigger atherosclerosis, a coronary artery disease the hallmark of which is the formation of fatty deposits inside the artery walls (17,35,36). Thus accumulating evidence suggests that chronic inflammatory processes would constitute a crucial part in the pathogenesis of metabolic disorders including obesity, lipid dysregulation, insulin resistance, and atherosclerosis.Cellular events of inflammatory responses are associated with the redox balance and mitogen-activated protein kinase (MAPK) signaling pathways. In macrophages, lipopolysaccharide (LPS), a major component of bacterial cell walls, potently increases the levels of cellular reactive oxygen species (ROS) and MAPK phosphorylation, resulting in promoting proinflammatory responses (51). Consistently, specific inhibition of cellular ROS and MAPK suppresses inflammatory signaling, implying that the cellular regulator for ROS and MAPK activity might be a key factor for inflammatory respons...