tretinoin and Insulin-Resistance

Mammalian adipose tissue is traditionally categorized into white and brown relating to their function and morphology: while white serves as an energy storage, brown adipose tissue acts as the heat generator maintaining the core body temperature. The most recently identified type of fat, beige adipocyte tissue, resembles brown fat by morphology and function but is developmentally more related to white. The synthesis of beige fat, so-called browning of white fat, has developed into a topical issue in diabetes and metabolism research. This is due to its favorable effect on whole-body energy metabolism and the fact that it can be recruited during adult life. Indeed, brown and beige adipose tissues have been demonstrated to play a role in glucose homeostasis, insulin sensitivity, and lipid metabolism-all factors related to pathogenesis of type 2 diabetes. Many agents capable of initiating browning have been identified so far and tested widely in humans and animal models including in vitro and in vivo experiments. Interestingly, several agents demonstrated to have browning activity are in fact secreted as adipokines from brown and beige fat tissue, suggesting a physiological relevance both in beige adipocyte recruitment processes and in maintenance of metabolic homeostasis. The newest findings on agents driving beige fat recruitment, their mechanisms, and implications on type 2 diabetes are discussed in this review.

Topics: Adipose Tissue, Beige; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Diabetes Mellitus, Type 2; Energy Metabolism; Glucagon-Like Peptide 1; Glucose; Humans; Insulin Resistance; Leptin; Lipid Metabolism; Lipotropic Agents; Melatonin; Natriuretic Peptides; Thermogenesis; Tretinoin

Evidence has accumulated that specific retinoids impact on developmental and biochemical processes influencing mammalian adiposity including adipogenesis, lipogenesis, adaptive thermogenesis, lipolysis and fatty acid oxidation in tissues. Treatment with retinoic acid, in particular, has been shown to reduce body fat and improve insulin sensitivity in lean and obese rodents by enhancing fat mobilization and energy utilization systemically, in tissues including brown and white adipose tissues, skeletal muscle and the liver. Nevertheless, controversial data have been reported, particularly regarding retinoids' effects on hepatic lipid and lipoprotein metabolism and blood lipid profile. Moreover, the molecular mechanisms underlying retinoid effects on lipid metabolism are complex and remain incompletely understood. Here, we present a brief overview of mammalian lipid metabolism and its control, introduce mechanisms through which retinoids can impact on lipid metabolism, and review reported activities of retinoids on different aspects of lipid metabolism in key tissues, focusing on retinoic acid. Possible implications of this knowledge in the context of the management of obesity and the metabolic syndrome are also addressed. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism.

Topics: Adipose Tissue; Animals; Energy Metabolism; Humans; Insulin Resistance; Lipid Metabolism; Liver; Liver X Receptors; Mice; Muscle, Skeletal; Orphan Nuclear Receptors; Rats; Receptors, Retinoic Acid; Tretinoin

Retinoic acid (RA) was found to be a ligand for peroxisome proliferation-activated receptor delta (PPARdelta) as well as the classical RA receptor (RAR). Carrier proteins that move the RA from the cytosol into the nucleus are the fatty acid-binding protein 5 (FABP5), activating PPARdelta, and the cellular retinoic acid-binding protein II (CRABPII), activating RAR. The ratio of FABP5/CRABPII concentrations determines which receptor is activated. By activating PPARdelta, RA was found to induce expression of genes affecting lipid and glucose homeostasis, in particular, leading to expression of the insulin-signaling gene PDK1 and improvement of insulin action. Hence, RA stimulates lipolysis and reduces triglyceride content. In vivo, obesity has led to downregulation of adipose PPARdelta expression. RA implantation into obese mice has caused upregulation of levels of PPARdelta and consequent weight loss as well as increased expression of PPARdelta target genes, including the insulin-signaling gene PDK1.

Topics: Animals; Enzyme Activation; Fatty Acid-Binding Proteins; Humans; Insulin Resistance; Ligands; Lipid Metabolism; Obesity; PPAR delta; Receptors, Retinoic Acid; Tretinoin

Skeletal muscle is a major mass peripheral tissue that accounts for approximately 40% of the total body mass and a major player in energy balance. It accounts for >30% of energy expenditure, is the primary tissue of insulin stimulated glucose uptake, disposal, and storage. Furthermore, it influences metabolism via modulation of circulating and stored lipid (and cholesterol) flux. Lipid catabolism supplies up to 70% of the energy requirements for resting muscle. However, initial aerobic exercise utilizes stored muscle glycogen but as exercise continues, glucose and stored muscle triglycerides become important energy substrates. Endurance exercise increasingly depends on fatty acid oxidation (and lipid mobilization from other tissues). This underscores the importance of lipid and glucose utilization as an energy source in muscle. Consequently skeletal muscle has a significant role in insulin sensitivity, the blood lipid profile, and obesity. Moreover, caloric excess, obesity and physical inactivity lead to skeletal muscle insulin resistance, a risk factor for the development of type II diabetes. In this context skeletal muscle is an important therapeutic target in the battle against cardiovascular disease, the worlds most serious public health threat. Major risk factors for cardiovascular disease include dyslipidemia, hypertension, obesity, sedentary lifestyle, and diabetes. These risk factors are directly influenced by diet, metabolism and physical activity. Metabolism is largely regulated by nuclear hormone receptors which function as hormone regulated transcription factors that bind DNA and mediate the patho-physiological regulation of gene expression. Metabolism and activity, which directly influence cardiovascular disease risk factors, are primarily driven by skeletal muscle. Recently, many nuclear receptors expressed in skeletal muscle have been shown to improve glucose tolerance, insulin resistance, and dyslipidemia. Skeletal muscle and nuclear receptors are rapidly emerging as critical targets in the battle against cardiovascular disease risk factors. Understanding the function of nuclear receptors in skeletal muscle has enormous pharmacological utility for the treatment of cardiovascular disease. This review focuses on the molecular regulation of metabolism by nuclear receptors in skeletal muscle in the context of dyslipidemia and cardiovascular disease.

Topics: Cardiovascular Diseases; Cholesterol; DNA-Binding Proteins; Dyslipidemias; Glucose; Humans; Insulin Resistance; Metabolic Diseases; Models, Biological; Muscle, Skeletal; Nuclear Receptor Subfamily 4, Group A, Member 1; Peroxisome Proliferator-Activated Receptors; Receptors, Cytoplasmic and Nuclear; Receptors, Estrogen; Receptors, Glucocorticoid; Receptors, Steroid; Receptors, Thyroid Hormone; Transcription Factors; Tretinoin

Recently neuronal insulin resistance was suggested playing a role in Alzheimer's disease. Streptozotocin (STZ) is commonly used to induce impairment in insulin metabolism. In our previous work on undifferentiated SH-SY5Y cells the compound exerted cytotoxicity without altering insulin sensitivity. Nevertheless, differentiation of the cells to a more mature neuron-like phenotype may considerably affect the significance of insulin signaling and its sensitivity to STZ. We aimed at studying the influence of STZ treatment on insulin signaling in SH-SY5Y cells differentiated by retinoic acid (RA). Cytotoxicity of STZ or low serum (LS) condition and protective effect of insulin were compared in RA differentiated SH-SY5Y cells. The effect of insulin and an incretin analogue, exendin-4 on insulin signaling was also examined by assessing glycogen synthase kinase-3 (GSK-3) phosphorylation. STZ was found less cytotoxic in the differentiated cells compared to our previous results in undifferentiated SH-SY5Y cells. The cytoprotective concentration of insulin was similar in the STZ and LS groups. However, the right-shifted concentration-response curve of insulin induced GSK-3 phosphorylation in STZ-treated differentiated cells is suggestive of the development of insulin resistance that was further confirmed by the insulin potentiating effect of exendin-4. Differentiation reduced the sensitivity of SH-SY5Y cells for the non-specific cytotoxicity of STZ and enhanced the relative significance of development of insulin resistance. The differentiated cells thus serve as a better model for studying the role of insulin signaling in neuronal survival. However, direct cytotoxicity of STZ also contributes to the cell death.

Topics: Cell Differentiation; Cell Line, Tumor; Cell Survival; Exenatide; Glycogen Synthase Kinase 3; Humans; Insulin; Insulin Resistance; Phosphorylation; Signal Transduction; Streptozocin; Tretinoin

All-trans-retinoic acid (atRA), an active metabolite of vitamin A, exerts a potential role in the prevention of cardiovascular diseases. It has been shown that atRA ameliorates atherosclerosis while the exact mechanism underlying this protection remains unknown. This study investigated the influence of atRA on insulin resistance (IR), atherosclerosis, and the process of perivascular adipose tissue (PVAT) browning. Moreover, syntheses of adiponectin, adipokine with anti-atherogenic effects, and tumor necrosis factor-alpha (TNF-α), a pro-inflammatory cytokine, were determined in PVAT. Apolipoprotein E-deficient mice (Apo-E) and control C57BL/6J wild-type mice were treated with atRA (5 mg/kg/day) or vehicle (corn oil) by plastic feeding tubes for 8 weeks. Long-term atRA treatment in Apo-E mice did not affect insulin resistance. AtRa administration ameliorated atherosclerosis, induced PVAT browning, and increased adiponectin production in PVAT in Apo-E mice. Furthermore, atRA increased nitric oxide (NO) level but did not affect adiponectin concentration in the aorta of Apo-E mice. These results indicate that atRA ameliorates atherosclerosis in Apo-E mice. We also observed the browning of PVAT. Besides, atRA increased the synthesis of adiponectin in PVAT and augmented NO level in the aorta in ApoE mice.

Topics: Adipokines; Adiponectin; Adipose Tissue; Animals; Aorta; Apolipoproteins E; Atherosclerosis; Diet, High-Fat; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Signal Transduction; Tretinoin; Tumor Necrosis Factor-alpha; Vasodilation

The retinol dehydrogenase Rdh10 catalyzes the rate-limiting reaction that converts retinol into retinoic acid (RA), an autacoid that regulates energy balance and reduces adiposity. Skeletal muscle contributes to preventing adiposity, by consuming nearly half the energy of a typical human. We report sexually dimorphic differences in energy metabolism and muscle function in Rdh10+/- mice. Relative to wild-type (WT) controls, Rdh10+/- males fed a high-fat diet decrease reliance on fatty-acid oxidation and experience glucose intolerance and insulin resistance. Running endurance decreases 40%. Rdh10+/- females fed this diet increase fatty acid oxidation and experience neither glucose intolerance nor insulin resistance. Running endurance increases 220%. We therefore assessed RA function in the mixed-fiber type gastrocnemius muscles (GM), which contribute to running, rather than standing, and are similar to human GM. RA levels in Rdh10+/- male GM decrease 38% relative to WT. Rdh10+/- male GM increase expression of Myog and reduce Eif6 mRNAs, which reduce and enhance running endurance, respectively. Cox5A, complex IV activity, and ATP decrease. Increased centralized nuclei reveal existence of muscle malady and/or repair in GM fibers. Comparatively, RA in Rdh10+/- female GM decreases by less than half the male decrease, from a more modest decrease in Rdh10 and an increase in the estrogen-induced retinol dehydrogenase Dhrs9. Myog mRNA decreases. Cox5A, complex IV activity, and ATP increase. Centralized GM nuclei do not increase. We conclude that Rdh10/RA affects whole body energy use and insulin resistance partially through sexual dimorphic effects on skeletal muscle gene expression, structure, and mitochondria activity.

Topics: Adiposity; Alcohol Oxidoreductases; Animals; Diet, High-Fat; Electron Transport Complex IV; Energy Metabolism; Female; Glucose Intolerance; Insulin Resistance; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal; Muscles; Oxidation-Reduction; Physical Endurance; Running; Sex Characteristics; Sex Factors; Tretinoin

RDH1 is one of the several enzymes that catalyze the first of the two reactions to convert retinol into all-trans-retinoic acid (atRA). Here, we show that Rdh1-null mice fed a low-fat diet gain more weight as adiposity (17% males, 13% females) than wild-type mice by 20 weeks old, despite neither consuming more calories nor decreasing activity. Glucose intolerance and insulin resistance develop following increased adiposity. Despite the increase in white fat pads, epididymal white adipose does not express Rdh1, nor does muscle. Brown adipose tissue (BAT) and liver express Rdh1 at relatively high levels compared to other tissues. Rdh1 ablation lowered body temperatures during ambient conditions. Given the decreased body temperature, we focused on BAT. A lack of differences in BAT adipogenic gene expression between Rdh1-null mice and wild-type mice, including Pparg, Prdm16, Zfp516 and Zfp521, indicated that the phenotype was not driven by brown adipose hyperplasia. Rather, Rdh1 ablation eliminated the increase in BAT atRA that occurs after re-feeding. This disruption of atRA homeostasis increased fatty acid uptake, but attenuated lipolysis in primary brown adipocytes, resulting in increased lipid content and larger lipid droplets. Rdh1 ablation also decreased mitochondrial proteins, including CYCS and UCP1, the mitochondria oxygen consumption rate, and disrupted the mitochondria membrane potential, further reflecting impaired BAT function, resulting in both BAT and white adipose hypertrophy. RNAseq revealed dysregulation of 424 BAT genes in null mice, which segregated predominantly into differences after fasting vs after re-feeding. Exceptions were Rbp4 and Gbp2b, which increased during both dietary conditions. Rbp4 encodes the serum retinol-binding protein-an insulin desensitizer. Gbp2b encodes a GTPase. Because Gbp2b increased several hundred-fold, we overexpressed it in brown adipocytes. This caused a shift to larger lipid droplets, suggesting that GBP2b affects signaling downstream of the β-adrenergic receptor during basal thermogenesis. Thus, Rdh1-generated atRA in BAT regulates multiple genes that promote BAT adaptation to whole-body energy status, such as fasting and re-feeding. These gene expression changes promote optimum mitochondria function and thermogenesis, limiting adiposity. Attenuation of adiposity and insulin resistance suggests that RDH1 mitigates metabolic syndrome.

Topics: Adipose Tissue, Brown; Adiposity; Animals; Diet, Fat-Restricted; Eating; Energy Metabolism; Fasting; Female; Gene Deletion; Glucose Intolerance; Hydroxysteroid Dehydrogenases; Insulin Resistance; Lipid Metabolism; Male; Mice, Inbred C57BL; Thermogenesis; Tretinoin; Vitamin A

Pharmacological dosing of all-

Topics: Adipogenesis; Adipose Tissue; Adiposity; Alcohol Oxidoreductases; Animals; Diet, High-Fat; Female; Fibroblasts; Glucose Intolerance; Heterozygote; Insulin Resistance; Lipid Metabolism; Liver; Male; Mice; Non-alcoholic Fatty Liver Disease; Oxidation-Reduction; Receptors, Retinoic Acid; Sex Factors; Tretinoin; Vitamin A

In this prospective study, we evaluated the association of retinoic acid (RA) with the metabolic syndrome (MetS) in the Chinese population.. A total of 1042 nondiabetic adults from the population-based Nutrition and Health of Aging Population were prospectively followed up for 4 years. Serum RA concentrations was determined and its relationship with the MetS and its component was investigated.. At baseline, higher RA levels were inversely associated with the presence of MetS (odds ratio 0.61; 95% confidence interval [CI] 0.44–0.74, P < .001) after adjustment for age, gender, body mass index, the homeostasis model assessment index for insulin resistance (HOMA-IR), and other confounding factors. Subjects with lower RA levels had a progressively worse cardiometabolic risk profile at baseline. Serum RA levels were inversely associated with 8-iso-prostaglandin F2α (P < .001), high-sensitivity C-reactive protein (P = .015), and IL-6 (P = .020) and positively correlated with high-density lipoprotein cholesterol (P = .038). Among 825 subjects without MetS at baseline, 146 had developed it at 4 years. Serum RA by quartiles was inversely correlated with the incident MetS (adjusted hazard ratio 0.67; 95% CI 0.48–0.81, P = .006). Apart from HOMA-IR (P < .001), the baseline RA level was the only independent predictor of the development of the MetS during the 4-year follow-up (odds ratio 0.53; 95% CI 0.40–0.69; P < .001) after adjustment for age, gender, body mass index, and HOMA-IR.. The serum RA level is inversely associated with the development of MetS independently of adiposity and insulin resistance.

Topics: Adiposity; Age Factors; Aged; Body Mass Index; C-Reactive Protein; Cholesterol, HDL; Dinoprost; Female; Follow-Up Studies; Health Surveys; Humans; Insulin Resistance; Male; Metabolic Syndrome; Middle Aged; Prospective Studies; Sex Factors; Tretinoin

Retinoic acid (RA), an active metabolite of vitamin A (retinol), has been implicated in the regulation of lipid metabolism and hepatic steatosis in animal models. However, the relation between RA and liver histology in patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is unknown.. This study aimed at examining the association of RA with NAFLD and NASH in Chinese subjects.. Serum RA concentration was determined by ELISA in 41 control subjects, 45 patients with NAFLD, and 38 patients with NASH. The associations of RA with adiposity, serum glucose, lipid profiles, and markers of liver damage were studied. Moreover, both mRNA and protein levels of retinoic X receptor α (RXRα) in the liver were analyzed in subjects with different degrees of hepatic steatosis.. Serum RA concentrations in patients with NAFLD (1.42 ± 0.47 ng/mL) and NASH (1.14 ± 0.26 ng/mL) were significantly lower than those in control subjects (2.70 ± 0.52 ng/mL) (P < 0.01). Furthermore, serum RA concentrations were significantly different between subjects with normal glucose tolerance and those with type 2 diabetes in control [2.87 ± 0.52 (n = 28) vs. 2.32 ± 0.44 ng/mL (n = 13)], NAFLD [1.61 ± 0.37 (n = 29) vs. 1.28 ± 0.41 ng/mL (n = 16)], and NASH [1.35 ± 0.34 (n = 24) vs. 1.07 ± 0.29 ng/mL (n = 14)] groups. In human liver tissue, RXRα mRNA expression was inversely correlated with the exacerbation of hepatic steatosis. Both serum RA concentrations and RXRα mRNA levels were inversely correlated with intrahepatic triglyceride content (r = -0.700, P < 0.001, and r = -0.611, P = 0.002, respectively). Compared with grade 0 severity, the concentration of RXRα protein was lower in more severe grades in patients with NAFLD.. These results show that circulating RA concentrations were lower in subjects with NAFLD and were associated with hepatic lipid metabolism and insulin resistance. This trial was registered at clinicaltrials.gov as NCT01940263.

Topics: Adult; Aged; Asian People; Body Mass Index; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Humans; Insulin Resistance; Lipid Metabolism; Liver; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Randomized Controlled Trials as Topic; Retinoid X Receptors; RNA, Messenger; Tretinoin; Triglycerides

The hepatic circadian clock plays a key role in the daily regulation of glucose metabolism, but the precise molecular mechanisms that coordinate these two biological processes are not fully understood. In this study, we identify a novel connection between the regulation of RORγ by the clock machinery and the diurnal regulation of glucose metabolic networks. We demonstrate that particularly at daytime, mice deficient in RORγ exhibit improved insulin sensitivity and glucose tolerance due to reduced hepatic gluconeogenesis. This is associated with a reduced peak expression of several glucose metabolic genes critical in the control of gluconeogenesis and glycolysis. Genome-wide cistromic profiling, promoter and mutation analysis support the concept that RORγ regulates the transcription of several glucose metabolic genes directly by binding ROREs in their promoter regulatory region. Similar observations were made in liver-specific RORγ-deficient mice suggesting that the changes in glucose homeostasis were directly related to the loss of hepatic RORγ expression. Altogether, our study shows that RORγ regulates several glucose metabolic genes downstream of the hepatic clock and identifies a novel metabolic function for RORγ in the diurnal regulation of hepatic gluconeogenesis and insulin sensitivity. The inhibition of the activation of several metabolic gene promoters by an RORγ antagonist suggests that antagonists may provide a novel strategy in the management of metabolic diseases, including type 2 diabetes.

Topics: Animals; Circadian Rhythm; Diabetes Mellitus, Type 2; Gene Expression Regulation; Gluconeogenesis; Glucose; Humans; Insulin; Insulin Resistance; Liver; Mice; Nuclear Receptor Subfamily 1, Group F, Member 3; Tretinoin

Tumor necrosis factor alpha (TNF-α) is a proven modulator of adipose metabolism, but the mechanisms by which this cytokine affects the development and function of adipose tissue have not been fully elucidated to date. Using differential display analysis, in this study, we demonstrate that gene expression of the serine protease inhibitor A3g (SerpinA3g) is specifically induced in 3T3-F442A preadipocytes by TNF-α but not by other adipogenic inhibitors, such as retinoic acid (RA) or transforming growth factor type beta (TGF-β). The specific induction of SerpinA3g by TNF-α was confirmed by RT-PCR in both preadipose and terminally differentiated 3T3-F442A cells. The knockdown of SerpinA3g using small interfering RNA prevented the antiadipogenesis elicited by TNF-α in 3T3-F442A cells but not the antiadipogenesis induced by RA or TGF-β. SerpinA3g-silenced 3T3-F442A cells also did not display TNF-α-induced insulin resistance. Our results demonstrate that SerpinA3g is specifically induced by TNF-α in 3T3-F442A cells, regardless of their stage of differentiation, and participates in the antiadipogenesis and insulin resistance induced by this cytokine. Our results suggest that SerpinA3g plays a role in the TNF-α modulation of adipose tissue development and metabolism. Additional studies are warranted regarding the mechanisms mediating adipose SerpinA3g effects.

Topics: 3T3 Cells; Adipocytes; Adipogenesis; Animals; Base Sequence; Insulin Resistance; Mice; Molecular Sequence Data; Serpins; Transforming Growth Factor beta; Tretinoin; Tumor Necrosis Factor-alpha

Unattended hepatic insulin resistance predisposes individuals to dyslipidemia, type 2 diabetes and many other metabolic complications. The mechanism of hepatic insulin resistance at the gene expression level remains unrevealed. To examine the effects of vitamin A (VA), total energy intake and feeding conditions on the insulin-regulated gene expression in primary hepatocytes of Zucker lean (ZL) and fatty (ZF) rats, we analyze the expression levels of hepatic model genes in response to the treatments of insulin and retinoic acid (RA). We report that the insulin- and RA-regulated glucokinase, sterol regulatory element-binding protein-1c and cytosolic form of phosphoenolpyruvate carboxykinase expressions are impaired in hepatocytes of ZF rats fed chow or a VA sufficient (VAS) diet ad libitum. The impairments are partially corrected when ZF rats are fed a VA deficient (VAD) diet ad libitum or pair-fed a VAS diet to the intake of their VAD counterparts in non-fasting conditions. Interestingly in the pair-fed ZL and ZF rats, transient overeating on the last day of pair-feeding regimen changes the expression levels of some VA catabolic genes, and impairs the insulin- and RA-regulated gene expression in hepatocytes. These results demonstrate that VA and feeding statuses modulate the hepatic insulin sensitivity at the gene expression level.

Topics: Analysis of Variance; Animals; Dietary Supplements; Gene Expression Regulation; Hepatocytes; Insulin; Insulin Resistance; Male; Phosphoenolpyruvate Carboxykinase (ATP); Rats; Rats, Zucker; Real-Time Polymerase Chain Reaction; Tretinoin

Insulin resistance is a fundamental feature of metabolic disorders such as metabolic syndrome. The formation of advanced glycation end-products (AGEs) is increased in patients with hyperglycemia, which results in the loss of protein function. Therefore, considerable attention has been paid to the pathological significance of AGEs in diseases associated with insulin resistance. We previously demonstrated that all-trans-retinoic acid (ATRA) ameliorated insulin resistance in mice that were fed a high-fat, high-fructose (HFHFr) diet. However, it is unclear whether the HFHFr diet increases the production of AGEs in the liver, and whether ATRA affects this production. In the present study, we investigated the production of glyceraldehyde-derived AGEs (Glycer-AGEs) in the liver of HFHFr diet-induced insulin-resistant mice using an antibody against Glycer-AGEs. We noted a remarkable formation of Glycer-AGEs with estimated molecular weights of approximately 265, 282, and 312 kDa in the liver of the insulin-resistant mice; however, the production of Glycer-AGEs was limited in the control. In accordance with previous observations, these Glycer-AGEs in mice disappeared after treatment with ATRA. These results suggest that hepatic Glycer-AGEs can be useful markers for the diagnosis and therapeutic evaluation of insulin resistance and may play a pathological role in the development of insulin resistance.

Topics: Animals; Glycation End Products, Advanced; Glyceraldehyde; Insulin Resistance; Liver; Mice; Mice, Inbred C57BL; Molecular Weight; Tretinoin

Topics: Animals; Fatty Liver; Insulin Resistance; Leptin; Male; Receptors, Leptin; Tretinoin

Topics: Animals; Fatty Liver; Insulin Resistance; Leptin; Male; Receptors, Leptin; Tretinoin

Transgenic mice expressing dominant-negative retinoic acid receptor (RAR) α specifically in the liver exhibit steatohepatitis, which leads to the development of liver tumors. Although the cause of steatohepatitis in these mice is unknown, diminished hepatic expression of insulin-like growth factor-1 suggests that insulin resistance may be involved. In the present study, we examined the effects of retinoids on insulin resistance in mice to gain further insight into the mechanisms responsible for this condition. Dietary administration of all-trans-retinoic acid (ATRA) significantly improved insulin sensitivity in C57BL/6J mice, which served as a model for high-fat, high-fructose diet-induced nonalcoholic fatty liver disease (NAFLD). The same effect was observed in genetically insulin-resistant KK-A(y) mice, occurring in concert with activation of leptin-signaling pathway proteins, including signal transducer and activator of transcription 3 (STAT3) and Janus kinase 2. However, such an effect was not observed in leptin-deficient ob/ob mice. ATRA treatment significantly up-regulated leptin receptor (LEPR) expression in the livers of NAFLD mice. In agreement with these observations, in vitro experiments showed that in the presence of leptin, ATRA directly induced LEPR gene expression through RARα, resulting in enhancement of STAT3 and insulin-induced insulin receptor substrate 1 phosphorylation. A selective RARα/β agonist, Am80, also enhanced hepatic LEPR expression and STAT3 phosphorylation and ameliorated insulin resistance in KK-A(y) mice.. We discovered an unrecognized mechanism of retinoid action for the activation of hepatic leptin signaling, which resulted in enhanced insulin sensitivity in two mouse models of insulin resistance. Our data suggest that retinoids might have potential for treating NAFLD associated with insulin resistance.

Topics: Animals; Cells, Cultured; Disease Models, Animal; Fatty Liver; Hepatocytes; Immunohistochemistry; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Non-alcoholic Fatty Liver Disease; Random Allocation; Receptors, Leptin; Reference Values; Sensitivity and Specificity; Signal Transduction; Tretinoin; Up-Regulation

Obesity and the related metabolic abnormalities are associated with increased risk of hepatocellular carcinoma (HCC). Malfunctioning of retinoid X receptor (RXR) α due to phosphorylation by Ras/MAPK also plays a critical role in liver carcinogenesis. In the present study, we examined the effects of acyclic retinoid (ACR), which targets RXRα, on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in C57BLKS/J- +Lepr(db)/+Lepr(db) (db/db) obese mice. Male db/db mice were given tap water containing 40 ppm DEN for 2 weeks, after which they were fed a diet containing 0.03% or 0.06% of ACR throughout the experiment. In mice treated with either dose of ACR for 34 weeks, the development of liver cell adenomas was significantly inhibited as compared with basal diet-fed mice. ACR markedly inhibited the activation of Ras and phosphorylation of the ERK (extracellular signal-regulated kinase) and RXRα proteins in the livers of experimental mice. It also increased the expression of RAR β and p21(CIP1) mRNA while decreasing the expression of cyclin D1, c-Fos, and c-Jun mRNA in the liver, thereby restoring RXRα function. Administration of ACR improved liver steatosis and activated the AMPK protein. The serum levels of insulin decreased by ACR treatment, whereas the quantitative insulin sensitivity check index (QUICKI) values increased, indicating improved insulin sensitivity. The serum levels of TNF-α and the expression levels of TNF- α, IL-6, and IL-1 β mRNA in the livers of DEN-treated db/db mice were decreased by ACR treatment, suggesting attenuation of the chronic inflammation induced by excessive fatty deposits. ACR may be, therefore, useful in the chemoprevention of obesity-related HCC.

Topics: Animals; Antineoplastic Agents; Blotting, Western; Cytokines; Diabetes Complications; Diabetes Mellitus; Diethylnitrosamine; Insulin Resistance; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Phosphorylation; ras Proteins; Receptors, Leptin; Retinoid X Receptor alpha; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; STAT3 Transcription Factor; Tretinoin

Recent investigations have demonstrated that elevated serum retinol-binding protein 4 (RBP4) secreted from adipose tissue plays a role in the development of systemic insulin resistance, and lowering RBP4 improves insulin sensitivity. These observations provide a rationale for the development of new antidiabetic agents aimed at reducing serum RBP4 concentrations. In this study, we sought to determine whether retinoic acid (RA) administration decreases serum RBP4 and suppresses insulin resistance in diabetic ob/ob mice. All-trans RA [100 mug/(moused) in corn oil] was administered by stomach intubation to a group of ob/ob mice, with the control group receiving the vehicle for 16 d. Body weight and food intake were monitored. Glucose and insulin tolerance tests were performed. We quantified serum RBP4 and retinol by Western blotting and HPLC, respectively. RA treatment reduced body weight (P < 0.05), basal serum glucose (P < 0.001), serum retinol (P < 0.01), and RBP4 (P < 0.05). It improved insulin sensitivity and decreased the retinol:RBP4 ratio (P < 0.05). These studies suggest that RA is an effective antidiabetic agent that could be considered in the treatment of type 2 diabetes.

Topics: Animals; Blood Glucose; Blotting, Western; Body Weight; Chromatography, High Pressure Liquid; Diabetes Mellitus, Experimental; Glucose Tolerance Test; Hypoglycemic Agents; Insulin Resistance; Mice; Mice, Obese; Retinol-Binding Proteins, Plasma; Tretinoin; Vitamin A

The pseudokinase tribbles homologue 3 (Drosophila) (TRIB3) negatively interferes with insulin-mediated phosphorylation and activation of v-akt murine thymoma viral oncogene homologue 1 (AKT1, also known as protein kinase B). Animal studies have shown that Trib3 expression was higher in the fasting state and in animal models of diabetes, promoting hyperglycaemia presumably by increasing glucose production in the liver. Less is known about the role of TRIB3 in insulin resistance in humans, although a gain-of-function mutation associated with abnormalities related to insulin resistance has been described in TRIB3.. We determined hepatic mRNA expression of TRIB3 and selected genes encoding enzymes, transcription factors and coactivators involved in glucose homeostasis. We also determined biochemical variables of intermediary metabolism in obese patients with varying degrees of insulin resistance.. In our study population hepatic TRIB3 mRNA expression was associated with surrogate markers of insulin resistance. TRIB3 expression was significantly increased in a subgroup with high HOMA of insulin resistance (HOMA-IR) compared with a low HOMA-IR group (p = 0.0033). TRIB3 transcript levels were correlated with PEPCK (also known as PCK2) mRNA expression (p = 0.0014) and mRNA expression of PPARGC1A (p = 0.0020), PPARGC1B (p < 0.0001), USF1 (p = 0.0017), FOXO1 (p = 0.0003) and SREBP-1c (also known as SREBF1; p = 0.0360). Furthermore ligands of peroxisome proliferator-activated receptor alpha/retinoid X receptor and overexpression of its coactivator PPARGC1A as well as overexpression of SREBP-1c and its coactivator PPARGC1B increased TRIB3 promoter activity in HepG2 cells.. We have found evidence for a role of aberrant hepatic TRIB3 transcript levels in insulin resistance in obese humans and identified potential transcriptional pathways involved in regulation of TRIB3 gene expression in the liver.

Topics: Carrier Proteins; Cell Cycle Proteins; Gene Expression; Heat-Shock Proteins; Hep G2 Cells; Humans; Insulin Resistance; Liver; Obesity; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; PPAR alpha; Protein Serine-Threonine Kinases; Pyrimidines; Repressor Proteins; RNA-Binding Proteins; RNA, Messenger; Sterol Regulatory Element Binding Protein 1; Transcription Factors; Tretinoin

Many biological activities of all-trans-retinoic acid (RA) are mediated by the ligand-activated transcription factors termed retinoic acid receptors (RARs), but this hormone can also activate the nuclear receptor peroxisome proliferation-activated receptor beta/delta (PPARbeta/delta). We show here that adipocyte differentiation is accompanied by a shift in RA signaling which, in mature adipocytes, allows RA to activate both RARs and PPARbeta/delta, thereby enhancing lipolysis and depleting lipid stores. In vivo studies using a dietary-induced mouse model of obesity indicated that onset of obesity is accompanied by downregulation of adipose PPARbeta/delta expression and activity. RA treatment of obese mice induced expression of PPARbeta/delta and RAR target genes involved in regulation of lipid homeostasis, leading to weight loss and improved insulin responsiveness. RA treatment also restored adipose PPARbeta/delta expression. The data indicate that suppression of obesity and insulin resistance by RA is largely mediated by PPARbeta/delta and is further enhanced by activation of RARs. By targeting two nuclear receptors, RA may be a uniquely efficacious agent in the therapy and prevention of the metabolic syndrome.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Adiposity; Animals; Cell Differentiation; Diet; Disease Models, Animal; Fatty Acid-Binding Proteins; Insulin Resistance; Lipolysis; Mice; Mice, Inbred C57BL; Neoplasm Proteins; Obesity; PPAR delta; PPAR-beta; Receptors, Retinoic Acid; Signal Transduction; Tretinoin

Therapeutic administration of retinoids is often accompanied with undesirable side effects, including an increase in lipid levels in up to 45% of treated patients. We tested the hypothesis of whether spontaneously hypertensive rat (SHR) and congenic SHR.PD-(D8Rat42-D8Arb23)/Cub (SHR-Lx) strains, differing only in a 14-gene region of chromosome 8 and previously shown to display differential sensitivity to the teratogenic effects of retinoic acid, could serve as a pharmacogenetic model set of the metabolic side effects of retinoid therapy.. Male, 15-week old rats (n = 12/strain) of SHR and SHR-Lx strains were fed a high-sucrose diet for 2 weeks and subsequently treated either with all-trans retinoic acid (15 mg/kg) or only with a vehicle for 16 days (n = 6/strain/treatment), while still on the high-sucrose diet. We assessed the morphometric and metabolic profiles of all groups, including glucose tolerance tests, levels of insulin, adiponectin, free fatty acids, concentrations of triglycerides and cholesterol in 20 lipoprotein fractions under conditions of both high-sucrose diet and high-sucrose diet plus all-trans retinoic acid administration.. SHR-Lx displayed substantially greater sensitivity to a number of all-trans retinoic acid-induced metabolic dysregulations compared with SHR, resulting in impairment of glucose tolerance, increased visceral adiposity, and substantially greater increase of circulating triglyceride concentrations, accompanied by a shift towards their less favorable distribution into the lipoprotein fractions. These observations closely mimic the common side effects of retinoid therapy in humans, rendering SHR-Lx an experimental pharmacogenetic model of atRA-induced dyslipidemia.

Topics: Animals; Animals, Congenic; Disease Models, Animal; Dyslipidemias; Glucose Tolerance Test; Hypertension; Insulin Resistance; Lipid Metabolism; Male; Pharmacogenetics; Rats; Rats, Inbred SHR; Sucrose; Tretinoin

Insulin resistance is the failure of insulin to stimulate the transport of glucose into its target cells. A highly regulatable supply of glucose is important for cardiomyocytes to cope with situations of metabolic stress. We recently observed that isolated adult rat cardiomyocytes become insulin resistant in vitro. Insulin resistance is combated at the whole body level with agonists of the nuclear receptor complex peroxisome proliferator-activated receptor gamma (PPARgamma)/retinoid X receptor (RXR). We investigated the effects of PPARgamma/RXR agonists on the insulin-stimulated glucose transport and on insulin signaling in insulin-resistant adult rat cardiomyocytes. Treatment of cardiomyocytes with ciglitazone, a PPARgamma agonist, or 9-cis retinoic acid (RA), a RXR agonist, increased insulin- and metabolic stress-stimulated glucose transport, whereas agonists of PPARalpha or PPARbeta/delta had no effect. Stimulation of glucose transport in response to insulin requires the phosphorylation of the signaling intermediate Akt on the residues Thr308 and Ser473 and, downstream of Akt, AS160 on several Thr and Ser residues. Phosphorylation of Akt and AS160 in response to insulin was lower in insulin-resistant cardiomyocytes. However, treatment with 9-cis RA markedly increased phosphorylation of both proteins. Treatment with 9-cis RA also led to better preservation of microtubules in cultured cardiomyocytes. Disruption of microtubules in insulin-responsive cardiomyocytes abolished insulin-stimulated glucose transport and reduced phosphorylation of AS160 but not Akt. Metabolic stress-stimulated glucose transport also involved AS160 phosphorylation in a microtubule-dependent manner. Thus, the stimulation of glucose uptake in response to insulin or metabolic stress is dependent in cardiomyocytes on the presence of intact microtubules.

Topics: Alitretinoin; AMP-Activated Protein Kinase Kinases; Animals; Cells, Cultured; Cytoskeleton; Glucose; Glucose Transporter Type 4; Insulin; Insulin Resistance; Male; Microtubules; Myocytes, Cardiac; Phenoxyacetates; PPAR gamma; Protein Kinases; Pyrimidines; Rats; Rats, Sprague-Dawley; Retinoid X Receptors; Signal Transduction; Thiazolidinediones; Tretinoin

A 40-year-old man was admitted with fever and purpura. He was diagnosed as having acute promyelocytic leukemia, and treated with all-trans retinoic acid. After achieving complete remission, he received consolidation therapy. During the chemotherapy, quadriplegia occurred three times. This was diagnosed as hypokalemic periodic paralysis because of the patient's low serum potassium level. Results of hormone and urine examinations showed no indication of secondary hypokalemia. However, the patient had a history of quadriplegia of unknown etiology at the age of 36. We speculated that in addition to the patient's predisposition to hypokalemic periodic paralysis, chemotherapy including prednisolone, and excessive ingestion of carbohydrate had induced his quadriplegia.

Topics: Adult; Antineoplastic Agents; Dietary Carbohydrates; Humans; Hyperinsulinism; Hypokalemia; Insulin Resistance; Leukemia, Promyelocytic, Acute; Male; Periodicity; Prednisolone; Quadriplegia; Recurrence; Tretinoin