Diacerhein improves glucose tolerance and insulin sensitivity in mice on a high-fat diet

Obesity and type 2 diabetes are characterized by insulin resistance, and the common basis of these events is a chronic and systemic inflammatory process marked by the activation of the c-Jun N-terminal kinase (JNK) and inhibitor-κB kinase (IKKβ)/nuclear factor-κB (NFκB) pathways, up-regulated cytokine synthesis, and endoplasmic reticulum dysfunction. The aim of this study was to evaluate the effects of diacerhein administration, an antiinflammatory drug that reduces the levels of inflammatory cytokines, on insulin sensitivity and signaling in diet-induced obese (DIO) mice. Swiss mice were fed with conventional chow (control group) or a high-fat diet (DIO group). Later, DIO mice were randomly subdivided into a new subgroup (DAR) that received 20 mg/kg diacerhein for 10 d. Western blotting was used to quantify the expression and phosphorylation of insulin receptor, insulin receptor substrate 1, and Akt and of inflammatory mediators that modulate insulin signaling in a negative manner (IKKβ, JNK, and inducible nitric oxide synthase). We show here, for the first time, that the administration of diacerhein in DIO mice improved endoplasmic reticulum stress, reduced JNK and IKKβ phosphorylation, and resulted in a marked improvement in fasting glucose, a decrease in macrophage infiltration in adipose tissue, and a reduced expression and activity of proinflammatory mediators accompanied by an improvement in the insulin signaling mainly in the liver and adipose tissue. Taken together, these results indicate that diacerhein treatment improves insulin sensitivity in obesity, mediated by the reversal of subclinical inflammation, and that this drug may be an alternative therapy for insulin resistance.     

Glucagon receptor antagonism improves islet function in mice with insulin resistance induced by a high-fat diet

Aims/hypothesis Increased glucagon secretion predicts deterioration of glucose tolerance, and high glucagon levels contribute to hyperglycaemia in type 2 diabetes. Inhibition of glucagon action may therefore be a potential novel target to reduce hyperglycaemia. Here, we investigated whether chronic treatment with a glucagon receptor antagonist (GRA) improves islet dysfunction in female mice on a high-fat diet (HFD). Materials and methods After 8 weeks of HFD, mice were treated with a small molecule GRA (300 mg/kg, gavage once daily) for up to 30 days. Insulin secretion was studied after oral and intravenous administration of glucose and glucagon secretion after intravenous arginine. Islet morphology was examined and insulin secretion and glucose oxidation were measured in isolated islets. Results Fasting plasma glucose levels were reduced by GRA (6.0 ± 0.2 vs 7.4 ± 0.5 mmol/l; p = 0.017). The acute insulin response to intravenous glucose was augmented (1,300 ± 110 vs 790 ± 64 pmol/l; p < 0.001). The early insulin response to oral glucose was reduced in mice on HFD + GRA (1,890 ± 160 vs 3,040 ± 420 pmol/l; p = 0.012), but glucose excursions were improved. Intravenous arginine significantly increased the acute glucagon response (129 ± 12 vs 36 ± 6 ng/l in controls; p < 0.01), notably without affecting plasma glucose. GRA caused a modest increase in alpha cell mass, while beta cell mass was similar to that in mice on HFD + vehicle. Isolated islets displayed improved glucose-stimulated insulin secretion after GRA treatment (0.061 ± 0.007 vs 0.030 ± 0.004 pmol islet⁻¹ h⁻¹ at 16.7 mmol/l glucose; p < 0.001), without affecting islet glucose oxidation. Conclusions/interpretation Chronic glucagon receptor antagonism in HFD-fed mice improves islet sensitivity to glucose and increases insulin secretion, suggesting improvement of key defects underlying impaired glucose tolerance and type 2 diabetes.     

高脂饮食性非酒精性脂肪性肝病小鼠肝脏陷窝蛋白-1的变化

目的 探索陷窝蛋白-1在高脂饮食性非酒精性脂肪性肝病(NAFLD)发病中的作用.方法 给予12只10周龄雄性C57BL/6小鼠高脂高胆固醇饮食14周,建立NAFLD的动物模型作为实验组.同时,普通饮食饲养同种系小鼠6只作为对照组.第14周末处死全部小鼠,比较两组体质量、肝质量和血脂变化.分别用实时荧光定量PCR(qPCR)和Western印迹法检测陷窝蛋白-1在NAFLD小鼠肝组织中的基因和蛋白表达水平变化.苏木精-伊红染色后光学显微镜下观察小鼠肝脏的脂肪变性情况,免疫组织化学染色后观察陷窝蛋白-1在肝组织中分布的变化.采用t检验比较两组肝组织中陷窝蛋白-1 mRNA及蛋白水平的差异,Mann-whitney U检验分析不同程度脂肪肝小鼠的肝脏陷窝蛋白-1表达的免疫组织化学积分差异.结果 实验组小鼠在高脂高胆固醇饮食14周后全部发生NAFLD,其中重度9只,中度3只.与对照组比较,实验组小鼠的血清TC[(1.940±0.300) mmol/L比(3.771±0.800) mmol/L,t=-3.760]、高密度脂蛋白胆固醇[(1.120±0.066)mmol/L比(2.224±0.420) mmol/L,t=-5.474]、低密度脂蛋白胆固醇[(0.510±0.191) mmol/L比(1.241±0.660) mmol/L,t=-3.332]均显著升高(P均＜0.01),但TG差异无统计学意义(P＞0.05).实验组小鼠肝脏陷窝蛋白[1的mRNA(1.536±0.226比0.980±0.272,t=3.371,P＜0.05)和蛋白水平(0.643±0.240比0.100±0.130,t=-4.847,P＜0.01)均显著高于对照组.免疫组织化学结果显示,表达增加的陷窝蛋白-1主要分布于肝细胞膜、脂滴膜和细胞质中.结论 高脂高胆固醇饮食诱导的NAFLD小鼠肝脏陷窝蛋白1水平上调,可能参与了NAFLD的发病机制.     

A high-fat diet induces bone loss in mice lacking the Alox5 gene

5-Lipoxygenase catalyzes leukotriene generation from arachidonic acid. The gene that encodes 5-lipoxygenase, Alox5, has been identified in genome-wide association and mouse Quantitative Trait Locus studies as a candidate gene for obesity and low bone mass. Thus, we tested the hypothesis that Alox5(-/-) mice would exhibit metabolic and skeletal changes when challenged by a high-fat diet (HFD). On a regular diet, Alox5(-/-) mice did not differ in total body weight, percent fat mass, or bone mineral density compared with wild-type (WT) controls (P < 0.05). However, when placed on a HFD, Alox5(-/-) gained more fat mass and lost greater areal bone mass vs. WT (P < 0.05). Microarchitectural analyses revealed that on a HFD, WT showed increases in cortical area (P < 0.01) and trabecular thickness (P < 0.01), whereas Alox5(-/-) showed no change in cortical parameters but a decrease in trabecular number (P < 0.05) and bone volume fraction compared with WT controls (P < 0.05). By histomorphometry, a HFD did not change bone formation rates of either strain but produced an increase in osteoclast number per bone perimeter in Alox5(-/-) mice (P < 0.03). In vitro, osteoclastogenesis of marrow stromal cells was enhanced in mutant but not WT mice fed a HFD. Gene expression for Rankl, Pparg, and Cox-2 was greater in the femur of Alox5(-/-) than WT mice on a HFD (P < 0.01), but these increases were suppressed in the Alox5(-/-) mice after 8 wk of treatment with celecoxib, a cyclooxygenase-2 inhibitor. In sum, there is a strong gene by environmental interaction for bone mass when mice lacking the Alox5 gene are fed a HFD.     

Exogenous IGF-1 improves tau pathology and neuronal pyroptosis in high-fat diet mice with cognitive dysfunction

Metabolic Brain Disease - Insulin-like growth factor-1 (IGF-1) improves obesity-induced cognitive dysfunction, but its mechanism is not fully clarified. The aim of the study was to reveal whether...     

Overexpression of lipoprotein lipase improves insulin resistance induced by a high-fat diet in transgenic rabbits

Aims/hypothesis Dysfunctions of lipoprotein lipase (LPL) have been found to be associated with dyslipidaemias, atherosclerosis, obesity and insulin resistance. There are two conflicting hypotheses regarding the roles of LPL in glucose metabolism and insulin resistance. Whether systemically increased LPL activity would be beneficial or detrimental to insulin sensitivity is yet to be resolved. To address this issue, we studied transgenic rabbits overexpressing human LPL transgene.Methods LPL transgenic and control rabbits were fed a 10% high-fat diet (HFD) for 16 weeks. To evaluate glucose metabolism, we compared plasma levels of glucose and insulin in transgenic rabbits with control rabbits and performed an intravenous glucose tolerance test. In addition, we measured adipose tissue accumulation in HFD-fed rabbits.Results Increased LPL activity in transgenic rabbits resulted in a significant reduction of plasma triglycerides and non-esterified fatty acids, but not in basal levels of glucose and insulin. HFD feeding induced an elevation of plasma glucose levels accompanied by hyperinsulinaemia in control rabbits, but was significantly inhibited in transgenic rabbits. The intravenous glucose tolerance test showed that transgenic rabbits had faster glucose clearance associated with lower levels of insulin secretion than control rabbits. In addition, there was a significant reduction of body adipose tissue in transgenic rabbits compared with in control rabbits fed an HFD. Scanning electron microscopic examination revealed that adipocytes in transgenic rabbits were predominately small cells.Conclusions/interpretation Our results showed that systemically increased LPL activity improves insulin resistance and reduces adipose accumulation in transgenic rabbits, indicating that systemic elevation of LPL may have potential benefits for the treatment of insulin resistance and obesity.Abbreviations ACO acyl-CoA oxidase - CPT1 carnitine-palmitoyl-transferase-1 - HFD high-fat diet - LPL lipoprotein lipase - MRI magnetic resonance imaging - PPAR peroxisome proliferator-activated receptor - TG triglycerides     

Modulation of gut microbiota by antibiotics improves insulin signalling in high-fat fed mice

Aims/hypothesis  

A high-fat dietary intake induces obesity and subclinical inflammation, which play important roles in insulin resistance. Recent studies have suggested that increased concentrations of circulating lipopolysaccharide (LPS), promoted by changes in intestinal permeability, may have a pivotal role in insulin resistance. Thus, we investigated the effect of gut microbiota modulation on insulin resistance and macrophage infiltration.     

Soraphen, an inhibitor of the acetyl-CoA carboxylase system, improves peripheral insulin sensitivity in mice fed a high-fat diet

Aim: Inhibition of the acetyl-CoA carboxylase (ACC) system, consisting of the isozymes ACC1 and ACC2, may be beneficial for treatment of insulin resistance and/or obesity by interfering with de novo lipogenesis and β-oxidation. We have evaluated effects of pharmacological inhibition of ACC by soraphen (SP) on high fat (HF) diet–induced insulin resistance in mice.
Method: Male C57Bl6/J mice were fed control chow, a HF diet or a HF diet supplemented with SP (50 or 100 mg/kg/day).
Results: Body weight gain and total body fat content of SP-treated animals were significantly reduced compared with HF-fed mice. Fractional synthesis of palmitate was significantly reduced in mice treated with SP, indicative for ACC1 inhibition. Plasma β-hydroxybutyrate levels were significantly elevated by SP, reflecting simultaneous inhibition of ACC2 activity. Mice treated with SP showed improved peripheral insulin sensitivity, as assessed by hyperinsulinaemic euglycaemic clamps.
Conclusion: Pharmacological inhibition of the ACC system is of potential use for treatment of key components of the metabolic syndrome.     

EGCG对高脂饮食诱发的小鼠非酒精性脂肪肝的影响

目的 探讨表没食子儿茶素没食子酸酯(EGCG)对高脂饮食(HFD)诱发的小鼠非酒精性脂肪肝的影响.方法 选取60只雄性C57BL/6小鼠,随机分为对照组、EGCG组、HFD组和HFD+EGCG组,分别以普通饲料、普通饲料+EGCG、HFD和HFD+EGCG喂饲.观察各组的腹腔葡萄糖耐量试验(IPGTT)结果、体质量、肝...     

A low-carbohydrate/high-fat diet improves glucoregulation in type 2 diabetes mellitus by reducing postabsorptive glycogenolysis

The aim of this study was to examine the mechanisms by which dietary carbohydrate and fat modulate fasting glycemia. We compared the effects of an eucaloric high-carbohydrate (89% carbohydrate) and high-fat (89% fat) diet on fasting glucose metabolism and insulin sensitivity in seven obese patients with type 2 diabetes using stable isotopes and euglycemic hyperinsulinemic clamps. At basal insulin levels glucose concentrations were 148 +/- 11 and 123 +/- 11 mg/dl (8.2 +/- 0.6 and 6.8 +/- 0.6 mmol/liter) on the high-carbohydrate and high-fat diet, respectively (P < 0.001), with insulin concentrations of 12 +/- 2 and 10 +/- 1 microIU/ml (82 +/- 11 and 66 +/- 10 pmol/liter) (P = 0.08). Glucose production was higher on the high-carbohydrate diet (1.88 +/- 0.06 vs. 1.55 +/- 0.05 mg/kg.min (10.44 +/- 0.33 vs. 8.61 +/- 0.28 micromol/kg.min) (P < 0.001) because of higher glycogenolysis. Gluconeogenic rates were not different between the diets. During the use of hyperinsulinemic euglycemic clamps, insulin-mediated suppression of glucose production and stimulation of glucose disposal were not different between the diets. Free fatty concentrations were suppressed by 89 and 62% (P < 0.0001) on the high-carbohydrate and high-fat diet, respectively. We conclude that short-term variations in dietary carbohydrate to fat ratios affect basal glucose metabolism in people with type 2 diabetes merely through modulation of the rate of glycogenolysis, without affecting insulin sensitivity of glucose metabolism.     

Selective inhibition of 11 beta-hydroxysteroid dehydrogenase type 1 improves hepatic insulin sensitivity in hyperglycemic mice strains

11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) has been proposed as a new target for type 2 diabetes drugs. The aim of the present study was to assess the effects of inhibition of 11 beta-HSD1 on blood glucose levels, glucose tolerance, and insulin sensitivity in mouse models of type 2 diabetes. BVT.2733 is an isoform-selective inhibitor of mouse 11 beta-HSD1. Hyperglycemic and hyperinsulinemic ob/ob, db/db, KKAy, and normal C57BL/6J mice were orally administered BVT.2733 (200 mg/kg.d, twice daily). In hyperglycemic, but not in normal mice, BVT.2733 lowered circulating glucose (to 50-88% of control) and insulin (52-65%) levels. In oral glucose tolerance tests in ob/ob and KKAy mice, glucose concentrations were 65-75% of vehicle values after BVT.2733 treatment, and in KKAy mice insulin concentrations were decreased (62-74%). Euglycemic, hyperinsulinemic clamps demonstrated decreased endogenous glucose production (21-61%). Analysis of hepatic mRNA in KKAy mice showed reduced phosphoenolpyruvate carboxykinase mRNA (71%). A slight reduction in food intake was observed in ob/ob and KKAy mice. Cholesterol, triglycerides, and free fatty acid levels were decreased to 81-86% in KKAy mice after a 4-h fast. The results support previous suggestions that selective 11 beta-HSD1 inhibitors lower blood glucose levels and improve insulin sensitivity in different mouse models of type 2 diabetes.     

The effect of a high-fat diet on brainstem and duodenal serotonin (5-HT) metabolism in Sprague-Dawley and Osborne-Mendel rats

Sprague-Dawley (S-D) and Osborne-Mendel (O-M) rats were fed either a low-fat diet (5 percent corn oil) or high-fat diet (20 percent corn oil) for a six-week-period. Brainstem and duodenal levels of tryptophan, serotonin (5-hydroxytryptamine, 5-HT) and 5-hydroxyindole-3-acetic acid (5-HIAA) were not altered by dietary treatment in the O-M rats. On the other hand, the high-fat diet significantly decreased brainstem 5-HT levels in S-D rats. Brainstem and duodenal 5-HT levels were decreased in O-M rats as compared to S-D rats and this phenomenon is not altered by dietary treatment. It is suggested that the O-M rat may have a alteration in the 5-HT metabolic system and that such a defect may contribute to the development of obesity.     

Lipoprotein lipase activator NO-1886 improves fatty liver caused by high-fat feeding in streptozotocin-induced diabetic rats

NO-1886 is a lipoprotein lipase (LPL) activator. Administration of NO-1886 results in an increase in plasma high-density lipoprotein cholesterol (HDL-C) and a decrease in plasma triglyceride (TG) levels. The aim of this study was to ascertain whether NO-1886 improves fatty liver caused by high-fat feeding in streptozotocin (STZ)-induced diabetic rats. Administration of NO-1886 resulted in increased plasma HDL-C levels and decreased TG levels without affecting total cholesterol and glucose levels in the diabetic rats. NO-1886 dose-dependently decreased liver TG contents and cholesterol contents, resulting in improvement of fatty liver. NO-1886 also reduced plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) that accompany fatty liver. The liver cholesterol contents were inversely correlated with plasma HDL-C levels (r = -0.5862, P <.001) and were positively correlated with plasma TG levels (r = 0.4083, P <.003). The liver TG contents were inversely correlated with plasma HDL-C levels (r = -0.6195, P <.001) and were positively correlated with plasma TG levels (r = 0.5837, P <.001). There was no correlation between plasma cholesterol levels, and cholesterol and TG contents in liver. These results indicate that reducing plasma TG levels and elevating in HDL-C levels may result in improving fatty liver.     

Selective inhibition of angiotensin-II-mediated aldosterone secretion by 5-hydroxyeicosatetraenoic acid

We have previously demonstrated that the 12-lipoxygenase (12-LO) pathway plays a key role in angiotensin-II (AII)-dependent aldosterone production. In the present study we examined the role of the 5LO pathway on AII-induced aldosterone secretion in rat glomerulosa cells in vitro. The 5LO product 5-hydroxyeicosatetraenoic acid (5HETE) and its unstable precursor 5-hydroxyperoxyeicosatetraenoic acid did not significantly alter basal aldosterone secretion in concentrations from 10(-9)-10(-7) M. In contrast, 5HETE reduced peak AII-induced aldosterone production from 59.1 +/- 9.0 to 37.96 +/- 7.2 ng/10(6) cells (P less than 0.01). This was accompanied by inhibition of the AII-stimulated rise in 12HETE production (10(-9)M AII, 160 +/- 4% of control; 10(-9) M AII plus 10(-7) M 5HETE, 90 +/- 1% of control production). However, 5HETE had no effect on the aldosterone response to potassium or ACTH, secretagogues that cause no activation of the 12LO pathway. These results suggest that the 5LO product 5HETE can selectively modulate AII-dependent aldosterone secretion. Further, the selective inhibitory effect of 5HETE on the AII effect in rat glomerulosa cells may be exerted by blockade of arachidonate metabolism via the 12LO pathway. These results suggest that the 5LO pathway may negatively modulate AII action in the adrenal zona glomerulosa.     

Green coffee bean extract improves obesity by decreasing body fat in high-fat diet-induced obese mice

Objective:To evaluate possible lipid catabolism and body fat regulation effects of 3-caffeoylquinic acid in Green coffee bean extract(GCBE) in high-fat diet(HFD)-induced obese mice.Methods:Obesity was induced in mice using a HFD for four weeks.Then,mice were fed only HFD or HFD with GCBE at 50,100,and 200 mg/kg.Fatty acid synthesis mechanism regulation of body fat was investigated through real-time PCR and Western blot assay.Body fat reduction was measured through dual-energy X-ray absorptiometry.Results:In HFD-induced obese mice,GCBE treatment significantly decreased body weight gain,liver weight and white adipose tissue weights with regulation of adipose tissue lipolysis hormones,like adiponectin and leptin.GCBE treatment decreased mR NA expression levels of adipogenesis and adipocyte metabolism related genes in adipose tissues and the liver,and decreased the corresponding protein expression.Dual energy X-ray absorptiometry measurements were used to compare body fat between mice on high-fat and those treated with GCBE.GCBE treated mice had a lower fat mass compared to HFD alone fed mice and relative body weight and fat mass were markedly decreased.Conclusions:GCBE has a potential anti-obesity effect with lowering body fat accumulation by regulating adipogenesis and lipid metabolism-related genes and proteins in WAT and liver.     

Ipragliflozin improves mitochondrial abnormalities in renal tubules induced by a high‐fat diet

Aims/Introduction

Complete mechanisms of renoprotective effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors have not been elucidated yet. Mitochondrial biogenesis is regulated by membrane GTPases, such as optic atrophy factor 1 and mitofusion 2. Here, we investigated whether SGLT2 inhibition in mice fed with a high‐fat diet (HFD) improved mitochondrial morphology and restored mitochondrial biogenesis‐related molecules.

Materials and Methods

Mice were fed a control diet or HFD with or without ipragliflozin treatment. After 16 weeks, the kidneys were taken out and utilized for the analysis.

Results

HFD‐fed mice treated with ipragliflozin showed increased caloric intake and ate more food than the control HFD‐fed mice. Body and kidney weights, and blood glucose levels were not altered by ipragliflozin treatment in HFD‐fed mice. Histological analysis showed that, compared with control mice, HFD‐fed mice displayed tubular vacuolation, dilatation and epithelial cell detachment; ipragliflozin ameliorated these alterations. Furthermore, ultrastructural analysis showed that the tubule mitochondria of HFD‐fed mice exhibited significant damage. Again, ipragliflozin reversed the damage to a normal state, and restored optic atrophy factor 1 and mitofusion 2 levels in HFD‐fed mice. Increased urine 8‐hydroxydeoxyguanosine levels in HFD‐fed mice were suppressed by ipragliflozin as well. In vitro experiments using HK‐2 cells revealed that either high glucose or high palmitate suppressed optic atrophy factor 1 and mitofusion 2 levels. Suppression of SGLT2 by a specific small interfering ribonucleic acid or ipragliflozin restored these GTPase levels to their normal values.

Conclusions

SGLT2 inhibition might act directly on tubular cells and protect kidney tubular cells from mitochondrial damage by metabolic insults regardless of blood glucose levels or improvement in bodyweight reduction.