High-fat Diet-induced Insulin Research Articles

Abstract TP252: Intranasal Insulin Treatment Improves Stroke Outcome In Both Male And Female Mice

Insulin resistance has been linked to increased risk of stroke recurrence, death, and poor outcome following stroke. Insulin resistance, a common phenomenon following stroke, is associated with elevated levels of insulin circulating in the periphery, which leads to brain insulin deficiency. Brain insulin promotes neuroplasticity and synaptogenesis, has anti-inflammatory, anti-thrombotic, vasodilatory, and anti-apoptotic properties. The impact of brain insulin deficiency and the therapeutic potential of increasing brain insulin levels has yet to be fully understood. Hence, purpose of this study is to assess the potential therapeutic benefits of intranasal insulin treatment on stroke outcomes in a mouse model of brain insulin deficiency. Ischemic stroke was induced using a 30 minute middle cerebral artery occlusion (MCAO) in 16 week old (12 week diet) male and female mice on either a standard diet (control) or a high-fat diet induced at 4 weeks of age, a model of brain insulin deficiency. Recovery assessments begin on day 0 following stroke and continue until day 14 post stroke. Recovery assessments entail observing survival, neurological, motor, and cognitive function after receiving either intranasal saline (0.9%) or intranasal insulin (1.75 U). These assessments were evaluated by survival, and completion of the neurological severity score, ladder, and problem solving tasks on days 0-14 post stroke. High-fat diet-induced brain insulin deficiency was associated with worse survival and neurological deficits following ischemic stroke, intranasal insulin improved stroke mortality and neurological assessments in high-fat diet mice. Thus, intranasal insulin may be a useful therapy for improving stroke outcomes.

MiR-125b-2 knockout increases high-fat diet-induced fat accumulation and insulin resistance

Obese individuals are more susceptible to comorbidities than individuals of healthy weight, including cardiovascular disease and metabolic disorders. MicroRNAs are a class of small and noncoding RNAs that are implicated in the regulation of chronic human diseases. We previously reported that miR-125b plays a critical role in adipogenesis in vitro. However, the involvement of miR-125b-2 in fat metabolism in vivo remains unknown. In the present study, miR-125b-2 knockout mice were generated using CRISPR/CAS9 technology, resulting in mice with a 7 bp deletion in the seed sequence of miR-125b-2. MiR-125b-2 knockout increased the weight of liver tissue, epididymal white fat and inguinal white fat. MiR-125b-2 knockout also increased adipocyte volume in HFD-induced obese mice, while there were no significant differences in body weight and feed intake versus mice fed a normal diet. Additionally, qRT-PCR and western blot analysis revealed that the expression of the miR-125b-2 target gene SCD-1 and fat synthesis-associated genes, such as PPARγ and C/EBPα, were significantly up-regulated in miR-125b-2KO mice (P < 0.05). Moreover, miR-125b-2KO altered HFD-induced changes in glucose tolerance and insulin resistance. In conclusion, we show that miR-125b-2 is a novel potential target for regulating fat accumulation, and also a candidate target to develop novel treatment strategies for obesity and diabetes.

Abstract MP121: Deleting the 2-oxoglutarate- and Iron-dependent Prolyl Hydroxylase Ogfod1 Alters Purine Nucleotide Regulation and is Cardioprotective

Prolyl hydroxylation is a post-translational modification that regulates protein stability, turnover, and activity. The proteins that catalyze prolyl hydroxylation belong to the 2-oxoglutarate- and iron-dependent oxygenase family of enzymes. A newly-described member of this family is 2-oxoglutarate- and iron-dependent oxygenase domain containing protein 1 (Ogfod1), which catalyzes prolyl hydroxylation of the ribosomal protein s23 (Rps23). To investigate the cardiovascular function of Ogfod1, we isolated hearts from 5 Ogfod1 -WT and 5 Ogfod1 -KO mice and used Liquid Chromatography and Tandem Mass Spectrometry (LC-MS/MS) to identify proteomic changes. Ingenuity Pathway Analysis (IPA) identified “Purine Nucleotides Degradation II (Aerobic)” ( P = 0.00017) to be one of the most significantly-enriched pathways. We then did metabolomics and found that Inosine 5’-monophosphate (IMP) was 3.5x higher in Ogfod1 -KO hearts ( P = 0.011), further supporting a role for Ogfod1 in regulating purine nucleotide metabolism. Recent evidence has shown that altering purine nucleotide degradation protects against diet-induced obesity and insulin resistance, so we tested this hypothesis in Ogfod1 -KO mice by feeding them high-fat diets. Ogfod1 ablation protects against high-fat diet-induced obesity and insulin resistance. Altering purine nucleotide degradation has also been shown to be protective against cardiac injury, so we tested the hypothesis that Ogfod1 loss protects the heart from ischemia-reperfusion (I/R) injury by subjecting perfused hearts from 6 Ogfod1 -WT and 6 Ogfod1 -KO mice to ischemia and reperfusion and assessed tissue death. We found a 37% decrease in infarct size in Ogfod1 -KO hearts (56% in Ogfod1 -WT and 35% in Ogfod1 -KO, P = 0.0003). In a separate set of experiments, we treated Ogofd1 -KO mice with isoproterenol to induce hypertrophy, and Ogfod1 -KO hearts showed protection against hypertrophic remodeling. Interestingly, OGFOD1 transcripts were up-regulated in human heart failure, indicating a potential role for OGFOD1 in the human failing heart. Altogether, these data show that Ogfod1 deletion alters the myocardial proteome and myocardial metabolism and protects against obesity, insulin sensitivity, I/R injury, and hypertrophy.

Integrated analysis of differentially expressed long noncoding RNAs and mRNAs associated with high-fat diet-induced hepatic insulin resistance in mice

BackgroundHepatic insulin resistance (IR) is an early pathological characteristic of many metabolic diseases, such as type 2 diabetes. Long noncoding RNAs (lncRNAs) have been identified as mediators of IR and related diseases. However, the roles of lncRNAs in hepatic IR remain largely unknown.MethodHigh-throughput sequencing was performed on ten liver tissue samples from five normal diet (ND)-fed mice and five high-fat diet (HFD)-induced hepatic IR mice, respectively. lncRNAs and mRNAs that were differentially expressed (DE) between the two groups were identified by bioinformatic analyses. Seven DE lncRNAs were validated by quantitative real-time PCR (q-PCR). The potential functions of the DE lncRNAs were predicted by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses of target genes. In addition, integrated analysis was performed for the DE lncRNAs and mRNAs to predict their interaction relationships.ResultsA total of 232 DE lncRNAs were identified in the HFD-induced hepatic IR mice compared with the ND-fed mice. These DE lncRNAs included 108 upregulated and 124 downregulated lncRNAs, and 7 of the DE lncRNAs were validated by q-PCR. In addition, 291 DE mRNAs including 166 upregulated and 125 downregulated mRNAs were identified in the HFD group. Furthermore, target genes of the DE lncRNAs were predicted, and functional enrichment results showed that the enriched genes were involved in IR- and glycolipid metabolism-related processes. Additionally, the coexpression network was also constructed to further reflect the potential functions of the DE lncRNAs.ConclusionThe study describes the expression profiles of lncRNAs and mRNAs and the functional networks involved in HFD-induced hepatic IR. These findings may provide a new perspective for the study of lncRNAs in hepatic IR- and glycolipid metabolism-related diseases.

1808-P: Hepatocyte Traf Family Members Link Inflammation to Liver Steatosis and Insulin Resistance

Obesity is associated with chronic inflammation that exacerbates insulin resistance and metabolic disease. Inflammation drives the pathogenesis of nonalcoholic fatty liver disease (NAFLD), hepatic manifestations of obesity. Hepatic inflammatory microenvironments are believed to induce reprogramming of metabolic pathways; however, intracellular molecules coupling inflammation to metabolism remain poorly understood. Cytokines, damage-associated (DAMPs) and pathogen-associated molecular patterns (PAMPs) are known to activate Traf family members that in turn activate the NF-κB and other inflammatory pathways. We previously reported that hepatic Traf2 and Traf3 augment hepatic glucose production. Here, we demonstrate that hepatocyte Traf2, Traf3 and Traf6 act in concert to promote liver steatosis and insulin resistance. We ablated hepatocyte Traf2, Traf3, and Traf6 individually and in combination (Traf2,3,6Δhep) in adult Traf2flox/flox, Traf3flox/flox, Traf6flox/flox, and Traf2,3,6flox/flox mice, respectively, using AAV-TBG-Cre vectors. Metabolic abnormality was more severe in Traf2,3,6Δhep mice relative to Traf2Δhep, Traf3Δhep and Traf6Δhep mice. Remarkably, Traf2,3,6Δhep mice were resistant to high fat diet-induced liver steatosis, insulin resistance, and glucose intolerance. Hepatic PPARα, a master regulator of fatty acid β oxidation, was substantially elevated in Traf2,3,6Δhep mice. Conversely, in primary hepatocytes, overexpression of Traf3 markedly decreased PPARα stability and protein levels. Traf3 coimmunoprecipitated with PPARα and decreased PPARα transcriptional activity. In primary hepatocytes, ablation of Traf2, Traf3 and Traf6 significantly increased fatty acid β oxidation, and overexpression of Traf3 had the opposite effects. Together, our results unveil an unrecognized hepatocyte Traf/PPARα/fatty acid β oxidation pathway that couples inflammation to liver steatosis and insulin resistance in obesity. Disclosure Z. Zhang: None. H. Lin: None. X. Zhong: None. L. Rui: None.

1964-P: Slug Epigenetically Represses Adipose Thermogenic Programs

Thermogenic fat, such as brown adipose tissue (BAT) and beige fat, gains increasing attention due to its ability to protect against obesity and type 2 diabetes. Brown adipocytes and beige adipocytes contain dense mitochondria that burn glucose and free fatty acids to produce heat, and mitochondrial Ucp1 mediates heat production. Coactivator PGC1α is a master regulator of mitochondrial biogenesis and Ucp1 expression, and profoundly influences the energy expenditure capability of thermogenic fat. We attempted to delineate transcriptional regulators that govern thermogenic fat activity through PGC1α, and identified transcriptional repressor Slug. Both human and mouse PGC1α promoters contain multiple Slug binding motifs. Slug potently suppressed the activity of PGC1α promoter luciferase reporters but not mutant PGC1α promoters lacking Slug motifs. Consistently, Slug physically bound to the PGC1α promoter and decreased the levels of PGC1α promoter H3K9 acetylation, a transcriptionally-active epigenetic mark, presumably by recruiting HDAC1/2 to the promoter. In line with this notion, treatment with HDAC1/2 inhibitor trichostatin A abrogated the ability of Slug to suppress PGC1α promoter luciferase reporters. Remarkably, deletion of Slug substantially increased expression of PGC1α and Ucp1 in both BAT and inguinal fat in mice, and increased H3K9 acetylation levels on the PGC1α promoter in BAT. Slug-deficient BAT had increased O2 consumption rates and thermogenesis capability. Slug knockout mice were resistant to high fat diet-induced obesity, insulin resistance, glucose intolerance, and fatty liver disease. Likewise, adipocyte-specific deletion of Slug also ameliorated HFD-induced glucose intolerance. Unlike global Slug knockout mice, adipocyte-specific Slug knockout mice displayed mild metabolic phenotypes. In conclusion, our data suggest that Slug regulates thermogenic fat energy expenditure at least in part by epigenetically suppressing the PGCα-mitochondria axis. Disclosure Q. Kang: None. L. Jiang: None. L. Rui: None.

1960-P: A Novel Nitric Oxide Releasing Nanomatrix Gel Prevents High-Fat Diet-Induced Obesity and Insulin Resistance

Endothelial dysfunction is characterized by reduction of the bioavailability of nitric oxide (NO), and is associated with metabolic syndrome including, obesity, insulin resistance, hypertension, coronary heart disease, and aging. Because NO plays important roles in mitochondrial biogenesis, we hypothesize that exogenous application of NO may prevent high fat diet (HFD)-induced obesity and insulin resistance by promotion of adipose tissue browning. In the current study, we developed a novel NO releasing nanomatrix gel with natural peptide amphiphiles (PANO). 8 week old male C57BL/6 mice were randomly divided into 2 groups, and then either vehicle (PA) or PANO was subcutaneously injected into brown adipose tissue area every 2 weeks for 11 weeks while the mice were fed HFD. The mice injected with PANO gained less body weight compared to the mice injected with vehicle. PANO injected mice demonstrated improved glucose tolerance and insulin tolerance. Fasting glucose, insulin and leptin levels were lower in the PANO injected mice compared to the vehicle injected mice. Furthermore, the expression of pro-inflammatory genes in epididymal fat tissue was lower, and the expression of uncoupled protein (UCP1) in brown adipose tissue and inguinal adipose tissue was higher in the PANO-injected mice compared to the vehicle injected mice. Thus, the novel nitric oxide releasing nanomatrix gel ameliorated HFD-induced obesity and insulin resistance by promotion of adipose tissue browning. The results suggest that injection of PANO can be a novel therapeutic for obesity and insulin resistance. Disclosure G. Ren: None. A.L. Shaw: None. P. Hwang: None. R.C. Millican: None. H. Jun: None. J. Kim: None. Funding National Institutes of Health (1R01HL125391-01)

Improvement in High-fat Diet-induced Obesity and Insulin Resistance upon Uptake of PS-B1, a Fermented Product Prepared from Soy Flour Using Lactic Acid Bacteria

PS-B1 is a fermented product prepared from soy flour using lactic acid bacteria. Over a 10-week period, C57BL/6J mice were reared under laboratory conditions on a normal diet (control, n=5), high-fat diet (HF, n=5), or high-fat diet supplemented with 4% PS-B1 (HF-P, n=6). After 10 weeks, the change in weight gain, intestinal and epididymal fat accumulation, serum and liver biochemical parameters, and gene expression in the mice was investigated. HF diet-induced weight gain and increase in intestinal and epididymal fat accumulation were lower in mice fed with HF-P diet than in mice fed with HF diet, suggesting that PS-B1 prevented HF diet-induced obesity in HF-P mice. Furthermore, the levels of liver lipids (triglycerides, TG; non-esterified fatty acid, NEFA; total cholesterol, TC), serum TC, serum glucose, and serum insulin were significantly increased in the HF group than those in control mice. In HF-P mice, neither serum TC nor serum glucose levels were reduced. In contrast, the levels of liver lipids and serum insulin were lower in HF-P mice than in HF mice, suggesting that PS-B1 reduced these parameters in HF-P mice. The homeostatic model assessment of insulin resistance (HOMA-IR) value, which was calculated from the serum glucose and insulin levels, was 21.5 ± 4.2 in the HF mice. However, the HOMA-IR (8.2 ± 0.2) values were significantly decreased in the HF-P mice, suggesting that PS-B1 improves insulin resistance. Additionally, we compared the expression levels of stearoyl-CoA desaturase-1 (Scd1) in the liver. Quantitative RT-PCR showed increased expression of Scd1 in HF mice compared to that in control mice. Furthermore, ingestion of PS-B1 led to reduced expression of Scd1 mRNA in HF-P mice, implying that PS-B1 is effective in reducing the expression of the gene encoding SCD1. These results suggest that the anti-obesity effect of PS-B1 and improvement in fat accumulation upon PS-B1 uptake may be due to improvement in insulin resistance and reduction in the expression level of Scd1.

Helminthostachys zeylanica alleviates hepatic steatosis and insulin resistance in diet-induced obese mice

BackgroundObesity and its associated health conditions, type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD), are worldwide health problems. It has been shown that insulin resistance is associated with increased hepatic lipid and causes hepatic steatosis through a myriad of mechanisms, including inflammatory signaling.MethodsHelminthostachys zeylanica (HZ) is used widely as a common herbal medicine to relieve fever symptoms and inflammatory diseases in Asia. In the present study, we evaluated whether HZ has therapeutic effects on obesity, NAFLD and insulin resistance. The protective effects of HZ extract were examined using free fatty acid-induced steatosis in human HuS-E/2 cells and a high-fat diet-induced NAFLD in mice.ResultsThe major components of the HZ extract are ugonins J and K, confirmed by HPLC. Incubation of human hepatocytes, HuS-E/2 cells, with palmitate markedly increased lipid accumulation and treatment with the HZ extract significantly decreased lipid deposition and facilitated AMPK and ACC activation. After 12 weeks of a high-fat diet with HZ extract treatment, the HFD mice were protected from hyperlipidemia and hyperglycemia. HZ extract prevented body weight gain, adipose tissue expansion and adipocyte hypertrophy in the HFD mice. In addition, fat accumulation was reduced in mice livers. Moreover, the insulin sensitivity-associated index, which evaluates insulin function, was also significantly restored.ConclusionsThese results suggest that HZ has a promising pharmacological effect on high-fat diet-induced obesity, hepatic steatosis and insulin resistance, which may have the potential for clinical application.

High-throughput sequencing of small RNAs and analysis of differentially expressed microRNAs associated with high-fat diet-induced hepatic insulin resistance in mice

BackgroundHepatic insulin resistance (IR) plays a crucial role in the development of many metabolic diseases, such as type 2 diabetes. MicroRNAs (miRNAs) are involved in the pathogenesis of IR and related diseases; however, studies of miRNAs in hepatic IR are limited.MethodIn this study, we adopted a high-throughput sequencing approach to construct small RNA libraries in the livers of normal mice and high-fat diet-induced hepatic IR mice.ResultsThrough analysis of data, 107 known and 56 novel miRNAs were identified as differentially expressed miRNAs between the two groups. Additionally, bioinformatics methods were used to predict targets of the differentially expressed miRNAs and to explore the potential downstream Gene Ontology categories and Kyoto Encyclopedia of Genes and Genomes pathways. Meanwhile, some differentially expressed miRNAs (miR-34a-5p, miR-149-5p, miR-335-3p, miR-10b-5p, miR-1a-3p, miR-411-5p, and miR-592-5p) were validated by quantitative-time PCR, and their potential target genes related to IR or glycolipid metabolism were also predicted and presented in this study.ConclusionTaken together, our results defined miRNA expression signature that may lead to hepatic IR in mice, and the findings provided a foundation for future studies to further explore the effects and underlying mechanisms of the miRNAs and their target genes in the pathogenesis of hepatic IR and related diseases.

Abstract 700: Adipocyte-Specific Calpain-2 Deficiency Attenuates Obesity-accelerated Abdominal Aortic Aneurysms in Mice

Background and Objective: Recent clinical studies demonstrated that abdominal adiposity is associated with increased risk of abdominal aortic aneurysm (AAA) development. Calpains are non-lysosomal calcium dependent cysteine proteases that are highly expressed in human and experimental AAAs. Using a pharmacological inhibitor and genetically deficient mice, we identified that calpain-2 (a major ubiquitous isoform) plays a critical role in Angiotensin II (AngII)-induced AAA formation in obese mice. In addition, we demonstrated that calpain inhibition strongly suppressed adipose tissue inflammation in obese mice. The purpose of this study was to determine the role of adipocyte-specific calpain-2 on obesity-accelerated AAA. Methods and Results: Calpain-2 floxed mice that were hemizygous for Adiponectin Cre (Cre+/0) were produced by breeding male Cre+/0 to female calpain-2 floxed mice. Littermates that were homozygous for the floxed calpain-2 gene, but without the Cre transgene (Cre0/0), were used as control mice. Western blot analyses showed that calpain-2 protein is depleted in various fat tissues including periaortic adipose, from Cre+/0 mice, while not influencing abundance in aorta and other tissues. Male Cre+/0 and Cre0/0 mice were fed a high fat diet (60% Kcal) for 20 weeks. After 16 weeks of diet feeding, mice (n=20-22) were infused with either saline or AngII (1,000 ng/kg/min) by osmotic minipumps for 4 weeks. Depletion of calpain-2 in adipocytes had no effect on high fat diet-induced body weight gain, fat mass, glucose and insulin tolerance. Interestingly, adipocyte-specific calpain-2 depletion significantly attenuated AngII-induced expansion of ex-vivo maximal diameter of abdominal aortas in obese mice (Saline- Cre0/0: 0.95 ± 0.03; Cre+/0: 0.98 ± 0.02 mm; AngII - Cre0/0: 1.95 ± 0.20; Cre+/0: 1.25 ± 0.08 mm P&lt;0.001). In addition, calpain-2 depletion also reduced the incidence of AngII-induced AAAs in mice (Cre0/0: 76% versus Cre+/0: 27%). Conclusion: These findings suggest that adipocyte-derived calpain-2 plays a critical role in AngII-induced AAA development in diet-induced obese mice.

Abstract 638: Response Gene to Complement 32 Promotes Atherosclerosis Through Endothelial Cell Dysfunction Induced Vascular Inflammation

Atherosclerosis is the major cause of cardiovascular diseases and the primary cause of death worldwide. Our previous studies have demonstrated that response gene to complement 32 (RGC-32) deficiency prevents the mice from high-fat diet-induced obesity and insulin resistance. The present study was conducted to determine the role of RGC-32 in the development of atherosclerosis. We observed that endothelial RGC-32 expression was dramatically induced in human and mouse atherosclerotic lesions. RGC-32 deficiency (RGC-32-/-) significantly attenuated the atherosclerotic lesion formation in arteries of ApoE-/- mice. Mechanistically, RGC-32-/- diminished the expression of vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 in primary cultured mouse endothelial cells induced by tumor necrosis factor (TNF)-α. RGC-32-/- also inhibited TNF-α-induced monocyte-endothelial cell interaction. These data demonstrate that RGC-32 contributes to the development of atherosclerosis by regulating the expression of endothelial adhesive molecules, and thus facilitating macrophage infiltration. Therefore, RGC-32 may be a potential novel drug target in the treatment of atherosclerosis and its related cardiovascular diseases.

Seaweed Supplementation Attenuates Long‐term High Fat Diet‐induced Chronic Inflammation and Insulin Resistance Regardless of Obesity in C57BL/6N Mice

Antidiabetic and anti‐inflammatory effects of brown seaweeds have been reported in various experimental models, however information is scarce on their effects combined with a long‐term high fat diet. In this present study, we investigated that effects and mechanisms of seaweed supplementation (Undaria pinnatifida (UP), Laminaria japonica (LJ), Sargassum fulvellum (SF), Hizikia fusiforme (HF)) along with high‐fat (HF) diet in C57BL/6N male mice for 16 weeks. Body weight, food intake, and fasting blood glucose concentrations were measured. Insulin tolerance test was performed at week 14. Animals were sacrificed at week 16 and tissues were dissected, weighted, and snap frozen for analysis. Bone‐marrow (BM) cells were isolated from femoral and tibial BM of a representative mouse from each group. As a result, 5% seaweed supplementation did not prevent HF‐induced obesity. Although there was a trend to have less weight gain in HF+LJ and HF+HF groups compared to HF group at week 8, this trend disappeared as HF continued. In spite of being obese, mice in HF+LJ group had significantly improved insulin resistance, lowered cholesterol in plasma and liver, and increased TG in feces compared to mice in HF group that were consistent with histological observations. In addition, BM‐derived macrophages(BMDM) from mice fed HF with seaweeds showed to have less inflammatory cytokines compared to BMDM from mice fed HF only. Increased phosphorylation of insulin signaling proteins was observed in liver of the seaweed supplemented HF groups compared to the HF group. In addition, levels of TG and cholesterol excretion were altered by seaweed supplementation. Conclusively, seaweed supplementation attenuated insulin resistance and chronic inflammation induced by a long‐term HF feeding partially due to altered insulin signaling and lipogenesis in liver and muscle as well as reduced inflammation in adipose tissue regardless of obesity in C57BL/6N mice.Support or Funding InformationThis work was supported by NRF‐2013R1A1A10575730.

Eicosapentaenoic acid Increases Brown Adipose Tissue Thermogenic Markers in High Fat Fed Mice

Brown adipose tissue (BAT) converts excess food energy into thermal energy, and has therefore attracted attention as a new area of research to counter obesity. We previously reported that eicosapentaenoic acid (EPA) reduces high fat diet-induced obesity and insulin resistance in mice, independent of energy intake; however, the role of EPA in regulating thermogenesis in brown fat is not well understood. Hence, we hypothesize that EPA induces thermogenesis in brown fat to counteract obesity and insulin resistance. To test our hypothesis, C57BL/6J mice fed with high fat (HF) with or without EPA were used. BAT from HF-EPA mice expressed higher mRNA levels of thermogenic genes such as FNDC5 and PGC1-alpha, compared to HF mice. Furthermore, EPA up-regulated uncoupling protein 1 (UCP-1) protein content in BAT. Another key marker for brown fat thermogenesis, PRDM16, was also significantly higher in EPA fed mice vs HF, confirming thermogenesis induction. To further study direct effects of EPA on BAT, a clonal brown fat cell line, HIB1, was treated with different doses of EPA. Mitochondrial content measured using a MitoTracker was dose-dependently and significantly higher in EPA treated vs. vehicle, suggesting higher mitochondrial activity in EPA treated cells. Currently, cell and molecular studies are underway to determine mechanisms mediating EPA effects on brown adipocyte metabolism and mitochondrial function. In conclusion, our results from in vivo and in vitro studies indicate that EPA reduces obesity and its associated metabolic disorders at least in part by activating BAT thermogenesis. Supported by AHA, USDA and TTU

P0954 : Pu-erh tea extract ameliorates high-fat diet-induced nonalcoholic steatohepatitis and insulin resistance by enhancing hepatic STAT3 phosphorylation in mice

P0954 : Pu-erh tea extract ameliorates high-fat diet-induced nonalcoholic steatohepatitis and insulin resistance by enhancing hepatic STAT3 phosphorylation in mice

Dissociation between high fat diet-induced obesity (DIO) and insulin resistance: lessons from AHNAK knockout mice

Dissociation between high fat diet-induced obesity (DIO) and insulin resistance: lessons from AHNAK knockout mice

Oral Administration of Alkylglycerols Differentially Modulates High-Fat Diet-Induced Obesity and Insulin Resistance in Mice

Alkylglycerols (AKGs) from shark liver oil (SLO) were demonstrated to have strong potency to stimulate immune response. However, no study has been conducted on the effects of AKGs on diet-induced obesity and metabolic inflammatory disorder. The purpose of the present study was to investigate the effect of two AKGs isoforms on obesity and insulin resistance in mice fed high-fat (HF) diet. Forty-eight C57BL/6 mice were divided into normal, HF, HF + 20 mg/kg selachyl alcohol (SA), HF + 200 mg/kg SA, HF + 20 mg/kg batyl alcohol (BA), and HF + 200 mg/kg BA groups. Body weight, fasting glucose, lipids, insulin and leptin levels, serum IL-1β, and TNF-α levels were compared among different groups. Our results showed that high-dose SA decreased body weight, serum triglyceride, cholesterol, fasting glucose level, insulin level, and serum leptin level of the HF fed mice, while high-dose BA increased fasting insulin level of the HF fed mice. Pretreatment of primary adipocytes with 10 μM SA or BA differentially modulates LPS-mediated MAPK and NF-κB signaling. Our study demonstrated that oral administration of AKGs has differential effects on HF-induced obesity and metabolic inflammatory disorder in mice.

Nonalcoholic Fatty Liver Disease: Its Mechanisms and Complications

Nonalcoholic Fatty Liver Disease: Its Mechanisms and Complications

(18) Fenretinide treatment for high fat diet-induced obesity and insulin sensitivity

(18) Fenretinide treatment for high fat diet-induced obesity and insulin sensitivity

Molecular Pathogenesis of Type 2 Diabetes in Knockout Mice Models

Type 2 diabetes is a complex disease caused by interactions of multiple genes and environmental factors such as high-fat diet and sedentary life-style. Since type 2 diabetes is characterized by insulin resistance and relative insulin deficiency, we have tried to dissect molecular pathogenesis of type 2 diabetes by generating several knockout mice models with a lack of each key molecules of signaling pathways of either insulin action or insulin secretion such as insulin receptor substrate-l (IRS-l)(l), IRS-2(2), P13 kinase(3), PPARg(4), b-cell glucokinase(5), or the NADH shuttle system(6). Moreover, in order to study gene-gene and gene-environment interactions in the development of type 2 diabetes, we have crossed these animals(7) and/or exposed them to a certain environmental factors such as high-fat diet(4). DNA chip analysis has also been used to systematically identify crucial pathways for the development of type 2 diabetes in each tissue of these animals. These efforts have begun to reveal some key aspects of molecular pathogenesis of type 2 diabetes(8). We have found that insulin resistan6e can lead to type 2 diabetes only when b cell defects exist simultaneously such as decreased insulin response to glucose(7) or impaired b cell hyperplasia(2). We have also found that PPARg plays a crucial role in the development of highfat diet-induced obesity, insulin resistance and type 2 diabetes (4). Importantly, pathways identified to have a role in the development of type 2 diabetes in these analyses can be tested as candidate susceptibility loci of human type 2 diabetes. Conversely, functional impact of human type 2 diabetes susceptibility loci can be analyzed by generating corresponding mutant mice. Finally, we have begun to apply information obtained in these analyses to develop potential tailar-made medicine to provide fundamental prevention and therapeutic strategies for type 2 diabetes.