Uric Acid Secretion from Adipose Tissue and Its Increase in Obesity

Obesity is often accompanied by hyperuricemia. However, purine metabolism in various tissues, especially regarding uric acid production, has not been fully elucidated. Here we report, using mouse models, that adipose tissue could produce and secrete uric acid through xanthine oxidoreductase (XOR) and that the production was enhanced in obesity. Plasma uric acid was elevated in obese mice and attenuated by administration of the XOR inhibitor febuxostat. Adipose tissue was one of major organs that had abundant expression and activities of XOR, and adipose tissues in obese mice had higher XOR activities than those in control mice. 3T3-L1 and mouse primary mature adipocytes produced and secreted uric acid into culture medium. The secretion was inhibited by febuxostat in a dose-dependent manner or by gene knockdown of XOR. Surgical ischemia in adipose tissue increased local uric acid production and secretion via XOR, with a subsequent increase in circulating uric acid levels. Uric acid secretion from whole adipose tissue was increased in obese mice, and uric acid secretion from 3T3-L1 adipocytes was increased under hypoxia. Our results suggest that purine catabolism in adipose tissue could be enhanced in obesity.     

The uremic toxin indoxyl sulfate exacerbates reactive oxygen species production and inflammation in 3T3-L1 adipose cells

Inflammation and oxidative stress are common features of patients with chronic kidney disease (CKD) and many uremic solutes retained in these patients could be involved in these processes, among which protein-bound solutes such as indoxyl sulfate (IS). White adipose tissue recently gained attention as an important source of inflammation and oxidative stress. To examine the effect of IS on adipocytes, 3T3-L1 adipose cells were incubated with IS to mimic the conditions encountered in uremic patients. Incubation of adipose cells with IS increased reactive oxygen species production generated mainly through activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase since it was prevented by the NADPH oxidase inhibitor apocynin. Exposure to IS furthermore exacerbated the secretion of tumor necrosis factor-α and interleukin-6 by adipose cells. This inflammatory response was prevented by NADPH oxidase inhibition pinpointing the pivotal role of intracellular oxidative stress. IS induces adipocyte perturbation and promotes inflammatory state mainly through induction of oxidative stress. IS, a uremic toxin, accumulates in CKD patients could, therefore, be an important mediator of adipocyte dysfunction in these patients.     

Green tea catechins ameliorate adipose insulin resistance by improving oxidative stress

Epidemiological data have suggested that drinking green tea is negatively associated with diabetes, and adipose oxidative stress may have a central role in causing insulin resistance, according to recent findings. The aim of this work is to elucidate a new mechanism for green tea's anti-insulin resistance effect. We used obese KK-ay mice, high-fat diet-induced obese rats, and induced insulin resistant 3T3-L1 adipocytes as models. Insulin sensitivity and adipose reactive oxidative species (ROS) levels were detected in animals and adipocytes. The oxidative stress assay and glucose uptake ability assay were performed, and the effects of EGCG on insulin signals were detected. Green tea catechins (GTCs) significantly decreased glucose levels and increased glucose tolerance in animals. GTCs reduced ROS content in both models of animal and adipocytes. EGCG attenuated dexamethasone and TNF-α promoted ROS generation and increased glucose uptake ability. EGCG also decreased JNK phosphorylation and promoted GLUT-4 translocation. EGCG and GTCs could improve adipose insulin resistance, and exact this effect on their ROS scavenging functions.     

Hyperuricemia enhances intracellular urate accumulation via down-regulation of cell-surface BCRP/ABCG2 expression in vascular endothelial cells

Hyperuricemia has been recognized as an independent risk factor for cardiovascular disease. Urate stimulates NADPH oxidase and induces production of reactive oxygen species (ROS); consequently, intracellular urate accumulation can induce oxidative stress leading to endothelial dysfunction. Here, we studied the mechanism involved, using human umbilical vascular endothelial cells (HUVEC) as a model. Pretreatment with 15 mg/dL unlabeled uric acid (corresponding to hyperuricemia) resulted in increased uptake of [¹⁴C]uric acid at steady-state by HUVEC, whereas pretreatment with 5 mg/dL uric acid (in the normal serum concentration range) did not. However, the initial uptake rate of [¹⁴C]uric acid was not affected by uric acid at either concentration. These results suggest that efflux transport of uric acid is decreased under hyperuricemic conditions. We observed a concomitant decrease of phosphorylated endothelial nitric oxide synthase. Plasma membrane expression of breast cancer resistance protein (BCRP), a uric acid efflux transporter, was decreased under hyperuricemia, though the total cellular expression of BCRP remained constant. Uric acid did not affect expression of another uric acid efflux transporter, multidrug resistance associated protein 4 (MRP4). Moreover, phosphorylation of Akt, which regulates plasma membrane localization of BCRP, was decreased. These uric acid-induced changes of BCRP and Akt were reversed in the presence of the antioxidant N-acetylcysteine. These results suggest that in hyperuricemia, uric acid-induced ROS generation inhibits Akt phosphorylation, causing a decrease in plasma membrane localization of BCRP, and the resulting decrease of BCRP-mediated efflux leads to increased uric acid accumulation and dysregulation of endothelial function.     

Folic acid supplementation inhibits NADPH oxidase-mediated superoxide anion production in the kidney

Hyperhomocysteinemia, a condition of elevated blood homocysteine (Hcy) levels, is a metabolic disease. It is a common clinical finding in patients with chronic kidney diseases and occurs almost uniformly in patients with end-stage renal disease. Hyperhomocysteinemia is also a risk factor for cardiovascular disease. Our recent studies indicate that hyperhomocysteinemia can lead to renal injury by inducing oxidative stress. Oxidative stress is one of the important mechanisms contributing to Hcy-induced tissue injury. Folic acid supplementation is regarded as a promising approach for prevention and treatment of cardiovascular disease associated with hyperhomocysteinemia due to its Hcy-lowering effect. However, its effect on the kidney is not clear. The aim of this study was to examine the effect of folic acid supplementation on Hcy-induced superoxide anion production via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the kidney during hyperhomocysteinemia. Hyperhomocysteinemia was induced in male Sprague-Dawley rats fed a high-methionine diet for 12 wk with or without folic acid supplementation. A group of rats fed a regular diet was used as control. There was a significant increase in levels of superoxide anions and lipid peroxides in kidneys isolated from hyperhomocysteinemic rats. Activation of NADPH oxidase was responsible for hyperhomocysteinemia-induced oxidative stress in the kidney. Folic acid supplementation effectively antagonized hyperhomocysteinemia-induced oxidative stress via its Hcy-lowering and Hcy-independent effect. In vitro study also showed that 5-methyltetrahydrofolate, an active form of folate, effectively reduced Hcy-induced superoxide anion production via NADPH oxidase. Xanthine oxidase activity was increased and superoxide dismutase (SOD) activity was decreased in the kidney of hyperhomocysteinemic rats, which might also contribute to an elevation of superoxide anion level in the kidney. Folic acid supplementation attenuated xanthine oxidase activity and restored SOD activity in the kidney of hyperhomocysteinemic rats. These results suggest that folic acid supplementation may offer renal protective effect against oxidative stress.     

Uric Acid: The Oxidant-Antioxidant Paradox

Uric acid, despite being a major antioxidant in the human plasma, both correlates and predicts development of obesity, hypertension, and cardiovascular disease, conditions associated with oxidative stress. While one explanation for this paradox could be that a rise in uric acid represents an attempted protective response by the host, we review the evidence that uric acid may function either as an antioxidant (primarily in plasma) or pro-oxidant (primarily within the cell). We suggest that it is the pro-oxidative effects of uric acid that occur in cardiovascular disease and may have a contributory role in the pathogenesis of these conditions.     

Uric acid: the oxidant-antioxidant paradox

Uric acid, despite being a major antioxidant in the human plasma, both correlates and predicts development of obesity, hypertension, and cardiovascular disease, conditions associated with oxidative stress. While one explanation for this paradox could be that a rise in uric acid represents an attempted protective response by the host, we review the evidence that uric acid may function either as an antioxidant (primarily in plasma) or pro-oxidant (primarily within the cell). We suggest that it is the pro-oxidative effects of uric acid that occur in cardiovascular disease and may have a contributory role in the pathogenesis of these conditions.     

Apocynin: a potent NADPH oxidase inhibitor for the management of atrial fibrillation

Abstract

Oxidative stress in atrial tissue may be causally related to atrial fibrillation as suggested by clinical and animal studies. Reactive oxygen species (ROS) are known to play a key role in fibrosis and the induction of after-depolarization and triggered activity. Therefore, suppressing oxidative stress may have a potential beneficial role in the management of atrial fibrillation. Since increased NADPH oxidase activity is shown to play a key role in generation of ROS in atrial tissue and in atrial fibrillation, our proposed strategy to target upstream inhibition of ROS production by inhibition of NADPH oxidase activity may provide a novel approach to prevent atrial fibrillation recurrences. We hypothesize that apocynin could be effective against atrial fibrillation, by virtue of its potent inhibitory effect of a major oxidative system (i.e. NADPH oxidase) combined with its demonstrated anti-inflammatory, antifibrotic and antihypertensive effects which partially are driven from its antioxidant property. Atrial fibrillation is known to be initiated by the interaction of these multiple factors.     

Janus-faced role of endothelial NO synthase in vascular disease: uncoupling of oxygen reduction from NO synthesis and its pharmacological reversal

Endothelial NO synthase (eNOS) is the predominant enzyme responsible for vascular NO synthesis. A functional eNOS transfers electrons from NADPH to its heme center, where L-arginine is oxidized to L-citrulline and NO. Common conditions predisposing to atherosclerosis, such as hypertension, hypercholesterolemia, diabetes mellitus and smoking, are associated with enhanced production of reactive oxygen species (ROS) and reduced amounts of bioactive NO in the vessel wall. NADPH oxidases represent major sources of ROS in cardiovascular pathophysiology. NADPH oxidase-derived superoxide avidly interacts with eNOS-derived NO to form peroxynitrite (ONOO(-)), which oxidizes the essential NOS cofactor (6R-)5,6,7,8-tetrahydrobiopterin (BH(4)). As a consequence, oxygen reduction uncouples from NO synthesis, thereby rendering NOS to a superoxide-producing pro-atherosclerotic enzyme. Supplementation with BH(4) corrects eNOS dysfunction in several animal models and in patients. Administration of high local doses of the antioxidant L-ascorbic acid (vitamin C) improves endothelial function, whereas large-scale clinical trials do not support a strong role for oral vitamin C and/or E in reducing cardiovascular disease. Statins, angiotensin-converting enzyme inhibitors and AT1 receptor blockers have the potential of reducing vascular oxidative stress. Finally, novel approaches are being tested to block pathways leading to oxidative stress (e.g. protein kinase C) or to upregulate antioxidant enzymes.     

越冬胁迫对草鱼抗氧化能力及脂肪酸组成的影响

为了探讨草鱼(Ctenopharyngodon idellus)越冬期间氧化应激状况及其与组织脂肪酸比例变化的关联性,将草鱼[初始体重(1053.33±16.11) g]分别置于室外水泥培育池,自然越冬处理0、1周、2周、4周、8周、12周和16周后,进行生物学性状指标,肝胰脏、肌肉、前肠、脂肪组织和血清抗氧化能力指标及肝胰脏、肌肉、脂肪组织脂肪酸比例的测定,同时进行了抗氧化能力指标与脂肪酸比例间的关联性分析。结果表明,在越冬期间,草鱼机体体重、肝胰脏重量、肥满度、肝体比、脏体比、肠体比和腹腔脂肪指数均发生显著下降(P<0.05);但是肾指数和脾指数显著上升(P>0.05)。氧化胁迫应激最大的3个组织分别是脂肪组织、肝胰脏和肌肉。肝胰脏PUFA比例对总体脂肪酸比例产生了主要的影响(主成分载荷特征值>0.5),肌肉C18:2n-6和C16:0比例对总体脂肪酸组成产生主要影响,脂肪组织中的PUFA、n-6PUFA、SFA和MUFA比例对总体脂肪酸比例产生了主要影响;关联分析表明草鱼脂肪组织中SFA在越冬期间供应能量同时,与氧化应激乃至机体损伤显示正相关关联性,肌肉中PUF...     

NADPH oxidase-derived reactive oxygen species increases expression of monocyte chemotactic factor genes in cultured adipocytes

Excess glucose and free fatty acids delivered to adipose tissue causes local inflammation, which contributes to insulin resistance. Glucose and palmitate generate reactive oxygen species (ROS) in adipocytes, leading to monocyte chemotactic factor gene expression. Docosahexaenoate (DHA) has the opposite effect. In this study, we evaluated the potential sources of ROS in the presence of excess nutrients. Differentiated 3T3-L1 adipocytes were exposed to palmitate and DHA (250 μM) in either 5 or 25 mM glucose to evaluate the relative roles of mitochondrial electron transport and NADPH oxidases (NOX) as sources of ROS. Excess glucose and palmitate did not increase mitochondrial oxidative phosphorylation. However, glucose exposure increased glycolysis. Of the NOX family members, only NOX4 was expressed in adipocytes. Moreover, its activity was increased by excess glucose and palmitate and decreased by DHA. Silencing NOX4 inhibited palmitate- and glucose-stimulated ROS generation and monocyte chemotactic factor gene expression. NADPH, a substrate for NOX, and pentose phosphate pathway activity increased with glucose but not palmitate and decreased with DHA exposure. Inhibition of the pentose phosphate pathway by glucose-6-phosphate dehydrogenase inhibitors and siRNA suppressed ROS generation and monocyte chemotactic factor gene expression induced by both glucose and palmitate. Finally, both high glucose and palmitate induced NOX4 translocation into lipid rafts, effects that were blocked by DHA. Excess glucose and palmitate generate ROS via NOX4 rather than by mitochondrial oxidation in cultured adipocytes. NOX4 is regulated by both NADPH generated in the PPP and translocation of NOX4 into lipid rafts, leading to expression of monocyte chemotactic factors.     

Dysregulation of adipose glutathione peroxidase 3 in obesity contributes to local and systemic oxidative stress

Glutathione peroxidase 3 (GPx3) accounts for the major antioxidant activity in the plasma. Here, we demonstrate that down-regulation of GPx3 in the plasma of obese subjects is associated with adipose GPx3 dysregulation, resulting from the increase of inflammatory signals and oxidative stress. Although GPx3 was abundantly expressed in kidney, lung, and adipose tissue, we observed that GPx3 expression was reduced selectively in the adipose tissue of several obese animal models as decreasing plasma GPx3 level. Adipose GPx3 expression was greatly suppressed by prooxidative conditions such as high levels of TNFalpha and hypoxia. In contrast, the antioxidant N-acetyl cysteine and the antidiabetic drug rosiglitazone increased adipose GPx3 expression in obese and diabetic db/db mice. Moreover, GPx3 overexpression in adipocytes improved high glucose-induced insulin resistance and attenuated inflammatory gene expression whereas GPx3 neutralization in adipocytes promoted expression of proinflammatory genes. Taken together, these data suggest that suppression of GPx3 expression in the adipose tissue of obese subjects might constitute a vicious cycle to expand local reactive oxygen species accumulation in adipose tissue potentially into systemic oxidative stress and obesity-related metabolic complications.     

PKC-delta-dependent activation of oxidative stress in adipocytes of obese and insulin-resistant mice: role for NADPH oxidase

Oxidative stress is thought to be one of the causative factors contributing to insulin resistance and type 2 diabetes. Previously, we showed that reactive oxygen species (ROS) production is significantly increased in adipocytes from high-fat diet-induced obese and insulin-resistant mice (HF). ROS production was also associated with the increased activity of PKC-delta. In the present studies, we hypothesized that PKC-delta contributes to ROS generation and determined their intracellular source. NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI) reduced ROS levels by 50% in HF adipocytes, and inhibitors of NO synthase (L-NAME, 1 mM), xanthine oxidase (allopurinol, 100 microM), AGE formation (aminoguanidine, 10 microM), or the mitochondrial uncoupler (FCCP, 10 microM) had no effect. Rottlerin, a selective PKC-delta inhibitor, suppressed ROS levels by approximately 50%. However, neither GO-6976 nor LY-333531, effective inhibitors toward conventional PKC or PKC-beta, respectively, significantly altered ROS levels in HF adipocytes. Subsequently, adenoviral-mediated expression of wild-type PKC-delta or its dominant negative mutant (DN-PKC-delta) in HF adipocytes resulted in either a twofold increase in ROS levels or their suppression by 20%, respectively. In addition, both ROS levels and PKC-delta activity were sharply reduced by glucose depletion. Taken together, these results suggest that PKC-delta is responsible for elevated intracellular ROS production in HF adipocytes, and this is mediated by high glucose and NADPH oxidase.     

Adipose tissue fatty acid metabolism and cardiovascular disease

PURPOSE OF REVIEW: Fatty acid and triacylglycerol metabolism in adipose tissue may be involved in the generation of risk factors for cardiovascular disease and type 2 diabetes. Pharmaceutical companies are targeting adipocyte metabolism in their search for drugs for treating, or reducing the risk of, these conditions. We review new developments in adipose tissue fatty acid metabolism and how that might relate to cardiovascular disease. RECENT FINDINGS: Fatty acid release from human adipose tissue is oscillatory, with a period of about 12 min. Remarkably, oscillatory fatty acid release is also seen in isolated adipocytes. Further evidence has emerged that not all adipose depots are equal, and that lower-body adipose tissue may exert protective effects against cardiovascular disease. There have been a number of developments in the area of fatty acid handling by adipocytes. Fatty acid binding proteins are clearly important in regulating fatty acid metabolism, with striking protection against atherosclerosis in mice deficient in both the binding proteins expressed in adipocytes. The demonstration that adipocytes lacking hormone-sensitive lipase still display lipolysis has led to the identification of novel lipases that may play crucial roles in adipose tissue fatty acid metabolism. Further evidence has accrued of the interaction between hormone-sensitive lipase and perilipin, the protein that coats the adipocyte lipid droplet. SUMMARY: Recent developments in our understanding of adipose tissue fatty acid metabolism open up the possibility of new pharmaceutical targets. However, interference with adipose tissue fatty acid metabolism is not to be undertaken lightly and needs a clear understanding of the normal role of adipocyte lipolysis.     

Coordinated reprogramming of metabolism and cell function in adipocytes from proliferation to differentiation

Adipose tissue plays a major role in regulating lipid and energy homeostasis by storing excess nutrients, releasing energetic substrates through lipolysis, and regulating metabolism of other tissues and organs through endocrine and paracrine signaling. Adipocytes within fat tissues store excess nutrients through increased cell number (hyperplasia), increased cell size (hypertrophy), or both. The differentiation of pre-adipocytes into mature lipid-accumulating adipocytes requires a complex interaction of metabolic pathways that is still incompletely understood. Here, we applied parallel labeling experiments and ¹³C-metabolic flux analysis to quantify precise metabolic fluxes in proliferating and differentiated 3T3-L1 cells, a widely used model to study adipogenesis. We found that morphological and biomass composition changes in adipocytes were accompanied by significant shifts in metabolic fluxes, encompassing all major metabolic pathways. In contrast to proliferating cells, differentiated adipocytes 1) increased glucose uptake and redirected glucose utilization from lactate production to lipogenesis and energy generation; 2) increased pathway fluxes through glycolysis, oxidative pentose phosphate pathway and citric acid cycle; 3) reduced lactate secretion, resulting in increased ATP generation via oxidative phosphorylation; 4) rewired glutamine metabolism, from glutaminolysis to de novo glutamine synthesis; 5) increased cytosolic NADPH production, driven mostly by increased cytosolic malic enzyme flux; 6) increased production of monounsaturated C16:1; and 7) activated a mitochondrial pyruvate cycle through simultaneous activity of pyruvate carboxylase, malate dehydrogenase and malic enzyme. Taken together, these results quantitatively highlight the complex interplay between pathway fluxes and cell function in adipocytes, and suggest a functional role for metabolic reprogramming in adipose differentiation and lipogenesis.     

Proteomic analysis of 3T3-L1 adipocyte mitochondria during differentiation and enlargement

The increase in adipose tissue mass arises in part from progressive lipid loading and triglyceride accumulation in adipocytes. Enlarged adipocytes produce the highest levels of pro-inflammatory molecules and reactive oxygen species (ROS). Since mitochondria are the site for major metabolic processes (e.g., TCA cycle) that govern the extent of triglyceride accumulation as well as the primary site of ROS generation, we quantitatively investigated changes in the adipocyte mitochondrial proteome during different stages of differentiation and enlargement. Mitochondrial proteins from 3T3-L1 adipocytes at different stages of lipid accumulation (days 0-18) were digested and labeled using the iTRAQ 8-plex kit. The labeled peptides were fractionated using a liquid phase isoelectric fractionation system (MSWIFT) to increase the depth of proteome coverage and analyzed using LC-MS/MS. A total of 631 proteins in the mitochondrial fraction, including endoplasmic reticulum-associated and golgi-related mitochondrial proteins, were identified and classified into 12 functional categories. A total of 123 proteins demonstrated a statistically significant change in expression in at least one of the time points over the course of the experiment. The identified proteins included enzymes and transporters involved in the TCA cycle, fatty acid oxidation, and ATP synthesis. Our results indicate that cultured adipocytes enter a state of metabolic-overdrive where increased flux through the TCA cycle and increased fatty acid oxidation occur simultaneously. The proteomic data also suggest that accumulation of reduced electron carriers and the resultant oxidative stress may be attractive targets for modulating adipocyte function in metabolic disorders.     

Inflammation and macrophage modulation in adipose tissues

The adipose tissue is an active endocrine organ that harbours not only mature and developing adipocytes but also a wide array of immune cells, including macrophages, a key immune cell in determining metabolic functionality. With adipose tissue expansion, M1 pro‐inflammatory macrophage infiltration increases, activates other immune cells, and affects lipid trafficking and metabolism, in part via inhibiting mitochondrial function and increasing reactive oxygen species (ROS). The pro‐inflammatory cytokines produced and released interfere with insulin signalling, while inhibiting M1 macrophage activation improves systemic insulin sensitivity. In healthy adipose tissue, M2 alternative macrophages predominate and associate with enhanced lipid handling and mitochondrial function, anti‐inflammatory cytokine production, and inhibition of ROS. The sequence of events leading to macrophage infiltration and activation in adipose tissue remains incompletely understood but lipid handling of both macrophages and adipocytes appears to play a major role.     

Apolipoprotein E limits oxidative stress-induced cell dysfunctions in human adipocytes

Oxidative stress in adipose tissue constitutes a pathological process involved in obesity-linked metabolic disorders. Apolipoprotein E (apoE), which exhibits antioxidant properties in plasma and brain, is highly produced by adipose tissue and adipocytes. In this study, we investigated the role of apoE in the human adipocyte response to oxidative stress. We first demonstrated that apoE secretion by adipocytes was stimulated by oxidative stress. We also observed that apoE overexpression protected adipocytes from hydrogen peroxide-induced damages, by mitigating intracellular oxidation and exerting extracellular antioxidant properties. Our findings clearly show a novel antioxidant role for apoE in adipose tissue.     

Highly hydroxylated fullerene localizes at the cytoskeleton and inhibits oxidative stress in adipocytes and a subcutaneous adipose-tissue equivalent

Adipose tissue is a crucial site for pathologic changes in obesity/metabolic syndrome-related diseases. Interaction between adipogenesis and reactive oxygen species (ROS) in adipose tissue involving chronic low-grade inflammation is postulated to be causal in the development of insulin resistance and other metabolic consequences. We used different culture systems to investigate the relationship between ROS and adipogenesis at three levels: within adipocytes, during adipocyte-monocyte interactions, and in a subcutaneous adipose tissue model. The effects of highly hydroxylated fullerene (HHF; C₆₀(OH)₃₆) on adipogenesis-accompanying oxidative stress and inflammatory changes were examined using these three systems. We demonstrated that H₂O₂ stimulates lipid accumulation in 3T3-L1 preadipocytes, and lipid uptake causes ROS generation in OP9 preadipocytes, both of which were then markedly suppressed with HHF treatment. HHF significantly inhibited the adipogenic stimulant insulin-rich serum replacement (SR)-induced triacylglycerol accumulation, ROS production, and macrophage activation in cultured OP9 cells and an OP9-U937 monocyte-like cell coculture system. H₂O₂-induced intracellular ROS production in OP9 adipocytes was also notably inhibited by HHF. We developed a three-dimensional subcutaneous adipose-tissue equivalent (SATE) consisting of air-exposed cultures of HaCaT keratinocytes on an OP9 adipocyte-populated collagen gel in a culture insert. With SR stimulation and under suitable conditions, fat accumulation, ROS generation, and macrophage infiltration were observed in the SATE and significantly inhibited by HHF. By western blotting, we demonstrated that HHF localized at the cytoskeleton, which controls the transport of lipids. In conclusion, HHF is able to inhibit oxidative stress in adipocytes and adipogenesis-related macrophage activation in adipose tissues through its antioxidation.