Mitochondrial Dysfunction as a Driver of Cognitive Impairment in Alzheimer's Disease.

Alzheimer's disease (AD) is the most frequent cause of age-related neurodegeneration and cognitive impairment, and there are currently no broadly effective therapies. The underlying pathogenesis is complex, but a growing body of evidence implicates mitochondrial dysfunction as a common pathomechanism involved in many of the hallmark features of the AD brain, such as formation of amyloid-beta (Aß) aggregates (amyloid plaques), neurofibrillary tangles, cholinergic system dysfunction, impaired synaptic transmission and plasticity, oxidative stress, and neuroinflammation, that lead to neurodegeneration and cognitive dysfunction. Indeed, mitochondrial dysfunction concomitant with progressive accumulation of mitochondrial Aß is an early event in AD pathogenesis. Healthy mitochondria are critical for providing sufficient energy to maintain endogenous neuroprotective and reparative mechanisms, while disturbances in mitochondrial function, motility, fission, and fusion lead to neuronal malfunction and degeneration associated with excess free radical production and reduced intracellular calcium buffering. In addition, mitochondrial dysfunction can contribute to amyloid-ß precursor protein (APP) expression and misprocessing to produce pathogenic fragments (e.g., Aß1-40). Given this background, we present an overview of the importance of mitochondria for maintenance of neuronal function and how mitochondrial dysfunction acts as a driver of cognitive impairment in AD. Additionally, we provide a brief summary of possible treatments targeting mitochondrial dysfunction as therapeutic approaches for AD.

Myricitrin Ameliorates Hyperglycemia, Glucose Intolerance, Hepatic Steatosis, and Inflammation in High-Fat Diet/Streptozotocin-Induced Diabetic Mice.

To test the hypothesis that myricitrin (MYR) improves type 2 diabetes, we examined the effect of MYR on hyperglycemia, glucose intolerance, hepatic steatosis, and inflammation in high-fat diet (HFD) and streptozotocin (STZ)-induced type 2 diabetic mice. Male C57BL/6J mice were randomly divided into three groups: non-diabetic, diabetic control, and MYR (0.005%, w/w)-supplemented diabetic groups. Diabetes was induced by HFD and STZ, and MYR was administered orally for 5 weeks. Myricitrin exerted no significant effects on food intake, body weight, fat weight, or plasma lipids levels. However, MYR significantly decreased fasting blood glucose levels, improved glucose intolerance, and increased pancreatic ß-cell mass compared to the diabetic control group. Myricitrin administration also markedly increased glucokinase mRNA expression and activity as well as lowered glucose-6-phosphatase and phosphoenolpyruvate carboxykinase mRNA expression and activity in the liver. In addition, liver weight, hepatic triglyceride content, and lipid droplet accumulation were markedly decreased following MYR administration. These changes were seemingly attributable to the suppression of the hepatic lipogenic enzymes-fatty acid synthase and phosphatidate phosphohydrolase. Myricitrin also significantly lowered plasma MCP-1 and TNF-α levels and the mRNA expression of hepatic pro-inflammatory genes. These results suggest that MYR has anti-diabetic potential.

Honokiol Improves Insulin Resistance, Hepatic Steatosis, and Inflammation in Type 2 Diabetic db/db Mice.

This study focuses on the effect of honokiol (HON) on glucose homeostasis, insulin resistance, dyslipidemia, hepatic steatosis, and inflammation in type 2 diabetic db/db mice. Male C57BL/KsJ-db/db mice were fed a normal diet with or without HON (0.02%, w/w) or pioglitazone (PIO, anti-diabetic agent, 0.01%, w/w) for 5 weeks. Blood biomarker, tissue morphology and enzymatic and genetic parameters were determined. PIO significantly decreased food intake, fasting blood glucose, and glycosylated hemoglobin (HbA1c) levels, but markedly increased body weight, adipose tissue weight, and plasma leptin levels. HON did not significantly affect food intake, body weight, or levels of plasma leptin and blood glucose. However, HON led to significant decreases in adipose tissue weight, plasma insulin, blood HbA1c and HOMA-IR levels and improved glucose tolerance. The anti-diabetic and anti-adiposity effects of HON were partially related to the inhibition of gluconeogenic enzymes and their mRNA expression in the liver; and the inhibition of lipogenic enzymes in adipose tissue, respectively. Unlike PIO, HON did not affect dyslipidemia, but ameliorated hepatic steatosis by inhibiting hepatic lipogenic enzymes activity. Moreover, HON exhibited anti-inflammatory effects similar to PIO. These results suggest that HON can protect against type 2 diabetes by improving insulin resistance, glucose and lipid metabolism, and inflammation.

Differences in metabolic biomarkers in the blood and gene expression profiles of peripheral blood mononuclear cells among normal weight, mildly obese and moderately obese subjects.

We compared metabolic biomarkers in the blood and peripheral blood mononuclear cell (PBMC) gene expression profiles among normal weight (BMI, 18·5-23 kg/m2), mildly obese (BMI, 25-27·5 kg/m2) and moderately obese Korean adult men (BMI, 27·5-30 kg/m2). High leptin, lipids (except LDL- and HDL-cholesterol) and apoB levels and low adiponectin and HDL-cholesterol levels were present in the plasma of both mildly and moderately obese subjects. Circulating levels of inflammatory cytokines and markers of insulin resistance, oxidative stress and liver damage were altered in moderately obese subjects but not in mildly obese subjects. PBMC transcriptome data showed enrichment of pathways involved in energy metabolism, insulin resistance, bone metabolism, cancer, inflammation and fibrosis in both mildly and moderately obese subjects. Signalling pathways involved in oxidative phosphorylation, TAG synthesis, carbohydrate metabolism and insulin production; mammalian target of rapamycin, forkhead box O, ras-proximate-1, RAS and transforming growth factor-ß signalling; as well as extracellular matrix-receptor interaction were enriched only in moderately obese subjects, indicating that changes in PBMC gene expression profiles, according to metabolic disturbances, were associated with the development and/or aggravation of obesity. In particular, fourteen and fifteen genes differentially expressed only in mildly obese subjects and in both mildly and moderately obese subjects, respectively, could be used as early or stable biomarkers for diagnosing and treating obesity-associated metabolic disturbance. We characterised BMI-associated metabolic and molecular biomarkers in the blood and provided clues about potential blood-based targets for preventing or treating obesity-related complications.

In vivo AAV1 transduction with hRheb(S16H) protects hippocampal neurons by BDNF production.

Recent evidence has shown that Ras homolog enriched in brain (Rheb) is dysregulated in Alzheimer's disease (AD) brains. However, it is still unclear whether Rheb activation contributes to the survival and protection of hippocampal neurons in the adult brain. To assess the effects of active Rheb in hippocampal neurons in vivo, we transfected neurons in the cornu ammonis 1 (CA1) region in normal adult rats with an adeno-associated virus containing the constitutively active human Rheb (hRheb(S16H)) and evaluated the effects on thrombin-induced neurotoxicity. Transduction with hRheb(S16H) significantly induced neurotrophic effects in hippocampal neurons through activation of mammalian target of rapamycin complex 1 (mTORC1) without side effects such as long-term potentiation impairment and seizures from the alteration of cytoarchitecture, and the expression of hRheb(S16H) prevented thrombin-induced neurodegeneration in vivo, an effect that was diminished by treatment with specific neutralizing antibodies against brain-derived neurotrophic factor (BDNF). In addition, our results showed that the basal mTORC1 activity might be insufficient to mediate the level of BDNF expression, but hRheb(S16H)-activated mTORC1 stimulated BDNF production in hippocampal neurons. These results suggest that viral vector transduction with hRheb(S16H) may have therapeutic value in the treatment of neurodegenerative diseases such as AD.

High-fat diet decreases energy expenditure and expression of genes controlling lipid metabolism, mitochondrial function and skeletal system development in the adipose tissue, along with increased expression of extracellular matrix remodelling- and inflammation-related genes.

The aim of the present study was to identify the genes differentially expressed in the visceral adipose tissue in a well-characterised mouse model of high-fat diet (HFD)-induced obesity. Male C57BL/6J mice (n 20) were fed either HFD (189 % of energy from fat) or low-fat diet (LFD, 42 % of energy from fat) for 16 weeks. HFD-fed mice exhibited obesity, insulin resistance, dyslipidaemia and adipose collagen accumulation, along with higher levels of plasma leptin, resistin and plasminogen activator inhibitor type 1, although there were no significant differences in plasma cytokine levels. Energy intake was similar in the two diet groups owing to lower food intake in the HFD group; however, energy expenditure was also lower in the HFD group than in the LFD group. Microarray analysis revealed that genes related to lipolysis, fatty acid metabolism, mitochondrial energy transduction, oxidation-reduction, insulin sensitivity and skeletal system development were down-regulated in HFD-fed mice, and genes associated with extracellular matrix (ECM) components, ECM remodelling and inflammation were up-regulated. The top ten up- or down-regulated genes include Acsm3, mt-Nd6, Fam13a, Cyp2e1, Rgs1 and Gpnmb, whose roles in the deterioration of obesity-associated adipose tissue are poorly understood. In conclusion, the genes identified here provide new therapeutic opportunities for prevention and treatment of diet-induced obesity.

Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease.

Accumulating evidence indicates that obesity is closely associated with an increased risk of metabolic diseases such as insulin resistance, type 2 diabetes, dyslipidemia and nonalcoholic fatty liver disease. Obesity results from an imbalance between food intake and energy expenditure, which leads to an excessive accumulation of adipose tissue. Adipose tissue is now recognized not only as a main site of storage of excess energy derived from food intake but also as an endocrine organ. The expansion of adipose tissue produces a number of bioactive substances, known as adipocytokines or adipokines, which trigger chronic low-grade inflammation and interact with a range of processes in many different organs. Although the precise mechanisms are still unclear, dysregulated production or secretion of these adipokines caused by excess adipose tissue and adipose tissue dysfunction can contribute to the development of obesity-related metabolic diseases. In this review, we focus on the role of several adipokines associated with obesity and the potential impact on obesity-related metabolic diseases. Multiple lines evidence provides valuable insights into the roles of adipokines in the development of obesity and its metabolic complications. Further research is still required to fully understand the mechanisms underlying the metabolic actions of a few newly identified adipokines.

The beneficial effects of combined grape pomace and omija fruit extracts on hyperglycemia, adiposity and hepatic steatosis in db/db mice: a comparison with major index compounds.

This study investigated the effects of combined grape pomace and omija fruit extracts (GO) on diabetes-related metabolic changes in type 2 diabetic db/db mice. The effects of GO were compared with those of a resveratrol and schizandrin mixture (RS), which is a mixture of major components of GO. Mice were fed a normal diet with RS (0.005% resveratrol and 0.02% schizandrin in diet, w/w) or GO (0.3% grape pomace ethanol extract and 0.05% omija fruit ethanol extract in diet, w/w) for seven weeks. RS and GO not only lowered the levels of blood and plasma glucose, HbA1c, insulin and homeostasis model assessment of insulin resistance (HOMA-IR) with a simultaneous decrease in hepatic gluconeogenic enzymes activities and adiposity, but also improved preservation of the pancreatic ß-cells. Plasma leptin and resistin levels were lower while the plasma adiponectin level was higher in the RS and GO groups than in the control group. Especially, GO increased hepatic glucokinase activity and gene expression and improved hepatic steatosis by elevating fatty acid oxidation compared to RS. These findings suggest that GO ameliorates hyperglycemia, adiposity and hepatic steatosis in type 2 diabetic mice.

Effects of Ecklonia stolonifera Extract on Metabolic Dysregulation in High-Fat Diet-Induced Obese Mice.

This study aimed to test the hypothesis that long-term and low-dose supplementation with an ethanol extract of Ecklonia stolonifera may confer protection against high-fat diet (HFD)-induced obesity in mice. Male C57BL/6J mice were divided into two groups, one of which was fed an HFD (40 kcal% fat) and the other an HFD+E. stolonifera (0.006%, w/w, ∼5 mg/kg body weight/day) for 16 weeks. E. stolonifera supplementation significantly reduced body weight from week 3 and until the end of the experiment. E. stolonifera-supplemented mice also exhibited lower fat mass (epididymal, perirenal, and mesenteric fat) and smaller adipocyte size than HFD control mice. The two groups displayed similar food intakes, but E. stolonifera markedly decreased lipogenesis and increased lipolysis and fatty acid oxidation in adipose tissue. Moreover, E. stolonifera significantly decreased plasma and hepatic lipid levels, hepatic lipid droplet accumulation, plasma aminotransferase levels, and liver weight by decreasing lipogenesis and increasing fatty acid oxidation. As E. stolonifera-supplemented mice showed improvements in hyperglycemia, insulin resistance, and inflammation, compared to control mice, it is possible that the beneficial effects of E. stolonifera on obesity might be associated with decreased inflammation and insulin resistance. Collectively, these results indicate that E. stolonifera could be used as a novel means of preventing and treating obesity and obesity-related metabolic disorders.

Fatty acids regulate endothelial lipase and inflammatory markers in macrophages and in mouse aorta: a role for PPARγ.

OBJECTIVE: Macrophage endothelial lipase (EL) is associated with increased atherosclerosis and inflammation. Because of their anti-inflammatory properties we hypothesized that n-3 fatty acids, in contrast to saturated fatty acids, would lower macrophages and arterial EL and inflammatory markers. METHODS AND RESULTS: Murine J774 and peritoneal macrophages were incubated with eicosapentaenoic acid or palmitic acid in the presence or absence of lipopolysaccaride (LPS). LPS increased EL mRNA and protein. Palmitic acid alone or with LPS dose-dependently increased EL mRNA and protein. In contrast, eicosapentaenoic acid dose-dependently abrogated effects of LPS or palmitic acid on increasing EL expression. EL expression closely linked to peroxisome proliferator activated receptor (PPAR)γ expression. Eicosapentaenoic acid blocked rosiglitazone (a PPARγ agonist)-mediated EL activation and GW9662 (a PPARγ antagonist)-blocked palmitic acid-mediated EL stimulation. Eicosapentaenoic acid alone or with LPS blunted LPS-mediated stimulation of macrophage proinflammatory interleukin-6, interleukin-12p40, and toll-like receptor-4 mRNA and increased anti-inflammatory interleukin-10 and mannose receptor mRNA. In vivo studies in low density lipoprotein receptor knockout mice showed that high saturated fat rich diets, but not n-3 diets, increased arterial EL, PPARγ, and proinflammatory cytokine mRNA. CONCLUSIONS: n-3 fatty acids, in contrast to saturated fatty acids, decrease EL in parallel with modulating pro- and anti-inflammatory markers, and these effects on EL link to PPARγ.

Sarcopenic Obesity: Involvement of Oxidative Stress and Beneficial Role of Antioxidant Flavonoids.

Sarcopenic obesity, which refers to concurrent sarcopenia and obesity, is characterized by decreased muscle mass, strength, and performance along with abnormally excessive fat mass. Sarcopenic obesity has received considerable attention as a major health threat in older people. However, it has recently become a health problem in the general population. Sarcopenic obesity is a major risk factor for metabolic syndrome and other complications such as osteoarthritis, osteoporosis, liver disease, lung disease, renal disease, mental disease and functional disability. The pathogenesis of sarcopenic obesity is multifactorial and complicated, and it is caused by insulin resistance, inflammation, hormonal changes, decreased physical activity, poor diet and aging. Oxidative stress is a core mechanism underlying sarcopenic obesity. Some evidence indicates a protective role of antioxidant flavonoids in sarcopenic obesity, although the precise mechanisms remain unclear. This review summarizes the general characteristics and pathophysiology of sarcopenic obesity and focuses on the role of oxidative stress in sarcopenic obesity. The potential benefits of flavonoids in sarcopenic obesity have also been discussed.

Pathophysiological Role of Microglial Activation Induced by Blood-Borne Proteins in Alzheimer's Disease.

The blood-brain barrier (BBB) restricts entry of neurotoxic plasma components, blood cells, and pathogens into the brain, leading to proper neuronal functioning. BBB impairment leads to blood-borne protein infiltration such as prothrombin, thrombin, prothrombin kringle-2, fibrinogen, fibrin, and other harmful substances. Thus, microglial activation and release of pro-inflammatory mediators commence, resulting in neuronal damage and leading to impaired cognition via neuroinflammatory responses, which are important features observed in the brain of Alzheimer's disease (AD) patients. Moreover, these blood-borne proteins cluster with the amyloid beta plaque in the brain, exacerbating microglial activation, neuroinflammation, tau phosphorylation, and oxidative stress. These mechanisms work in concert and reinforce each other, contributing to the typical pathological changes in AD in the brain. Therefore, the identification of blood-borne proteins and the mechanisms involved in microglial activation and neuroinflammatory damage can be a promising therapeutic strategy for AD prevention. In this article, we review the current knowledge regarding the mechanisms of microglial activation-mediated neuroinflammation caused by the influx of blood-borne proteins into the brain via BBB disruption. Subsequently, the mechanisms of drugs that inhibit blood-borne proteins, as a potential therapeutic approach for AD, along with the limitations and potential challenges of these approaches, are also summarized.

Mesenchymal Stem Cell Transplantation Ameliorates Ara-C-Induced Motor Deficits in a Mouse Model of Cerebellar Ataxia.

This study investigated the therapeutic effects of transplanting human mesenchymal stem cells (hMSCs) into wild-type mice that were intraperitoneally administered cytosine arabinoside (Ara-C) to develop cerebellar ataxia (CA) during the first three postnatal days. hMSCs were intrathecally injected into 10-week-old mice once or thrice at 4-week intervals. Compared to the nontreated mice, the hMSC-treated mice showed improved motor and balance coordination, as measured using the rotarod, open-field, and ataxic scoring assessments, and increased protein levels in Purkinje and cerebellar granule cells, as measured using calbindin and NeuN protein markers. Multiple hMSC injections preserved Ara-C-induced cerebellar neuronal loss and improved cerebellar weight. Furthermore, the hMSC implantation significantly elevated the levels of neurotrophic factors, including brain-derived and glial cell line-derived neurotrophic factors, and suppressed TNF-α-, IL-1ß-, and iNOS-mediated proinflammatory responses. Collectively, our results demonstrate that hMSCs exhibit therapeutic potential for Ara-C-induced CA by protecting neurons through the stimulation of neurotrophic factors and inhibition of cerebellar inflammatory responses, which can improve motor behavior and alleviate ataxia-related neuropathology. In summary, this study suggests that hMSC administration, particularly multiple treatments, can effectively treat ataxia-related symptoms with cerebellar toxicity.

n-3 fatty acids ameliorate hepatic steatosis and dysfunction after LXR agonist ingestion in mice.

UNLABELLED: Liver X receptor (LXR) agonists slow atherogenesis, but cause hepatic steatosis and dysfunction in part by increasing expression of sterol regulatory element binding protein 1-c (SREBP1-c), a transcription factor that upregulates fatty acid (FA) synthesis. n-3 FAs decrease hepatic FA synthesis by down-regulating SREBP1-c. To test the hypothesis that n-3 FAs decrease hepatic steatosis in mice given LXR agonist, C57BL/6 mice received daily gavage of an LXR agonist T0901317 (LXR(T)) or vehicle for 4weeks with concomitant intakes chow or high-fat diets enriched in saturated fat (SAT) or n-3 fat (n-3). Mice on LXR(T) and SAT developed hepatomegaly with a large increase in size and number of hepatic lipid droplets; an n-3 diet reduced liver weight/body weight with decreased hepatic steatosis and triglyceride levels. Effects of n-3 diet on hepatic lipogenesis were linked to a blunting of LXR(T) upregulation of hepatic SREBP1-c and FA synthase mRNA. n-3 diets also normalized LXR(T)-mediated increases of plasma ALT and AST levels, whereas SAT diet increased these markers. CONCLUSION: These studies suggest that n-3 FAs when given together with LXR agonists have the potential to improve both hepatic steatosis and hepatotoxicity in humans that might receive LXR agonists to decrease risk of atherosclerosis.

Time-course microarrays reveal early activation of the immune transcriptome and adipokine dysregulation leads to fibrosis in visceral adipose depots during diet-induced obesity.

BACKGROUND: Visceral white adipose tissue (WAT) hypertrophy, adipokine production, inflammation and fibrosis are strongly associated with obesity, but the time-course of these changes in-vivo are not fully understood. Therefore, the aim of this study was to establish the time-course of changes in adipocyte morphology, adipokines and the global transcriptional landscape in visceral WAT during the development of diet-induced obesity. RESULTS: C57BL/6 J mice were fed a high-fat diet (HFD) or normal diet (ND) and sacrificed at 8 time-points over 24 weeks. Excessive fat accumulation was evident in visceral WAT depots (Epidydimal, Perirenal, Retroperitoneum, Mesentery) after 2-4 weeks. Fibrillar collagen accumulation was evident in epidydimal adipocytes at 24 weeks. Plasma adipokines, leptin, resistin and adipsin, increased early and time-dependently, while adiponectin decreased late after 20 weeks. Only plasma leptin and adiponectin levels were associated with their respective mRNA levels in visceral WAT. Time-course microarrays revealed early and sustained activation of the immune transcriptome in epididymal and mesenteric depots. Up-regulated inflammatory genes included pro-inflammatory cytokines, chemokines (Tnf, Il1rn, Saa3, Emr1, Adam8, Itgam, Ccl2, 3, 4, 6, 7 and 9) and their upstream signalling pathway genes (multiple Toll-like receptors, Irf5 and Cd14). Early changes also occurred in fibrosis, extracellular matrix, collagen and cathepsin related-genes, but histological fibrosis was only visible in the later stages. CONCLUSIONS: In diet-induced obesity, early activation of TLR-mediated inflammatory signalling cascades by CD antigen genes, leads to increased expression of pro-inflammatory cytokines and chemokines, resulting in chronic low-grade inflammation. Early changes in collagen genes may trigger the accumulation of ECM components, promoting fibrosis in the later stages of diet-induced obesity. New therapeutic approaches targeting visceral adipose tissue genes altered early by HFD feeding may help ameliorate the deleterious effects of diet-induced obesity.

Differential effects of low-dose resveratrol on adiposity and hepatic steatosis in diet-induced obese mice.

Consumption of a high-fat diet (HFD) enriched in saturated fat induces excessive weight gain due to adiposity, which can lead to metabolic complications, as well as increased risk of fatty liver disease and CVD. The present study investigated the underlying mechanism and dose-response effects of resveratrol (RV) on obesity, hepatic steatosis and dyslipidaemia in mice fed a HFD. Male C57BL/6J mice were fed a normal diet or a HFD (20 % fat, w/w) combined with 0·005 or 0·02 % (w/w) RV for 10 weeks. As expected, mice fed a HFD developed obesity, as shown by increased body weight gain, visceral fat, hepatic fat and plasma cholesterol. RV significantly reduced visceral fat and plasma NEFA. In the liver of HFD-fed mice, RV significantly reduced TAG and cholesterol, as well as lipid droplet number and size. A low dose of RV (0·005 %) appeared to be more effective than a higher dose of RV (0·02 %) for suppressing adiposity and hepatic steatosis development with a significant decrease in body weight gain, plasma TAG and total cholesterol levels. These changes were seemingly attributable to a suppression of the fatty acid (FA) synthase, glucose-6-phosphate dehydrogenase, and phosphatidate phosphohydrolase and/or an activation of FA oxidation in the liver and epididymal adipose tissue. In conclusion, daily consumption of a low dose of RV is effective for protecting against diet-induced obesity, hepatic steatosis and dyslipidaemia in HFD-fed mice.

Anti-adiposity and lipid-lowering effects of schisandrol A in diet-induced obese mice.

Lignan schisandrol A (SolA) is known to have antioxidant and anti-inflammatory effects. However, the impact of SolA on obesity is poorly understood. To test the hypothesis that SolA has anti-obesity effects, C57BL/6J mice were fed a high-fat diet with or without SolA (0.006%, w/w) for 16 weeks. SolA decreased visceral fat mass (10%) by increasing energy expenditure and upregulating white adipose tissue thermogenic genes mRNA expression. Furthermore, SolA upregulated adipose Lpl mRNA expression and decreased plasma free fatty acid (FFA), triglyceride (TG), apolipoprotein (apo) B, aspartate aminotransferase levels and TG/HDL-cholesterol and apoB/apoA1 ratios as well as hepatic lipid droplets. Increased hepatic ß-oxidation and fecal FFA and TG levels were observed in the SolA-supplemented mice, suggesting an association of its lipid-lowering effect with increased hepatic ß-oxidation, fecal fat excretion and adipose Lpl. Conclusionally, this study provides evidence on the protective effects of SolA against adiposity, dyslipidemia and nonalcoholic fatty liver disease in obese mice.

Dietary Sinapic Acid Alleviates Adiposity and Inflammation in Diet-Induced Obese Mice.

Sinapic acid (SA), a hydroxycinnamic acid, is known to confer protection against oxidative stress, inflammation, diabetes, and liver disease. However, the effectiveness of SA in improving obesity remains obscure. Therefore, this study evaluated anti-obesity efficacy of SA and to elucidate its mechanism of action. Male mice were maintained for 16 weeks on high-fat diet (HFD) alone or with SA (0.004%, w/w) and bodyweight, fat mass, adipocyte size, food intake, and biochemical and molecular markers were evaluated. SA-supplemented mice demonstrated markedly decreased fat mass and adipocyte size compared to unsupplemented group, without any changes in bodyweight and food intake between the two groups. Plasma adipocytokines levels including leptin, resistin, monocyte chemoattractant protein (MCP)-1 and interleukin-6 were also markedly reduced by SA supplementation. SA tended to lower plasma insulin level and improved homeostatic index of insulin resistance and intraperitoneal glucose tolerance test in HFD-induced obese mice. The anti-adiposity effect of SA was maybe owing to down-regulation of the mRNA expression of lipogenic genes, including acetyl coenzyme A (CoA) carboxylase, fatty acid synthesis, stearoyl-CoA desaturase 1, and phosphatidate phosphatase, and peroxisome proliferator-activated receptor γ, a transcription factor responsible for governing lipid metabolism, in adipose tissues. SA significantly down-regulated pro-inflammatory nuclear factor kappa B, MCP-1, tumor necrosis factor-α, and Toll-like receptor 4 mRNA expression in adipose tissue. Thus, SA could be beneficial for the development of functional foods or herbal medications to combat obesity.

Efficacy of nobiletin in improving hypercholesterolemia and nonalcoholic fatty liver disease in high-cholesterol diet-fed mice.

BACKGROUND/OBJECTIVES: Nobiletin (NOB), a citrus flavonoid, is reported to have beneficial effects on cardiovascular and metabolic health. However, there is limited research investigating the effect of long-term supplementation with low-dose NOB on high-cholesterol diet (HCD)-induced hypercholesterolemia and non-obese nonalcoholic fatty liver disease (NAFLD). Therefore, we investigated the influence of NOB on hypercholesterolemia and NAFLD in HCD-fed mice. SUBJECTS/METHODS: C57BL/6J mice were fed a normal diet (ND) or HCD (35 kcal% fat, 1.25% cholesterol, 0.5% cholic acid) with or without NOB (0.02%) for 20 weeks. RESULTS: HCD feeding markedly reduced the final body weight compared to ND feeding, with no apparent energy intake differences. NOB supplementation suppressed HCD-induced weight loss without altering energy intake. Moreover, NOB significantly decreased the total cholesterol (TC) levels and the low-density lipoprotein (LDL)/very-LDL-cholesterol to TC ratio, and increased the high-density lipoprotein-cholesterol/TC ratio in plasma, compared to those for HCD feeding alone. The plasma levels of inflammatory and atherosclerosis markers (C-reactive protein, oxidized LDL, interleukin [IL]-1ß, IL-6, and plasminogen activator inhibitor-1) were significantly lower, whereas those of anti-atherogenic adiponectin and paraoxonase were higher in the NOB-supplemented group than in the HCD control group. Furthermore, NOB significantly decreased liver weight, hepatic cholesterol and triglyceride contents, and lipid droplet accumulation by inhibiting messenger RNA expression of hepatic genes and activity levels of cholesterol synthesis-, esterification-, and fatty acid synthesis-associated enzymes, concomitantly enhancing fatty acid oxidation-related gene expression and enzyme activities. Dietary NOB supplementation may protect against hypercholesterolemia and NAFLD via regulation of hepatic lipid metabolism in HCD-fed mice; these effects are associated with the amelioration of inflammation and reductions in the levels of atherosclerosis-associated cardiovascular markers. CONCLUSIONS: The present study suggests that NOB may serve as a potential therapeutic agent for the treatment of HCD-induced hypercholesterolemia and NAFLD.

Protective effects of p-coumaric acid against high-fat diet-induced metabolic dysregulation in mice.

p-Coumaric acid (PC), a naturally occurring phytochemical, possesses antioxidant and anti-inflammatory properties; however, the mechanisms underlying its protective effects against obesity-related metabolic dysfunction are largely unknown. Here, we treated C57BL/6J mice to a high-fat diet (HFD) with or without PC (10 mg/kg body weight/day) for 16 weeks to determine whether PC ameliorates HFD-induced obesity, insulin resistance, inflammation, and non-alcoholic fatty liver disease (NAFLD). We found no significant differences in food intake and body weight between the groups. However, PC-treated mice showed significantly lower white adipose tissue (WAT) weight, adipocyte size, and plasma leptin level, which were associated with decreased lipogenic enzyme activity and mRNA expression of their genes in the epididymal WAT. Moreover, hepatic lipogenic enzymes activities and expression of their genes and proteins were decreased with concomitant increases in hepatic fatty acid oxidation and mRNA expression of its gene; fecal lipid excretion was significantly increased, resulting in decreased liver weight, hepatic lipid levels, lipid droplet accumulation, and plasma aspartate aminotransferase and lipid levels. Additionally, PC-treated mice showed lower fasting blood glucose, plasma resistin, and MCP-1 levels, HOMA-IR, and mRNA expression of inflammatory genes in the epididymal WAT and liver. Our findings reveal potential mechanisms underlying the action of PC against HFD-induced adiposity, NAFLD, and other metabolic disturbances.