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...

Liver X receptors (LXRs) are nuclear hormone receptors that regulate cholesterol and fatty acid metabolism in liver tissue and in macrophages. Although LXR activation enhances lipogenesis, it is not well understood whether LXRs are involved in adipocyte differentiation. Here, we show that LXR activation stimulated the execution of adipogenesis, as determined by lipid droplet accumulation and adipocyte-specific gene expression in vivo and in vitro. In adipocytes, LXR activation with T0901317 primarily enhanced the expression of lipogenic genes such as the ADD1/SREBP1c and FAS genes and substantially increased the expression of the adipocyte-specific genes encoding PPAR␥ (peroxisome proliferator-activated receptor ␥) and aP2. Administration of the LXR agonist T0901317 to lean mice promoted the expression of most lipogenic and adipogenic genes in fat and liver tissues. It is of interest that the PPAR␥ gene is a novel target gene of LXR, since the PPAR␥ promoter contains the conserved binding site of LXR and was transactivated by the expression of LXR␣. Moreover, activated LXR␣ exhibited an increase of DNA binding to its target gene promoters, such as ADD1/SREBP1c and PPAR␥, which appeared to be closely associated with hyperacetylation of histone H3 in the promoter regions of those genes. Furthermore, the suppression of LXR␣ by small interfering RNA attenuated adipocyte differentiation. Taken together, these results suggest that LXR plays a role in the execution of adipocyte differentiation by regulation of lipogenesis and adipocyte-specific gene expression.Adipocyte differentiation, called adipogenesis, is a complex process accompanied by coordinated changes in morphology, hormone sensitivity, and gene expression. These changes are regulated by several transcription factors, including C/EBPs, peroxisome proliferator-activated receptor ␥ (PPAR␥), and ADD1/SREBP1c (44, 67). These transcription factors interact with each other to execute adipocyte differentiation, including lipogenesis and adipocyte-specific gene expression, which are pivotal for metabolism in adipocytes. Expression of C/EBP␤ and C/EBP␦ occurs at a very early stage of adipocyte differentiation, and overexpression of C/EBP␣ or C/EBP␤ promotes adipogenesis through cooperation with PPAR␥ (15, 32, 68, 69). PPAR␥, a member of the nuclear hormone receptor family, is predominantly expressed in brown and white adipose tissue (58, 59). PPAR␥ is activated by fatty acid-derived molecules such as prostaglandin J2 and synthetic thiazolidinediones (TZDs), novel drugs used in type II diabetes treatment (14,25,29). Recent studies involving PPAR␥ knockout mice indicated that the major roles of PPAR␥ are adipocyte differentiation and insulin sensitization (3,26,43). ADD1/SREBP1c, which also appears to be involved in adipocyte differentiation, is highly expressed in adipose tissue and liver and is also expressed early in adipocyte differentiation (22,60). ADD1/ SREBP1c stimulates the expression of several lipogenic genes, including FAS, LPL, ACC, SCD-1, and SCD-2 (22, 5...

AMP-activated protein kinase (AMPK) plays an important role in regulating whole body energy homeostasis. Recently, it has been demonstrated that berberine (BBR) exerts antiobesity and antidiabetic effects in obese and diabetic rodent models through the activation of AMPK in peripheral tissues. Here we show that BBR improves lipid dysregulation and fatty liver in obese mice through central and peripheral actions. In obese db/db and ob/ob mice, BBR treatment reduced liver weight, hepatic and plasma triglyceride, and cholesterol contents. In the liver and muscle of db/db mice, BBR promoted AMPK activity and fatty acid oxidation and changed expression of genes involved in lipid metabolism. Additionally, intracerebroventricular administration of BBR decreased the level of malonyl-CoA and stimulated the expression of fatty acid oxidation genes in skeletal muscle. Together, these data suggest that BBR would improve fatty liver in obese subjects, which is probably mediated not only by peripheral AMPK activation but also by neural signaling from the central nervous system.

Adiponectin is exclusively expressed in differentiated adipocytes and plays an important role in regulating energy homeostasis, including the glucose and lipid metabolism associated with increased insulin sensitivity. However, the control of adiponectin gene expression in adipocytes is poorly understood. We show here that levels of adiponectin mRNA and protein are reduced in the white adipose tissue of ob/ob and db/db mice and that there is a concomitant reduction of the adipocyte determination-and differentiation-dependent factor 1 (ADD1)/sterol regulatory element-binding protein 1c (SREBP1c) transcription factor. To determine whether ADD1/SREBP1c regulates adiponectin gene expression, we isolated and characterized the mouse adiponectin promoter. Analysis of the adiponectin promoter revealed putative binding sites for the adipogenic transcription factors ADD1/SREBP1c, peroxisomal proliferator-activated receptor ␥ and CCAAT enhancerbinding proteins. DNase I footprinting and chromatin immunoprecipitation analyses revealed that ADD1/ SREBP1c binds in vitro and in vivo to the proximal promoter containing sterol regulatory element (SRE) motifs. A luciferase reporter containing the promoter was transactivated by ADD1/SREBP1c, and introduction of SRE mutations into the construct abolished transactivation. Adenoviral overexpression of ADD1/SREBP1c also elevated adiponectin mRNA and protein levels in 3T3-L1 adipocytes. Furthermore, insulin stimulated adiponectin mRNA expression in adipocytes and augmented transactivation of the adiponectin promoter by ADD1/ SREBP1c. Taken together, these data indicate that ADD1/SREBP1c controls adiponectin gene expression in differentiated adipocytes.

Obesity is caused by an imbalance between caloric intake and energy expenditure and accumulation of excess lipids in adipose tissues. Recent studies have demonstrated that green tea and its processed products (e.g., oolong and black tea) are introduced to exert beneficial effects on lipid metabolism. Here, we propose that fermented green tea (FGT) extract, as a novel processed green tea, exhibits antiobesity effects. FGT reduced body weight gain and fat mass without modifying food intake. mRNA expression levels of lipogenic and inflammatory genes were downregulated in white adipose tissue of FGT-administered mice. FGT treatment alleviated glucose intolerance and fatty liver symptoms, common complications of obesity. Notably, FGT restored the changes in gut microbiota composition (e.g., the Firmicutes/Bacteroidetes and Bacteroides/Prevotella ratios), which is reported to be closely related with the development of obesity and insulin resistance, induced by high-fat diets. Collectively, FGT improves obesity and its associated symptoms and modulates composition of gut microbiota; thus, it could be used as a novel dietary component to control obesity and related symptoms.

(1) Background: Extensive research has focused on flavan-3-ols, but information about the bioactivities of green tea flavonols is limited. (2) Methods: In this study, we investigated the antioxidative, anti-inflammatory, and anticancer effects of flavonol glycosides and aglycones from green tea using in vitro cell models. The fractions rich in flavonol glycoside (FLG) and flavonol aglycone (FLA) were obtained from green tea extract after treatment with tannase and cellulase, respectively. (3) Results: FLG and FLA contained 16 and 13 derivatives, respectively, including apigenin, kaempferol, myricetin, and quercetin, determined by mass spectrometry. FLA exhibited higher radical-scavenging activity than that of FLG. FLG and FLA attenuated the levels of intracellular oxidative stress in neuron-like PC-12 cells. The treatment of RAW 264.7 murine macrophages with FLG and FLA significantly reduced the mRNA expression of inflammation-related genes in a dose-dependent manner. Furthermore, FLG and FLA treatments decreased the viability of the colon adenoma cell line DLD-1 and breast cancer cell line E0771. Moreover, the treatment with FLG or FLA combined with paclitaxel had synergistic anticancer effects on the DLD-1 cell line. (4) Conclusions: Flavonols from green tea exerted beneficial effects on health and may be superior to flavan-3-ols.

Obesity is characterized by excessive accumulation of lipid metabolites in adipose tissues as well as in nonadipose tissues, such as liver, muscle, and pancreas ( 1 ). Because obesity is considered as a major risk factor for most metabolic diseases, including hyperlipidemia, hypercholesterolemia, type 2 diabetes, hypertension, and cardiovascular disease ( 2-4 ), numerous investigations have been conducted to elucidate the key components in energy homeostasis, which is crucial to develop therapeutic agents for obesity and obesity-associated metabolic disorders.AMP-activated protein kinase (AMPK) is a master energy sensor that integrates nutrients, hormones, and stress signals to maintain whole-body energy homeostasis ( 5, 6 ). Under various stress conditions, AMPK is activated by allosteric stimulation in response to an increased AMP/ATP ratio or mitochondria activity change. AMPK activation also is induced by upstream stress kinases, such as liver kinase B1 (LKB1) or calcium/calmodulin-dependent protein kinase kinase (CaMKK) ( 7-10 ). Activated AMPK is involved in the regulation of diverse metabolic pathways.

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