Metabolic Syndrome In Mice Research Articles

From the Literature

From the Literature

Grape polyphenols reduce gut-localized reactive oxygen species associated with the development of metabolic syndrome in mice.

High-fat diet (HFD)-induced leaky gut syndrome combined with low-grade inflammation increase reactive oxygen species (ROS) in the intestine and may contribute to dysbiosis and metabolic syndrome (MetS). Poorly bioavailable and only partially metabolizable dietary polyphenols, such as proanthocyanidins (PACs), may exert their beneficial effects on metabolic health by scavenging intestinal ROS. To test this hypothesis, we developed and validated a novel, noninvasive, in situ method for visualizing intestinal ROS using orally administered ROS-sensitive indocyanine green (ICG) dye. C57BL/6J mice fed HFD for 10 weeks accumulated high levels of intestinal ROS compared to mice fed low-fat diet (LFD). Oral administration of poorly bioavailable grape polyphenol extract (GPE) and β-carotene decreased HFD-induced ROS in the gut to levels comparable to LFD-fed mice, while administration of more bioavailable dietary antioxidants (α-lipoic acid, vitamin C, vitamin E) did not. Forty percent of administered GPE antioxidant activity was measured in feces collected over 24 h, confirming poor bioavailability and persistence in the gut. The bloom of beneficial anaerobic gut bacteria, such as Akkermansia muciniphila, associated with improved metabolic status in rodents and humans may be directly linked to protective antioxidant activity of some dietary components. These findings suggest a possible mechanistic explanation for the beneficial effects of poorly bioavailable polyphenols on metabolic health.

Time-Restricted Feeding Prevents Obesity and Metabolic Syndrome in Mice Lacking a Circadian Clock

Increased susceptibility of circadian clock mutant mice to metabolic diseases has led to the idea that a molecular clock is necessary for metabolic homeostasis. However, these mice often lack a normal feeding-fasting cycle. We tested whether time-restricted feeding (TRF) could prevent obesity and metabolic syndrome in whole-body Cry1;Cry2 and in liver-specific Bmal1 and Rev-erbα/β knockout mice. When provided access to food ad libitum, these mice rapidly gained weight and showed genotype-specific metabolic defects. However, when fed the same diet under TRF (food access restricted to 10hr during the dark phase) they were protected from excessive weight gain and metabolic diseases. Transcriptome and metabolome analyses showed that TRF reduced the accumulation of hepatic lipids and enhanced cellular defenses against metabolic stress. These results suggest that the circadian clockmaintains metabolic homeostasis by sustaining daily rhythms in feeding and fasting and by maintaining balance between nutrient and cellular stress responses.

7-Hydroxymatairesinol improves body weight, fat and sugar metabolism in C57BJ/6 mice on a high-fat diet.

7-Hydroxymatairesinol (7-HMR) is a plant lignan abundant in various concentrations in plant foods. The objective of this study was to test HMRLignan™, a purified form of 7-HMR, and the corresponding Picea abies extract (total extract P. abies; TEP) as dietary supplements on a background of a high-fat diet (HFD)-induced metabolic syndrome in mice and in the 3T3-L1 adipogenesis model. Mice, 3 weeks old, were fed a HFD for 60 d. Subgroups were treated with 3 mg/kg body weight 7-HMR (HMRLignan™) or 10 mg/kg body weight TEP by oral administration. 7-HMR and TEP limited the increase in body weight (-11 and -13 %) and fat mass (-11 and -18 %) in the HFD-fed mice. Epididymal adipocytes were 19 and -12 % smaller and the liver was less steatotic (-62 and -65 %). Serum lipids decreased in TEP-treated mice (-11 % cholesterol, -23 % LDL and -15 % TAG) and sugar metabolism was ameliorated by both lignan preparations, as shown by a more than 70 % decrease in insulin secretion and insulin resistance. The expression of several metabolic genes was modulated by the HFD with an effect that was reversed by lignan. In 3T3-L1 cells, the 7-HMR metabolites enterolactone (ENL) and enterodiol (END) showed a 40 % inhibition of cell differentiation accompanied by the inhibited expression of the adipogenic genes PPARγ, C/EBPα and aP2. Furthermore, END and ENL caused a 10 % reduction in TAG uptake in HEPA 1-6 hepatoma cells. In conclusion, 7-HMR and TEP reduce metabolic imbalances typical of the metabolic syndrome and obesity in male mice, whereas their metabolites inhibit adipogenesis and lipid uptake in vitro.

The usefulness of short-term high-fat/high salt diet as a model of metabolic syndrome in mice

Diabetic cardiomyopathy (DC) describes diabetes-associated changes in the structure and function of myocardium that are not directly linked to other factors such as hypertension. Currently there are some models of DC; however, they take a large time period to mimic key features. In the present study, we investigated the effects of a short-term high-fat/high salt diet (HFHS) treatment on myocardial function and structure, and vascular reactivity in C57BL/6 male mice. After 14 weeks HFHS induced hypertension (MAP = 144.95 ± 16.13 vs 92.90 ± 18.95 mm Hg), low glucose tolerance (AUC = 1049.01 ± 74.79 vs 710.50 ± 52.57 a.u.), decreased insulin sensitivity (AUC = 429.83 ± 35.22 vs 313.67 ± 19.55 a.u.) and increased adiposity (epididymal fat weight 0.96 ± 0.10 vs 0.59 ± 0.06 OW/BW × 102), aspects present in metabolic syndrome. Cardiac evaluation showed diastolic dysfunction (E/A ratio = 1.20 vs 1.90 u.a.) and cardiomyocyte hypertrophy (cardiomyocyte area = 502.82 ± 31.46 vs 385.58 ± 22.11 μm2). Lastly, vascular reactivity was impaired with higher contractile response (136.10 ± 3.49 vs 120.37 ± 5.43%) and lower response to endothelium-dependent vasorelaxation (74.01 ± 4.35 vs 104.84 ± 3.57%). In addition, the diet was able to induce an inward coronary remodeling (vascular total area: SCNS 6185 ± 800.6 vs HFHS 4085 ± 213.7 μm2). Therefore, we conclude that HFHS short-term treatment was able to induce metabolic syndrome-like state, cardiomyopathy and vascular injury working as an important tool to study cardiometabolic diseases.

Long-Term Dietary Nitrate Supplementation Does Not Prevent Development of the Metabolic Syndrome in Mice Fed a High-Fat Diet.

Background Nitric oxide (NO) is an important vascular signaling molecule that plays a role in vascular homeostasis. A reduction in NO bioavailability is thought to contribute to endothelial dysfunction, an early risk factor for both cardiovascular disease and type 2 diabetes. Dietary nitrate, through the nitrate-nitrite-NO pathway, may provide an alternate source of NO when the endogenous eNOS system is compromised. In addition to a role in the vascular system, NO may also play a role in the metabolic syndrome including obesity and glucose tolerance. Aim To investigate the effect of long-term dietary nitrate supplementation on development of the metabolic syndrome in mice fed a high-fat diet. Methods Following 1 week of acclimatisation, male (6–8 weeks) C57BL6 mice were randomly assigned to the following groups (10/group) for 12 weeks: (i) normal chow + NaCl (1 mmol/kg/day), (ii) normal chow + NaNO3 (1 mmol/kg/day), (iii) high-fat diet + NaCl (1 mmol/kg/day), and (iv) high-fat diet + NaNO3 (1 mmol/kg/day). Body weight and food consumption were monitored weekly. A subset of mice (5/group) underwent running wheel assessment. At the end of the treatment period, all mice underwent fasting glucose tolerance testing. Caecum contents, serum, and tissues (liver, skeletal muscle, white and brown adipose, and kidney) were collected, frozen, and stored at −80°C until analysis. Results Consumption of the high-fat diet resulted in significantly greater weight gain that was not affected by dietary nitrate. Mice on the high-fat diet also had impaired glucose tolerance that was not affected by dietary nitrate. There was no difference in adipose tissue expression of thermogenic proteins or energy expenditure as assessed by the running wheel activity. Mice on the high-fat diet and those receiving dietary nitrate had reduced caecum concentrations of both butyrate and propionate. Conclusions Dietary nitrate does not prevent development of the metabolic syndrome in mice fed a high-fat diet. This may be due, in part due, to reductions in the concentration of important short-chain fatty acids.

Luteolin-Enriched Artichoke Leaf Extract Alleviates the Metabolic Syndrome in Mice with High-Fat Diet-Induced Obesity.

This current study aimed to elucidate the effects and possible underlying mechanisms of long-term supplementation with dietary luteolin (LU)-enriched artichoke leaf (AR) in high-fat diet (HFD)-induced obesity and its complications (e.g., dyslipidemia, insulin resistance, and non-alcoholic fatty liver disease) in C57BL/6N mice. The mice were fed a normal diet, an HFD, or an HFD plus AR or LU for 16 weeks. In the HFD-fed mice, AR decreased the adiposity and dyslipidemia by decreasing lipogenesis while increasing fatty acid oxidation, which contributed to better hepatic steatosis. LU also prevented adiposity and hepatic steatosis by suppressing lipogenesis while increasing biliary sterol excretion. Moreover, AR and LU prevented insulin sensitivity by decreasing the level of plasma gastric inhibitory polypeptide and activity of hepatic glucogenic enzymes, which may be linked to the lowering of inflammation as evidenced by the reduced plasma interleukin (IL)-6, IL-1β, and plasminogen activator inhibitor-1 levels. Although the anti-metabolic syndrome effects of AR and LU were similar, the anti-adiposity and anti-dyslipidemic effects of AR were more pronounced. These results in mice with diet-induced obesity suggest that long-term supplementation with AR can prevent adiposity and related metabolic disorders such as dyslipidemia, hepatic steatosis, insulin resistance, and inflammation.

Isoquercetin and inulin synergistically modulate the gut microbiome to prevent development of the metabolic syndrome in mice fed a high fat diet

Dietary fibre positively influences gut microbiome composition, enhancing the metabolism of dietary flavonoids to produce bioactive metabolites. These synergistic activities facilitate the beneficial effects of dietary flavonoids on cardiometabolic health parameters. The aims of this study were to investigate whether isoquercetin (a major dietary flavonoid) and inulin (soluble fibre), either alone or in combination could improve features of the metabolic syndrome. Following a 1 week acclimatization, male C57BL6 mice (6–8 weeks) were randomly assigned to; (i) normal chow diet (n = 10), (ii) high fat (HF) diet (n = 10), (iii) HF diet + 0.05% isoquercetin (n = 10), (iv) HF diet + 5% inulin, or (v) HF diet + 0.05% isoquercetin + 5% inulin (n = 10). Body weight and food intake were measured weekly. At 12 weeks, glucose and insulin tolerance tests were performed, and blood, faecal samples, liver, skeletal muscle and adipose tissue were collected. At 12 weeks, mice on the HF diet had significantly elevated body weights as well as impaired glucose tolerance and insulin sensitivity compared to the normal chow mice. Supplementation with either isoquercetin or inulin had no effect, however mice receiving the combination had attenuated weight gain, improved glucose tolerance and insulin sensitivity, reduced hepatic lipid accumulation, adipocyte hypertrophy, circulating leptin and adipose FGF21 levels, compared to mice receiving the HF diet. Additionally, mice on the combination diet had improvements in the composition and functionality of their gut microbiome as well as production of short chain fatty acids. In conclusion, long-term supplementation with the dietary flavonoid isoquercetin and the soluble fibre inulin can attenuate development of the metabolic syndrome in mice fed a high fat diet. This protective effect appears to be mediated, in part, through beneficial changes to the microbiome.

ErbB4 deletion predisposes to development of metabolic syndrome in mice.

ErbB4, a member of the EGF receptor family, plays a variety of roles in physiological and pathological states. Genetic studies have indicated a link between ErbB4 and type 2 diabetes and obesity, but its role in metabolic syndrome (MetS) has not been reported. In the current study we found that mice with ErbB4 deletion developed MetS after 24 wk on a medium-fat diet (MFD), as indicated by development of obesity, dyslipidemia, hepatic steatosis, hyperglycemia, hyperinsulinemia, and insulin resistance, compared with wild-type mice. ErbB4 deletion mice also exhibited increased amounts of subcutaneous and visceral fat, with increased serum leptin levels, compared with wild-type mice, whereas levels of adiponectin were not significantly different. Histologically, severe inflammation, indicated by F4/80 immunostaining and M1 macrophage polarization, was detected in inguinal and epididymal white adipose tissue in ErbB4 deletion mice. ErbB4 expression decreased during 3T3-L1 preadipocyte differentiation. Administration of neuroregulin 4, a specific ligand for ErbB4, to 3T3-L1 adipocytes had no effect on adipogenesis and lipolysis but significantly inhibited lipogenesis, promoted browning, induced GLUT4 redistribution to the cell membrane, and increased glucose uptake. Neuroregulin 4 also significantly increased glucose uptake in adipocytes isolated from wild-type mice, while these effects were significantly decreased in adipocytes isolated from ErbB4 deletion mice. In conclusion, our results indicate that ErbB4 may play an important role in glucose homeostasis and lipogenesis. ErbB4 deficiency-related obesity and adipose tissue inflammation may contribute to the development of MetS.

Growth Differentiation Factor 15 Ameliorates Nonalcoholic Steatohepatitis Associated with Metabolic Syndrome in Mice

Growth differentiation factor 15 (GDF15) is an endocrine hormone belonging TGFβ superfamily member. GDF15 administration or GDF15 overexpression has been reported to have anti-obesity and antidiabetic effects. Although nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) is frequently associated with metabolic syndrome or diabetes, the functional role of endogenous GDF15 and therapeutic effect of exogenous GDF15 in NASH associated metabolic syndrome have not been addressed. We studied whether GDF15 has therapeutic effects on NASH and associated metabolic syndrome. To this end, Gdf15-knockout and Gdf15-transgenic mice were employed, and mice were fed Amylin liver NASH (AMLN) diet as a physiologically relevant dietary mouse model of NASH associated with metabolic syndrome. GDF15 expression was increased in the livers of mice fed AMLN diet and human subjects with NASH. Elevated expression of GDF15 was due to diet-induced endoplasmic reticulum (ER) stress in the liver. Importantly, Gdf15-knockout mice exhibited deteriorated metabolic syndrome and aggravated NASH phenotypes such as increased steatosis, hepatic inflammation, fibrosis and liver injury. Furthermore, we found that GDF15 directly suppresses expression of fibrosis-related genes and osteopontin (OPN) in the liver in vivo. OPN expression was increased in hepatocytes and stellate cells in the liver of Gdf15-knockout mice. Finally, we found that GDF15-transgenic mice showed attenuated NASH phenotypes and improved glucose tolerance in mice fed AMLN diet. Our results suggest that induction of endogenous GDF15 is a compensatory mechanism to protect against NASH associated with metabolic syndrome and that GDF15 could be an attractive therapeutic candidate for treatment of these diseases. Disclosure M. Lee: Other Relationship; Self; Jeil Pharmaceutical Co. Ltd.. Y. Lee: None. S. Kim: None. K. Kim: None.

Role of activating transcription factor 3 in fructose-induced metabolic syndrome in mice.

Activating transcription factor 3 (ATF3) has been implicated in cardiovascular disease and inflammation. This study examined the effects of ATF3 knockout (KO) on blood pressure, glucose intolerance, dyslipidemia, inflammation, and visceral adiposity in mice fed who did and did not consume a high-fructose diet. Male mice were divided into four groups (N = 15 for each group): the Con (control) group (wild-type mice fed a standard chow diet), Fru group (wild-type mice fed a high-fructose [60% fructose] diet), ATF3KO-Con group (ATF3 KO mice fed a standard chow diet), and ATF3KO-Fru group (ATF3 KO mice fed a high-fructose [60% fructose] diet). Experiments were conducted for 8 weeks. Our data demonstrated that ATF3 KO mice have lower systolic blood pressure (SBP) levels than do wild-type mice, and that high-fructose diets increase SBP levels in both wild-type and ATF3 KO mice. ATF3 KO in mice increased the serum levels of glucose, insulin, triglycerides, tumor necrosis factor-alpha, and intercellular adhesion molecule-1, impaired endothelium-dependent aortic relaxation, increased aorta wall thickness and lipid peroxide, and expanded visceral adiposity. These symptoms resembled those exhibited by the wild-type mice fed a high-fructose diet, which caused hyperglycemia, insulin resistance, dyslipidemia, endothelium-dependent aortic dysfunction, inflammation, aorta remodeling, and visceral adiposity. A high-fructose diet among ATF3 KO mice deteriorated metabolic parameters and inflammatory cytokines. The present results therefore suggest that ATF3 deficiency is involved in the pathogenesis of metabolic syndrome and ATF3 might have a therapeutic role in fructose-induced impairment of endothelium-dependent aortic relaxation, a rising of inflammatory cytokines, and metabolic syndrome.

Fecal transplant from resveratrol-fed donors improves glycaemia and cardiovascular features of the metabolic syndrome in mice.

Oral administration of resveratrol attenuates several symptoms associated with the metabolic syndrome, such as impaired glucose homeostasis and hypertension. Recent work has shown that resveratrol can improve glucose homeostasis in obesity via changes in the gut microbiota. Studies involving fecal microbiome transplants (FMTs) suggest that either live gut microbiota or bacterial-derived metabolites from resveratrol ingestion are responsible for producing the observed benefits in recipients. Herein, we show that obese mice receiving FMTs from healthy resveratrol-fed mice have improved glucose homeostasis within 11 days of the first transplant, and that resveratrol-FMTs is more efficacious than oral supplementation of resveratrol for the same duration. The effects of FMTs from resveratrol-fed mice are also associated with decreased inflammation in the colon of obese recipient mice. Furthermore, we show that sterile fecal filtrates from resveratrol-fed mice are sufficient to improve glucose homeostasis in obese mice, demonstrating that nonliving bacterial, metabolites, or other components within the feces of resveratrol-fed mice are sufficient to reduce intestinal inflammation. These postbiotics may be an integral mechanism by which resveratrol improves hyperglycemia in obesity. Resveratrol-FMTs also reduced the systolic blood pressure of hypertensive mice within 2 wk of the first transplant, indicating that the beneficial effects of resveratrol-FMTs may also assist with improving cardiovascular conditions associated with the metabolic syndrome.

Tributyltin reduces the levels of serum adiponectin and activity of AKT and induces metabolic syndrome in male mice.

Tributyltin (TBT), a proven environmental obesogen, functions as a nanomolar agonist of the peroxisome proliferator activated receptor-γ (PPARγ). However, the adverse effects of TBT on metabolism are incompletely understood. In this study, male ICR mice were administered TBT (5 and 50 μg·kg-1 ) by an intraperitoneal injection once every 3 days for 30 days from 28 days of age and bred for another 30 days after the last administration of TBT. We analyzed the effects of these exposures on the fat depot weights, serum lipid profile, serum leptin and adiponectin, hepatic lipid accumulation, and activity of AKT in the liver and skeletal muscle isolated from mice 8 mins after receiving an insulin injection. Pubertal exposure to TBTCl resulted in a higher body weight, increased epididymal and liver fat accumulation, hyperlipidemia, an elevated low-density lipoprotein/high-density lipoprotein ratio, serum adiponectin deficiency, worse glucose tolerance, and lower insulin-dependent AKT phosphorylation in the liver and muscle in mice. These results showed that TBT exposure induced peripheral insulin resistance and metabolic syndrome in mice.

Effect of Metabolic Syndrome on Anxiety in Mice

Metabolic syndrome is a combination of obesity, dyslipidemia, insulin resistance and hypertension. Clinical evidence indicated the coexistence of metabolic syndrome and depression. However, relatively few studies have been attempted to determine the pathogenesis of metabolic syndrome-associated anxiety. In the present study, the role of metabolic syndrome in the development of anxiety and the role of neurotransmitters in metabolic syndrome-associated anxiety were evaluated in Swiss albino mice. A high fat and high carbohydrate diet was used to develop the metabolic syndrome in mice while monitoring elevated fasting blood glucose, hyperlipidemia, and hypertension. Anxiety levels were measured using elevated plus maze and marble burying test with corresponding determination of serum corticosterone levels. The role of γ-aminobutyric acid and serotonin in metabolic syndrome-associated anxiety were also evaluated. The high fat and high carbohydrate fed animals developed metabolic syndrome, characterized by significant high fasting blood glucose and insulin resistance compared to controls. These animals also had significant increase in body weight and waist circumference, low-density lipoprotein and triglyceride levels, reduced high-density lipoprotein content and high blood pressure. Both metabolic syndrome and water avoidance-anxiety groups spent significantly lower time and showed fewer entries into the open arm of elevated plus maze. They also buried more marbles, thus showing clear signs of anxiety when compared to controls. The corticosterone level in metabolic syndrome and anxiety-induced animals were higher than controls. GABA agonists showed a dose-dependent reduction in metabolic syndrome-associated anxiety as revealed by more time spent on the open arm of plus maze with a corresponding decrease in plasma corticosterone levels. Metabolic syndrome animals spontaneously developed anxiety-like behavior. GABA agonists partially reversed the metabolic syndrome-associated anxiety, suggesting a role for GABAergic pathway.

Small-molecule TFEB pathway agonists that ameliorate metabolic syndrome in mice and extend C. elegans lifespan

Drugs that mirror the cellular effects of starvation mimics are considered promising therapeutics for common metabolic disorders, such as obesity, liver steatosis, and for ageing. Starvation, or caloric restriction, is known to activate the transcription factor EB (TFEB), a master regulator of lipid metabolism and lysosomal biogenesis and function. Here, we report a nanotechnology-enabled high-throughput screen to identify small-molecule agonists of TFEB and discover three novel compounds that promote autophagolysosomal activity. The three lead compounds include the clinically approved drug, digoxin; the marine-derived natural product, ikarugamycin; and the synthetic compound, alexidine dihydrochloride, which is known to act on a mitochondrial target. Mode of action studies reveal that these compounds activate TFEB via three distinct Ca2+-dependent mechanisms. Formulation of these compounds in liver-tropic biodegradable, biocompatible nanoparticles confers hepatoprotection against diet-induced steatosis in murine models and extends lifespan of Caenorhabditis elegans. These results support the therapeutic potential of small-molecule TFEB activators for the treatment of metabolic and age-related disorders.

A Disintegrin and Metalloproteinase with Thrombospondin Motifs 18 Deficiency Leads to Visceral Adiposity and Associated Metabolic Syndrome in Mice

Visceral adiposity is of greater risk than obesity in s.c. adipose tissue for diabetes and cardiovascular disease. Its pathogenesis remains unclear, but it is associated with extracellular matrix (ECM) remodeling. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) are a family of secreted zinc-dependent metalloproteinases that play crucial roles in development and various diseases because of their ECM remodeling activity. ADAMTS18 is an orphan ADAMTS whose function and substrate remain unclear. Herein, we showed that Adamts18 mRNA was abundantly expressed in visceral (gonadal) white adipose tissue (vWAT) during the early stage of development after birth. Adamts18 knockout (KO) mice showed increased body fat percentage and larger adipocyte size in vWAT relative to wild-type littermates. These findings may be partly attributed to ECM remodeling, especially increased expression of laminin 1 and adipokine thrombospondin 1 in vWAT. Attenuated extracellular signal-regulated kinase 1 and 2 activity, along with increased expression of adipocyte-specific transcription factors peroxisome proliferator-activated receptor-γ, CCAAT/enhancer binding protein β, and marker gene Fabp4, was detected in vWAT of Adamts18 KO mice. Furthermore, Adamts18 KO mice showed early metabolic syndrome, including hyperlipidemia, blood glucose metabolic disorder, and hypertension. ADAMTS18 deficiency promotes atherosclerosis in apolipoprotein E-deficient mice. These results indicate a novel function of ADAMTS18 in vWAT development and associated metabolic disorders.

Farnesyltransferase inhibitors prevent HIV protease inhibitor (lopinavir/ritonavir)-induced lipodystrophy and metabolic syndrome in mice.

Highly active antiretroviral therapy (HAART) has successfully reduced the mortality rate of patients with human immune deficiency virus (HIV) and HIV protease inhibitors (HIV PIs) are key components of HAART. Complications of HAART, particularly those associated with HIV PIs including lipodystrophy and metabolic disturbance, have emerged as an important public health issue. No specific treatment is available to prevent and/or treat HIV PI-associated lipodystrophy and metabolic syndrome. The present study demonstrated that a relatively low-dose of farnesyltransferase inhibitor (FTI), tipifarnib (3 mg/kg/day, subcutaneous injection) and lonafarnib (5 mg/kg/day, subcutaneous injection), prevented the onset of lipodystrophy and metabolic syndrome induced by the combination of two HIV PIs, lopinavir (50 mg/kg/day, intraperitoneal injection) and ritonavir (12.5 mg/kg/day, intraperitoneal injection), in mice. Consistent with previous studies, treatment with lopinavir/ritonavir for 2 weeks decreased body weight, adipose tissue mass, levels of plasma adiponectin and leptin, and increased plasma levels of triglycerides, total cholesterol and insulin. Tipifarnib and lonafarnb prevented or ameliorated all of these alterations in the HIV PI-treated mice. These data identify FTIs as a novel potential strategy to prevent or treat HIV PI-associated lipodystrophy and metabolic syndrome in HIV-infected patients on HAART.

Oncostatin M in the development of metabolic syndrome and its potential as a novel therapeutic target.

Oncostatin M (OSM), a member of the IL-6 family of cytokines, plays an important role in various biologic actions, including cell growth, neuronal development, and inflammatory responses. Recently, we demonstrated the unique relationship between OSM and metabolic syndrome in mice. Mice lacking OSM receptor β subunit (OSMRβ-/- mice) exhibited late-onset obesity. Before the onset of obesity, adipose tissue inflammation and insulin resistance were observed in OSMRβ-/- mice. In addition, high-fat diet-induced metabolic disorders, including obesity, adipose tissue inflammation, insulin resistance, and hepatic steatosis, were aggravated in OSMRβ-/- mice compared to those in wild-type mice. Consistent with these findings, OSM treatment dramatically improved these metabolic disorders in the mouse model of metabolic syndrome. Interestingly, OSM directly changed the phenotypes of adipose tissue macrophages toward anti-inflammatory M2 type. Furthermore, fatty acid content in the hepatocytes was decreased by OSM through expression regulation of several key enzymes of hepatic lipid metabolism. These findings suggest that OSM is a novel therapeutic target for metabolic syndrome.

Cucurbitacin E reduces obesity and related metabolic dysfunction in mice by targeting JAK-STAT5 signaling pathway.

Several members of cucurbitaceae family have been reported to regulate growth of cancer by interfering with STAT3 signaling. In the present study, we investigated the unique role and molecular mechanism of cucurbitacins (Cucs) in reducing symptoms of metabolic syndrome in mice. Cucurbitacin E (CuE) was found to reduce adipogenesis in murine adipocytes. CuE treatment diminished hypertrophy of adipocytes, visceral obesity and lipogenesis gene expression in diet induced mice model of metabolic syndrome (MetS). CuE also ameliorated adipose tissue dysfunction by reducing hyperleptinemia and TNF-alpha levels and enhancing hypoadiponectinemia. Results show that CuE mediated these effects by attenuating Jenus kinase- Signal transducer and activator of transcription 5 (JAK- STAT5) signaling in visceral fat tissue. As a result, CuE treatment also reduced PPAR gamma expression. Glucose uptake enhanced in adipocytes after stimulation with CuE and insulin resistance diminished in mice treated with CuE, as reflected by reduced glucose intolerance and glucose stimulated insulin secretion. CuE restored insulin sensitivity indirectly by inhibiting JAK phosphorylation and improving AMPK activity. Consequently, insulin signaling was up-regulated in mice muscle. As CuE positively regulated adipose tissue function and suppressed visceral obesity, dyslipedemia, hyperglycemia and insulin resistance in mice model of MetS, we suggest that CuE can be used as novel approach to treat metabolic diseases.

The kielin/chordin-like protein (KCP) attenuates high-fat diet-induced obesity and metabolic syndrome in mice

Obesity and its associated complications such as insulin resistance and non-alcoholic fatty liver disease are reaching epidemic proportions. In mice, the TGF-β superfamily is implicated in the regulation of white and brown adipose tissue differentiation. The kielin/chordin-like protein (KCP) is a secreted regulator of the TGF-β superfamily pathways that can inhibit both TGF-β and activin signals while enhancing bone morphogenetic protein (BMP) signaling. However, KCP's effects on metabolism and obesity have not been studied in animal models. Therefore, we examined the effects of KCP loss or gain of function in mice that were maintained on either a regular or a high-fat diet. KCP loss sensitized the mice to obesity and associated complications such as glucose intolerance and adipose tissue inflammation and fibrosis. In contrast, transgenic mice that expressed KCP in the kidney, liver, and adipose tissues were resistant to developing high-fat diet-induced obesity and had significantly reduced white adipose tissue. Moreover, KCP overexpression shifted the pattern of SMAD signaling in vivo, increasing the levels of phospho (P)-SMAD1 and decreasing P-SMAD3. Adipocytes in culture showed a cell-autonomous effect in response to added TGF-β1 or BMP7. Metabolic profiling indicated increased energy expenditure in KCP-overexpressing mice and reduced expenditure in the KCP mutants with no effect on food intake or activity. These findings demonstrate that shifting the TGF-β superfamily signaling with a secreted protein can alter the physiology and thermogenic properties of adipose tissue to reduce obesity even when mice are fed a high-fat diet.