Effects of Flavanone Derivatives on Adipocyte Differentiation and Lipid Accumulation in 3T3-L1 Cells.

Flavanones, a class of flavonoids, are abundant in fruits, vegetables, and herbs. They are known to have several biological activities, such as anti-inflammatory and anti-cancer activities, but their effects on obesity remain unclear. Obesity is closely associated with adipocyte differentiation and lipid accumulation in adipose tissue.

Inhibitory Effects of Hydrolysable Tannins on Lipid Accumulation in 3T3-L1 Cells.

Obesity is currently the most common cause of metabolic diseases including type 2 diabetes and hyperlipidemia. Obesity results from excess lipid accumulation in adipose tissue. Several studies have investigated the inhibitory effects of natural plant-derived products on adipocyte differentiation and lipid accumulation.

Adiponectin regulates the circadian rhythm of glucose and lipid metabolism.

Adiponectin is a cytokine secreted from adipocytes and regulates metabolism. Although serum adiponectin levels show diurnal variations, it is not clear if the effects of adiponectin are time-dependent. Therefore, this study conducted locomotor activity analyses and various metabolic studies using the adiponectin knockout (APN (-/-)) and the APN (+/+) mice to understand whether adiponectin regulates the circadian rhythm of glucose and lipid metabolism.

Deletion of Prevents Diet-Induced Ectopic Fat Accumulation by Controlling Oxidative Capacity in the Skeletal Muscle.

Brain and muscle arnt-like protein 1 (BMAL1), is a transcription factor known to regulate circadian rhythm. BMAL1 was originally characterized by its high expression in the skeletal muscle. Since the skeletal muscle is the dominant organ system in energy metabolism, the possible functions of BMAL1 in the skeletal muscle include the control of metabolism.

Relevance of the hippocampal endoplasmic reticulum stress response in a mouse model of chronic kidney disease.

It has been shown that the incidence of cognitive impairment increases with the severity of chronic kidney disease (CKD). A previous study has demonstrated that hippocampal oxidative stress contributes to cognitive dysfunction in CKD model mice. Endoplasmic reticulum (ER) stress is thought to contribute significantly to neuronal dysfunction, but its role in the hippocampal dysfunction seen in CKD still remains unclear.

Indirubin 3'-oxime inhibits anticancer agent-induced YB-1 nuclear translocation in HepG2 human hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is a disease with poor prognosis. Nuclear accumulation of YB-1 is closely related to the malignancy of HCC. Treatment with anticancer agents often induces translocation of YB-1 from cytoplasm to nucleus and activates the expression of multidrug resistance gene 1 (MDR1).

Neuroprotective effect of S-allyl-l-cysteine derivatives against endoplasmic reticulum stress-induced cytotoxicity is independent of calpain inhibition.

S-allyl-l-cysteine (SAC) is known to have neuroprotective properties. We synthesized various SAC derivatives and tested their effects on endoplasmic reticulum stress-induced neurotoxicity in cultured hippocampal neurons (HPNs). Among the compounds tested, S-propyl-l-cysteine (SPC) exhibited the strongest neuroprotective activity in HPNs, followed by S-ethyl-l-cysteine (SEC) and S-methyl-l-cysteine (SMC).

Inhibitory effects of compounds isolated from the dried branches and leaves of murta (Myrceugenia euosma) on lipid accumulation in 3T3-L1 cells.

As obesity is a global health concern the demand for anti-obesity drugs is high. In this study, we investigated the anti-obesity effect of the dried branches and leaves of murta (Myrceugenia euosma Legrand, Myrtaceae). A methanol extract of the dried branches and leaves of murta inhibited adipogenesis in 3T3-L1 cells.

Aryl Hydrocarbon Receptor Plays Protective Roles against High Fat Diet (HFD)-induced Hepatic Steatosis and the Subsequent Lipotoxicity via Direct Transcriptional Regulation of Socs3 Gene Expression.

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor regulating the expression of genes involved in xenobiotic response. Recent studies have suggested that AhR plays essential roles not only in xenobiotic detoxification but also energy metabolism. Thus, in this study, we studied the roles of AhR in lipid metabolism.

Estrogen sulfotransferase/SULT1E1 promotes human adipogenesis.

Estrogen sulfotransferase (EST/SULT1E1) is known to catalyze the sulfoconjugation and deactivation of estrogens. The goal of this study is to determine whether and how EST plays a role in human adipogenesis. By using human primary adipose-derived stem cells (ASCs) and whole-fat tissues from the abdominal subcutaneous fat of obese and nonobese subjects, we showed that the expression of EST was low in preadipocytes but increased upon differentiation.

Aryl hydrocarbon receptor modulates NADPH oxidase activity via direct transcriptional regulation of p40phox expression.

A member of the NADPH oxidase subunits, p40(phox) plays an important role in the regulation of NADPH oxidase activity and the subsequent production of reactive oxygen species (ROS). In this study, we show that mouse p40(phox) is a novel transcriptional target of the aryl hydrocarbon receptor (AhR), known as a dioxin receptor or xenobiotic receptor, in the liver. Treatment of mice with 3-methylcholanthrene (3MC) increased p40(phox) gene expression in the liver, but this induction of p40(phox) gene expression was diminished by the deletion of the AhR gene in the liver.

Role of nuclear receptors in lipid dysfunction and obesity-related diseases.

This article is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 12 meeting in San Diego, CA. The presentations discussed the roles of a number of nuclear receptors in regulating glucose and lipid homeostasis, the pathophysiology of obesity-related disease states, and the promise associated with targeting their activities to treat these diseases. While many of these receptors (in particular, constitutive androstane receptor and pregnane X receptor) and their target enzymes have been thought of as regulators of drug and xenobiotic metabolism, this symposium highlighted the advances made in our understanding of the endogenous functions of these receptors.

Estrogen sulfotransferase inhibits adipocyte differentiation.

The estrogen sulfotransferase (EST) is a phase II drug-metabolizing enzyme known to catalyze the sulfoconjugation of estrogens. EST is highly expressed in the white adipose tissue of male mice, but the role of EST in the development and function of adipocytes remains largely unknown. In this report, we showed that EST played an important role in adipocyte differentiation.

Transcriptional profiling reveals a role for RORalpha in regulating gene expression in obesity-associated inflammation and hepatic steatosis.

Retinoid-related orphan receptor (ROR)α4 is the major RORα isoform expressed in adipose tissues and liver. In this study we demonstrate that RORα-deficient staggerer mice (RORα(sg/sg)) fed with a high-fat diet (HFD) exhibited reduced adiposity and hepatic triglyceride levels compared with wild-type (WT) littermates and were resistant to the development of hepatic steatosis, adipose-associated inflammation, and insulin resistance. Gene expression profiling showed that many genes involved in triglyceride synthesis and storage, including Cidec, Cidea, and Mogat1, were expressed at much lower levels in liver of RORα(sg/sg) mice.

MicroRNA hsa-miR-613 targets the human LXRα gene and mediates a feedback loop of LXRα autoregulation.

The nuclear receptor liver X receptor (LXR) is a ligand-dependent transcription factor that plays an important role in the metabolism and homeostasis of cholesterol, lipids, bile acids, and steroid hormones. MicroRNAs (miRNAs) are recently recognized important negative regulators of gene expression. In this report, we showed that miRNA hsa-miR-613 played an important role in the autoregulation of the human LXRα gene.

Nuclear orphan receptor TAK1/TR4-deficient mice are protected against obesity-linked inflammation, hepatic steatosis, and insulin resistance.

Objective: The nuclear receptor TAK1/TR4/NR2C2 is expressed in several tissues that are important in the control of energy homeostasis. In this study, we investigate whether TAK1 functions as a regulator of lipid and energy homeostasis and has a role in metabolic syndrome.

Research Design And Methods: We generated TAK1-deficient (TAK1⁻(/)⁻) mice to study the function of TAK1 in the development of metabolic syndrome in aged mice and mice fed a high-fat diet (HFD).

A novel role for the dioxin receptor in fatty acid metabolism and hepatic steatosis.

Background & Aims: The aryl hydrocarbon receptor (AhR) also known as the dioxin receptor or xenobiotic receptor is a member of the basic helix-loop-helix/period AhR nuclear translocator single minded family. The goal of this study was to determine the endobiotic role of AhR in hepatic steatosis.

Methods: Wild-type, constitutively activated AhR transgenic, AhR null and CD36/fatty acid translocase null mice were used to investigate the role of AhR in steatosis and the involvement of CD36 in the steatotic effect of AhR.

Structural basis for hydroxycholesterols as natural ligands of orphan nuclear receptor RORgamma.

The retinoic acid-related orphan receptor gamma (RORgamma) has important roles in development and metabolic homeostasis. Although the biological functions of RORgamma have been studied extensively, no ligands for RORgamma have been identified, and no structure of RORgamma has been reported. In this study, we showed that hydroxycholesterols promote the recruitment of coactivators by RORgamma using biochemical assays.

The constitutive androstane receptor is an anti-obesity nuclear receptor that improves insulin sensitivity.

Obesity and type 2 diabetes are related metabolic disorders of high prevalence. The constitutive androstane receptor (CAR) was initially characterized as a xenobiotic receptor regulating the responses of mammals to xenotoxicants. In this study, we have uncovered an unexpected role of CAR in preventing obesity and alleviating type 2 diabetes.

PXR and CAR in energy metabolism.

The nuclear receptors pregnane X receptor (PXR, or NR1I2) and constitutive androstane receptor (CAR, or NR1I3) were originally identified as xenosensors that regulate the expression of Phase I and Phase II drug-metabolizing enzymes and transporters. Recent results suggest that PXR and CAR also have important endobiotic roles in energy metabolism by affecting the metabolism of fatty acids, lipids and glucose. PXR and CAR exert their effects on energy metabolism through direct gene regulation or through crosstalk with other transcriptional regulators.

The aldo-keto reductase Akr1b7 gene is a common transcriptional target of xenobiotic receptors pregnane X receptor and constitutive androstane receptor.

Aldo-keto reductase (AKR) family 1, member 7 (AKR1B7), a member of the AKR superfamily, has been suggested to play an important role in the detoxification of lipid peroxidation by-products. The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are xenosensors postulated to alleviate xeno- and endobiotic chemical insults. In this study, we show that the mouse Akr1b7 is a shared transcriptional target of PXR and CAR in the liver and intestine.

Glucocorticoids antagonize estrogens by glucocorticoid receptor-mediated activation of estrogen sulfotransferase.

Glucocorticoids and estrogens are two classes of steroid hormones that have essential but distinct physiologic functions. Estrogens also represent a risk factor for breast cancer. It has been suggested that glucocorticoids can attenuate estrogen responses, but the mechanism by which glucocorticoids inhibit estrogenic activity is unknown.

The emerging role of nuclear receptor RORalpha and its crosstalk with LXR in xeno- and endobiotic gene regulation.

Retinoid-related orphan receptors (RORs), including the alpha, beta and gamma isoforms (NR1F1-3), are orphan nuclear receptors that have been implicated in tissue development, immune responses, and circadian rhythm. Although RORalpha and RORgamma have been shown to be expressed in the liver, the hepatic function of these two RORs remains unknown. We have recently shown that loss of RORalpha and/or RORgamma can positively or negatively influence the expression of multiple Phase I and Phase II drug metabolizing enzymes and transporters in the liver.

Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARgamma in promoting steatosis.

Background & Aims: Liver X receptor (LXR) is known to promote hepatic lipogenesis by activating the lipogenic transcriptional factor sterol regulatory element-binding protein (Srebp). Pregnane X receptor (PXR), a previously known "xenobiotic receptor," could mediate a Srebp-independent lipogenic pathway by activating the free fatty acid uptake transporter Cd36. The goal of this study is to investigate further the role of Cd36 in hepatic steatosis.

Identification of oxysterol 7alpha-hydroxylase (Cyp7b1) as a novel retinoid-related orphan receptor alpha (RORalpha) (NR1F1) target gene and a functional cross-talk between RORalpha and liver X receptor (NR1H3).

The retinoid-related orphan receptors (RORs) and liver X receptors (LXRs) were postulated to have distinct functions. RORs play a role in tissue development and circadian rhythm, whereas LXRs are sterol sensors that affect lipid homeostasis. In this study, we revealed a novel function of RORalpha (NR1F1) in regulating the oxysterol 7alpha-hydroxylase (Cyp7b1), an enzyme critical for the homeostasis of cholesterol, bile acids, and oxysterols.