Stearoyl-CoA desaturase-1 is associated with insulin resistance in morbidly obese subjects

Animal studies have revealed the association between stearoyl-CoA desaturase 1 (SCD1) and obesity and insulin resistance. However, only a few studies have been undertaken in humans. We studied SCD1 in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) from morbidly obese patients and their association with insulin resistance, sterol regulatory element binding protein-1 (SREBP-1) and ATPase p97, proteins involved in SCD1 synthesis and degradation. The insulin resistance was calculated in 40 morbidly obese patients and 11 overweight controls. Measurements were made of VAT and SAT SCD1, SREBP-1 and ATPase p97 mRNA expression and protein levels. VAT and SAT SCD1 mRNA expression levels in the morbidly obese patients were significantly lower than in the controls (P = 0.006), whereas SCD1 protein levels were significantly higher (P < 0.001). In the morbidly obese patients, the VAT SCD1 protein levels were decreased in patients with higher insulin resistance (P = 0.007). However, SAT SCD1 protein levels were increased in morbidly obese patients with higher insulin resistance (P < 0.05). Multiple linear regressions in the morbidly obese patients showed that the variable associated with the SCD1 protein levels in VAT was insulin resistance, and the variables associated with SCD1 protein levels in SAT were body mass index (BMI) and ATPase p97. In conclusion, these data suggest that the regulation of SCD1 is altered in individuals with morbid obesity and that the SCD1 protein has a different regulation in the two adipose tissues, as well as being closely linked to the degree of insulin resistance.     

Chromium (D-phenylalanine)3 alleviates high fat-induced insulin resistance and lipid abnormalities

High-fat diet has been implicated as a major cause of insulin resistance and dyslipidemia. The objective of this study was to evaluate the impact of dietary-supplementation of chromium (d-phenylalanine)₃ [Cr(d-Phe)₃] on glucose and insulin tolerance in high-fat diet fed mice. C57BL/6-mice were randomly assigned to orally receive vehicle or Cr(d-Phe)₃ (45 μg of elemental chromium/kg/day) for 8-weeks. High-fat-fed mice exhibited impaired whole-body-glucose and -insulin tolerance and elevated serum triglyceride levels compared to normal chow-fed mice. Insulin-stimulated glucose up-take in the gastrocnemius muscles, assessed as 2-[³H-deoxyglucose] incorporation was markedly diminished in high-fat fed mice compared to control mice. Treatment with chromium reconciled the high-fat diet-induced alterations in carbohydrate and lipid metabolism. Treatment of cultured, differentiated myotubes with palmitic acid evoked insulin resistance as evidenced by lower levels of insulin-stimulated Akt-phosphorylation, elevated JNK-phosphorylation, (assessed by Western blotting), attenuation of phosphoinositol-3-kinase activity (determined in the insulin-receptor substrate-1-immunoprecipitates by measuring the extent of phosphorylation of phosphatidylinositol by γ-³²P-ATP), and impairment in cellular glucose up-take, all of which were inhibited by Cr(d-Phe)₃. These results suggest a beneficial effect of chromium-supplementation in insulin resistant conditions. It is likely that these effects of chromium may be mediated by augmenting downstream insulin signaling.     

Transgenic expression of myostatin propeptide prevents diet-induced obesity and insulin resistance

Obesity and insulin resistance cause serious consequences to human health. To study effects of skeletal muscle growth on obesity prevention, we focused on a key gene of skeletal muscle named myostatin, which plays an inhibitory role in muscle growth and development. We generated transgenic mice through muscle-specific expression of the cDNA sequence (5'-region 886 nucleotides) encoding for the propeptide of myostatin. The transgene effectively depressed myostatin function. Transgenic mice showed dramatic growth and muscle mass by 9 weeks of age. Here we reported that individual major muscles of transgenic mice were 45-115% heavier than those of wild-type mice, maintained normal blood glucose, insulin sensitivity, and fat mass after a 2-month regimen with a high-fat diet (45% kcal fat). In contrast, high-fat diet induced wild-type mice with 170-214% more fat mass than transgenic mice and developed impaired glucose tolerance and insulin resistance. Insulin signaling, measured by Akt phosphorylation, was significantly elevated by 144% in transgenic mice over wild-type mice fed a high-fat diet. Interestingly, high-fat diet significantly increased adiponectin secretion while blood insulin, resistin, and leptin levels remained normal in the transgenic mice. The results suggest that disruption of myostatin function by its propeptide favours dietary fat utilization for muscle growth and maintenance. An increased secretion of adiponectin may promote energy partition toward skeletal muscles, suggesting that a beneficial interaction between muscle and adipose tissue play a role in preventing obesity and insulin resistance.     

Resistance to IP leptin-induced adipose apoptosis caused by high-fat diet in mice

The objectives of this experiment were to determine whether leptin causes adipocyte apoptosis in mice, whether peripheral administration is an effective means of studying leptin-induced adipocyte apoptosis, and whether high-fat feeding results in reduced responsiveness to leptin-induced adipocyte apoptosis. Continuous 13-day intraperitoneal infusion of 10 microg/day leptin significantly increased adipocyte apoptosis in the epididymal/parametrial fat pads of male and female mice, but only male mice developed reduced responsiveness to leptin-induced adipocyte apoptosis after high-fat (45% fat) feeding for 5 or 15 weeks. There was a positive correlation between serum leptin concentration and percent apoptotic adipocytes. These findings demonstrate that leptin administered peripherally is effective in inducing adipocyte apoptosis in mice, thus extending the possibility of studying this effect of leptin in a wider variety of animal models. In addition, high-fat feeding has a gender-specific effect on development of reduced responsiveness to leptin-induced adipocyte apoptosis.     

Methionine sulfoxide reductase B1 deficiency does not increase high-fat diet-induced insulin resistance in mice

Methionine-S-sulfoxide reductase (MsrA) protects against high-fat diet-induced insulin resistance due to its antioxidant effects. To determine whether its counterpart, methionine-R-sulfoxide reductase (MsrB) has similar effects, we compared MsrB1 knockout and wild-type mice using a hyperinsulinemic-euglycemic clamp technique. High-fat feeding for eight weeks increased body weights, fat masses, and plasma levels of glucose, insulin, and triglycerides to similar extents in wild-type and MsrB1 knockout mice. Intraperitoneal glucose tolerance test showed no difference in blood glucose levels between the two genotypes after eight weeks on the high-fat diet. The hyperglycemic-euglycemic clamp study showed that glucose infusion rates and whole body glucose uptakes were decreased to similar extents by the high-fat diet in both wild-type and MsrB1 knockout mice. Hepatic glucose production and glucose uptake of skeletal muscle were unaffected by MsrB1 deficiency. The high-fat diet-induced oxidative stress in skeletal muscle and liver was not aggravated in MsrB1-deficient mice. Interestingly, whereas MsrB1 deficiency reduced JNK protein levels to a great extent in skeletal muscle and liver, it markedly elevated phosphorylation of JNK, suggesting the involvement of MsrB1 in JNK protein activation. However, this JNK phosphorylation based on a p-JNK/JNK level did not positively correlate with insulin resistance in MsrB1-deficient mice. Taken together, our results show that, in contrast to MsrA deficiency, MsrB1 deficiency does not increase high-fat diet-induced insulin resistance in mice.     

Hydrodynamic delivery of IL-38 gene alleviates obesity-induced inflammation and insulin resistance

Obesity is associated with a chronic inflammatory response. Interleukin (IL)-38 is a poorly characterized cytokine of the IL-1 family with anti-inflammatory activity. The role of IL-38 in obesity-induced inflammation and insulin resistance remains unknown. In this study, we investigated the effects of IL-38 expression by hydrodynamic-based gene delivery on high-fat diet-induced obesity in mice. Transfer of plasmid DNA encoding IL-38 reduced weight gain, liver fat content, adipose tissue weight, and obesity-induced insulin resistance compared with administration of a control plasmid. Moreover, IL-38 gene delivery inhibited the production of inflammatory mediators including IL-1β, IL-6, and monocyte chemotactic protein-1. These results suggest that IL-38 is a potential new target for the treatment of obesity.     

SOCS-1 deficiency does not prevent diet-induced insulin resistance

Obesity is associated with inflammation and increased expression of suppressor of cytokine signaling (SOCS) proteins, which inhibit cytokine and insulin signaling. Thus, reducing SOCS expression could prevent the development of obesity-induced insulin resistance. Using SOCS-1 knockout mice, we investigated the contribution of SOCS-1 in the development of insulin resistance induced by a high-fat diet (HFD). SOCS-1 knockout mice on HFD gained 70% more weight, displayed a 2.3-fold increase in epididymal fat pads mass and increased hepatic lipid content. This was accompanied by increased mRNA expression of leptin and the macrophage marker CD68 in white adipose tissue and of SREBP1c and FAS in liver. HFD also induced hyperglycemia in SOCS-1 deficient mice with impairment of glucose and insulin tolerance tests. Thus, despite the role of SOCS proteins in obesity-related insulin resistance, SOCS-1 deficiency alone is not able to prevent insulin resistance induced by a diet rich in fat.     

Nobiletin improves obesity and insulin resistance in high-fat diet-induced obese mice

Nobiletin (NOB) is a polymethoxylated flavone present in citrus fruits and has been reported to have antitumor and anti-inflammatory effects. However, little is known about the effects of NOB on obesity and insulin resistance. In this study, we examined the effects of NOB on obesity and insulin resistance, and the underlying mechanisms, in high-fat diet (HFD)-induced obese mice. Obese mice were fed a HFD for 8 weeks and then treated without (HFD control group) or with NOB at 10 or 100 mg/kg. NOB decreased body weight gain, white adipose tissue (WAT) weight and plasma triglyceride. Plasma glucose levels tended to decrease compared with the HFD group and improved plasma adiponectin levels and glucose tolerance. Furthermore, NOB altered the expression levels of several lipid metabolism-related and adipokine genes. NOB increased the mRNA expression of peroxisome proliferator-activated receptor (PPAR)-γ, sterol regulatory element-binding protein-1c, fatty acid synthase, stearoyl-CoA desaturase-1, PPAR-α, carnitine palmitoyltransferase-1, uncoupling protein-2 and adiponectin, and decreased the mRNA expression of tumor necrosis factor-α and monocyte chemoattractant protein-1 in WAT. NOB also up-regulated glucose transporter-4 protein expression and Akt phosphorylation and suppressed IκBα degradation in WAT. Taken together, these results suggest that NOB improves adiposity, dyslipidemia, hyperglycemia and insulin resistance. These effects may be elicited by regulating the expression of lipid metabolism-related and adipokine genes, and by regulating the expression of inflammatory makers and activity of the insulin signaling pathway.     

Monoglyceride lipase deficiency in mice impairs lipolysis and attenuates diet-induced insulin resistance

Monoglyceride lipase (MGL) influences energy metabolism by at least two mechanisms. First, it hydrolyzes monoacylglycerols (MG) into fatty acids and glycerol. These products can be used for energy production or synthetic reactions. Second, MGL degrades 2-arachidonoyl glycerol (2-AG), the most abundant endogenous ligand of cannabinoid receptors (CBR). Activation of CBR affects energy homeostasis by central orexigenic stimuli, by promoting lipid storage, and by reducing energy expenditure. To characterize the metabolic role of MGL in vivo, we generated an MGL-deficient mouse model (MGL-ko). These mice exhibit a reduction in MG hydrolase activity and a concomitant increase in MG levels in adipose tissue, brain, and liver. In adipose tissue, the lack of MGL activity is partially compensated by hormone-sensitive lipase. Nonetheless, fasted MGL-ko mice exhibit reduced plasma glycerol and triacylglycerol, as well as liver triacylglycerol levels indicative for impaired lipolysis. Despite a strong elevation of 2-AG levels, MGL-ko mice exhibit normal food intake, fat mass, and energy expenditure. Yet mice lacking MGL show a pharmacological tolerance to the CBR agonist CP 55,940 suggesting that the elevated 2-AG levels are functionally antagonized by desensitization of CBR. Interestingly, however, MGL-ko mice receiving a high fat diet exhibit significantly improved glucose tolerance and insulin sensitivity in comparison with wild-type controls despite equal weight gain. In conclusion, our observations implicate that MGL deficiency impairs lipolysis and attenuates diet-induced insulin resistance. Defective degradation of 2-AG does not provoke cannabinoid-like effects on feeding behavior, lipid storage, and energy expenditure, which may be explained by desensitization of CBR.     

Stearoyl-CoA desaturase-1 deficiency reduces ceramide synthesis by downregulating serine palmitoyltransferase and increasing beta-oxidation in skeletal muscle

Stearoyl-CoA desaturase (SCD) has recently been shown to be a critical control point of lipid partitioning and body weight regulation. Lack of SCD1 function significantly increases insulin sensitivity in skeletal muscles and corrects the hypometabolic phenotype of leptin-deficient ob/ob mice, indicating the direct antilipotoxic action of SCD1 deficiency. The mechanism underlying the metabolic effects of SCD1 mutation is currently unknown. Here we show that SCD1 deficiency reduced the total ceramide content in oxidative skeletal muscles (soleus and red gastrocnemius) by approximately 40%. The mRNA levels and activity of serine palmitoyltransferase (SPT), a key enzyme in ceramide synthesis, as well as the incorporation of [14C]palmitate into ceramide were decreased by approximately 50% in red muscles of SCD1-/- mice. The content of fatty acyl-CoAs, which contribute to de novo ceramide synthesis, was also reduced. The activity and mRNA levels of carnitine palmitoyltransferase I (CPT I) and the rate of beta-oxidation were increased in oxidative muscles of SCD1-/- mice. Furthermore, SCD1 deficiency increased phosphorylation of AMP-activated protein kinase (AMPK), suggesting that AMPK activation may be partially responsible for the increased fatty acid oxidation and decreased ceramide synthesis in red muscles of SCD1-/- mice. SCD1 deficiency also reduced SPT activity and ceramide content and increased AMPK phosphorylation and CPT I activity in muscles of ob/ob mice. Taken together, these results indicate that SCD1 deficiency reduces ceramide synthesis by decreasing SPT expression and increasing the rate of beta-oxidation in oxidative muscles.     

Dual action of adiponectin on insulin secretion in insulin-resistant mice

Adiponectin is secreted by adipocytes and has been implicated as a mediator of insulin sensitivity. In this study, the acute effects of adiponectin on islets isolated from normal or diet-induced insulin resistant mice were examined. In normal islets, adiponectin (5 microg/ml) had no significant effect on insulin secretion. In contrast, in islets from mice rendered insulin resistant by high-fat feeding, adiponectin inhibited insulin secretion at 2.8 mM (P < 0.01) but augmented insulin secretion at 16.7 mM glucose (P < 0.05). The augmentation of glucose-stimulated insulin secretion by adiponectin was accompanied by increased glucose oxidation (P < 0.005), but without any significant effect on palmitate oxidation or the islet ATP/ADP ratio. Furthermore, RT-PCR revealed the expression of the adiponectin receptor AdipoR1 mRNA in mouse islets, however, with no difference in the degree of expression level between the two feeding groups. The results thus uncover a potential dual role for adiponectin to modify insulin secretion in insulin resistance.     

雷帕霉素对小鼠葡萄糖代谢水平的影响

目的探讨雷帕霉素对葡萄糖代谢水平影响的特点、机制。方法选择4周龄、雄性C57BL/6小鼠,高热量、高脂饮食喂养8周后为肥胖组(HF,n=18),普通饲料喂养为正常组(NC,n=18)。两组小鼠分别给予安慰剂(n=6)、腹腔注射雷帕霉素(2 mg/kg,隔日1次,n=6)、喂饮2.37%亮氨酸水(n=6),2周后分别行灌胃葡萄糖耐量试验(glucose tolerance test,GTT)、胰岛素耐受性试验(insulin tolerance test,ITT)以及胰岛组织病理学检查。结果正常组小鼠腹腔注射雷帕霉素后葡萄糖负荷30min血糖水平显著升高(与安慰剂组比P=0.038,与亮氨酸组比P=0.035)。肥胖组小鼠腹腔注射雷帕霉素后空腹血糖水平显著高于安慰剂组(P=0.031),葡萄糖负荷30 min血糖显著高于安慰剂组(P=0.013)、亮氨酸组(P=0.041)。仅正常组小鼠胰岛素敏感性与安慰剂组相比显著降低(P=0.039)。雷帕霉素干预后腹腔脂肪量显著减少(正常组与安慰剂组比P0.001,肥胖组与安慰剂组比P=0.013)。结论雷帕霉素对哺乳动物糖代谢水平有显著影响,正常小鼠与机体胰岛素敏感性下降有关;肥胖小鼠与胰岛素分泌功能受损、胰岛素抵抗相关。     

Diet-induced obesity increases NF-κB signaling in reporter mice

The nuclear factor (NF)-κB is a primary regulator of inflammatory responses and may be linked to pathology associated with obesity. We investigated the progression of NF-κB activity during a 12-week feeding period on a high-fat diet (HFD) or a low-fat diet (LFD) using NF-κB luciferase reporter mice. In vivo imaging of luciferase activity showed that NF-κB activity was higher in the HFD mice compared with LFD-fed mice. Thorax region of HFD females displayed fourfold higher activity compared with LFD females, while no such increase was evident in males. In male HFD mice, abdominal NF-κB activity was increased twofold compared with the LFD males, while females had unchanged NF-κB activity in the abdomen by HFD. HFD males, but not females, exhibited evident glucose intolerance during the study. In conclusion, HFD increased NF-κB activity in both female and male mice. However, HFD differentially increased activity in males and females. The moderate increase in abdomen of male mice may be linked to glucose intolerance.     

Global deletion of lipocalin 2 does not reverse high-fat diet-induced obesity resistance in stearoyl-CoA desaturase-1 skin-specific knockout mice

Over the past century, obesity has developed into a paramount health issue that affects millions of people worldwide. Obese individuals have an increased risk to develop other metabolic disorders, such as insulin resistance and atherosclerosis, among others. Previously we determined that mice lacking stearoyl-CoA desaturase-1 (SCD1) enzyme specifically in the skin (SKO) were lean and protected from high-fat diet induced adiposity. Additionally, lipocalin 2 (Lcn2) mRNA was found to be 27-fold higher in the skin of SKO mice compared to control mice. Given reports suggesting that Lcn2 plays a role in protection against diet-induced weight gain, adiposity and insulin resistance, we hypothesized that deletion of Lcn2 alongside the skin-specific SCD1 deficiency would diminish the obesity resistance observed in SKO mice. To test this, we developed mice lacking SCD1 expression in the skin and also lacking Lcn2 expression globally and surprisingly, these mice did not gain significantly more weight than the SKO mice under high-fat diet conditions. Therefore, we conclude that Lcn2 does not mediate the protection against high-fat diet-induced adiposity observed in SKO mice.     

Childhood obesity and insulin resistance

Insulin resistance (IR) in childhood has importance to the understanding and prevention of the growing epidemic of insulin resistance syndrome (IRS) in adults with attendant obesity, type 2 diabetes (T2DM), atherosclerotic diseases, hypertension, gout, non-alcoholic, steato-hepatitis (NASH), gall bladder disease, nephropathy, polycystic ovarian disease (PCOS), infertility and premature senility. The severity of IR and its’ complications in children unfortunately and usually progresses in their pubertal transition to adulthood; affected young children are more likely than adults to have underlying causal monogenic disorders; the sequence of natural history and events give insights into disease pathogeneses, and optimal life style choices that last are best made during the early formative years. Some features of IR in children discussed herein are: a strong tendency to low birth weight for gestational age, adverse effects of adrenarche and therapeutic steroid therapy, predisposition to premature pubarche, acanthosis nigricans, tall stature despite pituitary GH suppression, allergic diathesis, hyperandrogenism and PCOS, dyslipidemia and fatty liver disease, and diagnosis by clinical and biochemical markers of IR including insulin regulated hepatic hormonal binding proteins such as IGFBP-1. The national preoccupation with the “metabolic syndrome” T2DM and obesity, should be appropriately directed to an improved understanding of IR in children and their management, if the looming health crisis in affected adults is to be seriously addressed. The nation is facing its’ first generation of children who will be less healthy and die younger than the previous generation (Marks (2005) Presentation to the American Association of Diabetes Educators 32nd Annual Meeting and Exhibition, August 10–13, Washington, DC).     

Improvement of high fat-diet-induced insulin resistance in dipeptidyl peptidase IV-deficient Fischer rats

F344/DuCrj rats are genetically deficient in dipeptidyl peptidase IV (DPPIV). This enzyme degrades glucagon-like peptide-1 (GLP-1), which induces glucose-dependent insulin secretion. Glucose tolerance of F344/DuCrj rats is improved as a result of enhanced insulin release induced by high levels of plasma GLP-1. In this study, we fed F344/DuCrj rats and DPPIV-positive F344/Jcl rats, aged five weeks, on a high-fat (HF) diet to examine the effect of DPPIV deficiency on food intake and insulin resistance. F344/Jcl rats gained significantly more body weight and consumed significantly more food than F344/DuCrj rats from Week 4 on either control or HF diet. Glucose excursion in the oral glucose tolerance test (OGTT) was improved in F344/DuCrj rats fed on the control or HF diet at all times examined, compared with F344/Jcl rats. Homeostasis model assessment (HOMA) insulin resistance values of F344/DuCrj and F344/Jcl rats fed on HF diet were higher than those of animals fed on control diet up to Week 6. However, HOMA insulin resistance values of F344/DuCrj rats fed on HF diet became significantly lower than those of F344/Jcl rats on HF diet during Weeks 8-10. The area under the insulin curve in the OGTT at Week 10 showed that the insulin resistance of HF-diet-fed F344/DuCrj rats was greatly ameliorated. Plasma active GLP-1 concentrations of F344/DuCrj rats in the fed state were significantly higher than those of F344/Jcl rats. These observations suggest that DPPIV deficiency results in improved glucose tolerance and ameliorated insulin resistance owing to enhanced insulin release and inhibition of food intake as a result of high active GLP-1 levels.     

Reversal of obesity and insulin resistance by a non-peptidic glucagon-like peptide-1 receptor agonist in diet-induced obese mice

Background

Glucagon-like peptide-1 (GLP-1) is recognized as an important regulator of glucose homeostasis. Efforts to utilize GLP-1 mimetics in the treatment of diabetes have yielded clinical benefits. A major hurdle for an effective oral therapy has been the difficulty of finding a non-peptidic GLP-1 receptor (GLP-1R) agonist. While its oral bioavailability still poses significant challenges, Boc5, one of the first such compounds, has demonstrated the attainment of GLP-1R agonism in diabetic mice. The present work was to investigate whether subchronic Boc5 treatment can restore glycemic control and induce sustainable weight loss in diet-induced obese (DIO) mice, an animal model of human obesity and insulin resistance.

Methodology/Principal Findings

DIO mice were treated three times a week with Boc5 (0.3, 1 and 3 mg) for 12 weeks. Body weight, body mass index (BMI), food intake, fasting glucose, intraperitoneal glucose tolerance and insulin induced glucose clearance were monitored regularly throughout the treatment. Glucose-stimulated insulin secretion, β-cell mass, islet size, body composition, serum metabolic profiles, lipogenesis, lipolysis, adipose hypertrophy and lipid deposition in the liver and muscle were also measured after 12 weeks of dosing. Boc5 dose-dependently reduced body weight, BMI and food intake in DIO mice. These changes were associated with significant decreases in fat mass, adipocyte hypertrophy and peripheral tissue lipid accumulation. Boc5 treatment also restored glycemic control through marked improvement of insulin sensitivity and normalization of β-cell mass. Administration of Boc5 (3 mg) reduced basal but enhanced insulin-mediated glucose incorporation and noradrenaline-stimulated lipolysis in isolated adipocytes from obese mice. Furthermore, circulating leptin, adiponectin, triglyceride, total cholesterol, nonesterified fatty acid and high-density lipoprotein/low-density lipoprotein ratio were normalized to various extents by Boc5 treatment.

Conclusions/Significance

Boc5 may produce metabolic benefits via multiple synergistic mechanisms and may represent an attractive tool for therapeutic intervention of obesity and diabetes, by means of non-peptidic GLP-1R agonism.