salicylates and Obesity

The incidence of complex noncommunicable diseases has strongly increased over the last several decades in the US, Europe and other parts of the world that have adopted a western lifestyle (M. Ezzati, E. Riboli, Science- 2012, 337, 1482-1487; S. Smyth, A. Heron, Nat. Med.- 2006, 12, 75). Despite considerable investment in the development of new types of drugs, options for the treatment of many common diseases remain inadequate. If current trends prevail, the rising incidence of disorders such as obesity and type 2 diabetes mellitus (T2DM) will soon result in an unsustainable burden on society (World Health Organization Technical Report Series- 2000, 894, i-xii, 1-253). Given the difficulty of treating fully developed complex disorders, new strategies for early intervention and prevention of common diseases are of great interest. Dietary natural products with beneficial effects, such as the recently described antidiabetic and lipid-lowering amorfrutins, could pave the way for efficiently treating and preventing metabolic and other complex diseases (C. Weidner, et al. Proc. Natl. Acad. Sci. USA- 2012, 109, 7257-7262).

Topics: Biological Products; Diabetes Mellitus, Type 2; Dietary Supplements; Humans; Obesity; PPAR gamma; Salicylates

Chronic inflammation may participate in the pathogenesis of insulin resistance, type 2 diabetes, and cardiovascular disease and may be a common denominator that links obesity to these disease states.. Epidemiologic studies have linked inflammatory biomarkers to incident diabetes and cardiovascular disease risk. Cellular and animal studies have provided support to the idea that inflammation mediates these disease processes, providing impetus to pharmacologically target these pathways for disease treatment and prevention. We review clinical strategies to target inflammation, with a focus on the antiinflammatory and antihyperglycemic effects of salicylates.. The evolving concept of diet-induced obesity driving insulin resistance, type 2 diabetes, and cardiovascular disease through immunologic processes provides new opportunities for the use of antiinflammatory strategies to correct the metabolic consequences of excess adiposity.

Topics: Adipose Tissue; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Inflammation; Insulin Resistance; Obesity; Salicylates

Antidiabetic effects associated with salicylates have been known for years, although the underlying mechanisms were not understood. We have been reinvestigating these effects in the light of recent discoveries in the areas of signal transduction and insulin resistance. Our findings showed that signaling pathways leading to I kappa B kinase beta (IKK beta) and NF-kappa B are activated in insulin-responsive tissues of obese and high-fat-fed animals. Since activation correlates with the development of insulin resistance, we asked whether signaling through this might be involved in the pathogenesis of insulin resistance. Heterozygous gene deletion (Ikk beta+/-) or salicylates, working as IKK beta inhibitors, improved insulin sensitivity in insulin-resistant rodent models. Furthermore, high doses of salicylates (aspirin or salicylate) improved insulin sensitivity in patients with type II diabetes. Our studies implicate an inflammatory process in the pathogenesis of insulin resistance in obesity and type II diabetes mellitus and identify the IKK beta/NF-kappa B pathway as a molecular mediator of insulin resistance and pharmacological target for insulin sensitization.

Topics: Animals; Dietary Fats; Humans; I-kappa B Kinase; Inflammation; Insulin Resistance; Mice; NF-kappa B; Obesity; Protein Serine-Threonine Kinases; Rats; Salicylates

Inflammation may contribute to pathological associations among obesity, diabetes mellitus, and cardiovascular disease.. To determine whether targeting inflammation using salsalate compared with placebo reduces progression of noncalcified coronary artery plaque.. In the Targeting Inflammation Using Salsalate in Cardiovascular Disease (TINSAL-CVD) trial participants were randomly assigned between September 23, 2008, and July 5, 2012, to 30 months of salsalate or placebo in addition to standard, guideline-based therapies. Randomization was computerized and centrally allocated, with patients, health care professionals, and researchers masked to treatment assignment. Participants were overweight and obese statin-using patients with established, stable coronary heart disease.. Salsalate (3.5 g/d) or placebo orally over 30 months.. The primary outcome was progression of noncalcified coronary artery plaque assessed by multidetector computed tomographic angiography. Secondary outcomes were other measures of safety and efficacy.. Two hundred fifty-seven participants were randomized to salsalate (n = 129) or placebo (n = 128). Their mean (SD) age was 60.8 (7.0) years, and 94.0% (236 of 251) were male. One hundred ninety participants (89 in the salsalate group and 101 in the placebo group) completed the study. Compared with baseline, there was no increase in noncalcified plaque volume in the placebo-treated patients and no difference in change between the salsalate and placebo groups (mean difference, -1 mm3; 95% CI, -11 to 9 mm3; P = .87). Salsalate treatment decreased total white blood cell, lymphocyte, monocyte, and neutrophil counts and increased adiponectin levels without change in C-reactive protein levels. Fasting glucose, triglycerides, uric acid, and bilirubin levels were decreased in the salsalate group compared with the placebo group, while hemoglobin levels were increased. Urinary albumin levels increased, with tinnitus and atrial arrhythmias more common, in the salsalate group compared with the placebo group.. Salsalate when added to current therapies that include a statin does not reduce progression of noncalcified coronary plaque volume assessed by multidetector computed tomographic angiography in statin-using patients with established, stable coronary heart disease. The absence of progression of noncalcified plaque volume in the placebo group may limit interpretation of the trial results.. clinicaltrials.gov Identifier: NCT00624923.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Double-Blind Method; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Male; Middle Aged; Obesity; Overweight; Plaque, Atherosclerotic; Salicylates

Salsalate treatment has well-known effects on improving glycemia, and the objective of this study was to examine whether the mechanism of this effect was related to changes in adipose tissue.. A randomized double-blind and placebo-controlled trial in obese Hispanics (18-35 years) was conducted. The intervention consisted of 4 g day(-1) of salsalate (n = 11) versus placebo (n = 13) for 4 weeks. Outcome measures included glycemia, adiposity, ectopic fat, and adipose tissue gene expression and inflammation.. In those receiving salsalate, plasma fasting glucose decreased by 3.4% (P < 0.01), free fatty acids decreased by 42.5% (P = 0.06), and adiponectin increased by 27.7% (P < 0.01). Salsalate increased insulin AUC by 38% (P = 0.01) and HOMA-B by 47.2% (P < 0.01) while estimates of insulin sensitivity/resistance were unaffected. These metabolic improvements occurred without changes in total, abdominal, visceral, or liver fat. Plasma markers of inflammation/immune activation were unchanged following salsalate. Salsalate had no effects on adipose tissue including adipocyte size, presence of crown-like structures, or gene expression of adipokines, immune cell markers, or cytokines downstream of NF-κB with the exception of downregulation of IL-1β (P < 0.01).. Findings suggest that metabolic improvements in response to salsalate occurred without alterations in adiposity, ectopic fat, or adipose tissue gene expression and inflammation.

Topics: Adipose Tissue; Administration, Oral; Adult; Anti-Inflammatory Agents, Non-Steroidal; California; Double-Blind Method; Female; Glucose Tolerance Test; Glycemic Index; Hispanic or Latino; Humans; Inflammation; Insulin; Insulin Secretion; Male; Obesity; Salicylates; Treatment Outcome

To elucidate whether increased insulin concentration after salsalate treatment (3 g/day for 7 days) is attributable to an increased insulin secretion rate (ISR) or to reduced metabolic clearance of endogenous insulin (MCI) during stepped glucose infusion (SGI). The analysis was performed in obese subjects who participated in a randomized double-blind, parallel, placebo-controlled clinical trial. A total of 27 participants (16 on salsalate, 11 on placebo) completed baseline and follow-up SGI. During SGI in the salsalate group, C-peptide concentrations were reduced by 11%, while plasma insulin concentrations were increased by 30%, corresponding to a 30% reduction in MCI (p < 0.0001). At molar increments of glucose, insulin concentrations were increased by 27% (p = 0.02), but ISR was unchanged. Salsalate did not alter insulin secretion, but lowered MCI, indicating that a reduction in insulin clearance is the principal mechanism for increased insulin levels after salsalate administration.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Blood Glucose; C-Peptide; Double-Blind Method; Female; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Male; Obesity; Salicylates; Secretory Rate

Recent trials show salicylates improve glycemic control in type 2 diabetes, but the mechanism is poorly understood. Expression of the glucocorticoid-generating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in adipose tissue is increased in vitro by proinflammatory cytokines and upregulated in obesity. 11β-HSD1 inhibition enhances insulin sensitivity. We hypothesized that salicylates downregulate 11β-HSD1 expression, contributing to their metabolic efficacy. We treated diet-induced obese (DIO) 11β-HSD1-deficient mice and C57Bl/6 mice with sodium salicylate for 4 weeks. Glucose tolerance was assessed in vivo. Tissue transcript levels were assessed by quantitative PCR and enzyme activity by incubation with (3)H-steroid. Two weeks' administration of salsalate was also investigated in a randomized double-blind placebo-controlled crossover study in 16 men, with measurement of liver 11β-HSD1 activity in vivo and adipose tissue 11β-HSD1 transcript levels ex vivo. In C57Bl/6 DIO mice, salicylate improved glucose tolerance and downregulated 11β-HSD1 mRNA and activity selectively in visceral adipose. DIO 11β-HSD1-deficient mice were resistant to these metabolic effects of salicylate. In men, salsalate reduced 11β-HSD1 expression in subcutaneous adipose, and in vitro salicylate treatment reduced adipocyte 11β-HSD1 expression and induced adiponectin expression only in the presence of 11β-HSD1 substrate. Reduced intra-adipose glucocorticoid regeneration by 11β-HSD1 is a novel mechanism that contributes to the metabolic efficacy of salicylates.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Adipocytes; Adipose Tissue; Adult; Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Cell Differentiation; Cell Line; Cross-Over Studies; Gene Expression Regulation; Glucose Tolerance Test; Humans; Insulin Resistance; Male; Mice; Mice, Knockout; Middle Aged; Obesity; Salicylates; Sodium Salicylate

Low-grade inflammation may contribute to obesity-related insulin resistance and has been associated with increased risk of type 2 diabetes mellitus. The present study evaluated whether treatment with salsalate, a traditional anti-inflammatory medication, would improve insulin action in obese non-diabetic individuals.. The study was a randomised, double-blind, placebo-controlled, parallel trial conducted at the inpatient clinical research unit of the NIDKK (Phoenix, AZ, USA). Participants were 54 adults (18 to 45 years of age) with BMI >or= 30 kg/m(2). The intervention was salsalate (3 g/day, n = 28) or identical placebo (n = 26) for 7 days. The allocation was kept concealed by giving the investigator only a number corresponding to a vial of placebo or salsalate sequentially randomised in blocks by sex. Main outcomes were changes in insulin action assessed as rate of glucose disposal (R (d)) by euglycaemic-hyperinsulinaemic clamp (insulin infusion rate 40 mU m(-2) min(-1)) and glucose tolerance by 75 g OGTT.. The study was completed by 47 participants, of which 40 were analysed (salsalate n = 22, placebo n = 18). Salsalate treatment resulted in decreased fasting plasma glucose concentration (mean [SD]; 4.83 [0.28] vs 5.11 [0.33] mmol/l, p = 0.001) and glucose AUC during the OGTT (p = 0.01), and in increased R (d) (20 [8] vs 18 [6] micromol [kg estimated metabolic body size](-1) min(-1), p = 0.002), while there was no significant change in these variables with placebo (p > 0.3 for all). The effect of salsalate on R (d) disappeared (p = 0.9) after normalising to increased insulin concentrations (701 [285] vs 535 [201] pmol/l, p < 0.0001) measured during the clamp. No side effects of salsalate were observed during the study.. The glucose-lowering potential of salicylates appears to be due to effects on insulin concentration rather than improved insulin action. Salicylate-based compounds may be useful for the treatment and prevention of type 2 diabetes.

Topics: Adiponectin; Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; Blood Glucose; Body Mass Index; C-Reactive Protein; Double-Blind Method; Fatty Acids, Nonesterified; Female; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Male; Middle Aged; Obesity; Placebos; Salicylates; Sample Size; Young Adult

We tested the hypothesis that nuclear factor-kappaB (NF-kappaB) activity contributes to vascular endothelial dysfunction with aging and obesity in humans.. We conducted a randomized, double-blind, placebo-controlled crossover study in 14 nondiabetic overweight or obese (body mass index > or =25 kg/m(2)) middle-aged and older (age 52 to 68 years) adults. Salsalate (nonacetylated salicylate, 4500 mg/d), a compound that inhibits NF-kappaB activity, or placebo was administered for 4-day periods. Plasma salicylate concentrations reached the midtherapeutic range (21.8+/-1.1 mg/100 mL, P< or =0.0001 versus placebo) by day 4 of salsalate treatment. Salsalate increased expression of the inhibitor of NF-kappaB and reduced total and nuclear expression of NF-kappaB in endothelial cells obtained from the subjects (all P<0.05). Salsalate increased brachial artery flow-mediated dilation by 74% (from 4.0+/-0.4% to 6.6+/-0.5%, P<0.001) but did not affect endothelium-independent dilation (P=0.83). The change in brachial artery flow-mediated dilation with salsalate was inversely related to baseline flow-mediated dilation (r=-0.77, P<0.01). Infusion of vitamin C increased brachial artery flow-mediated dilation during placebo (P<0.001) but not after salsalate (P=0.23). Salsalate reduced nitrotyrosine (P=0.06) and expression of NADPH oxidase p47(phox) (P<0.05) in endothelial cells obtained from the subjects but did not influence circulating or endothelial cell inflammatory proteins.. Our findings provide the first direct evidence that NF-kappaB, in part via stimulation of oxidative stress, plays an important role in mediating vascular endothelial dysfunction in overweight and obese middle-aged and older humans.

Topics: Administration, Oral; Aged; Aging; Anti-Inflammatory Agents, Non-Steroidal; Body Mass Index; Cross-Over Studies; Cyclooxygenase 1; Cyclooxygenase 2; Cytokines; Endothelium, Vascular; Female; Humans; I-kappa B Proteins; Male; Middle Aged; NADPH Oxidases; NF-kappa B; NF-KappaB Inhibitor alpha; Obesity; Overweight; Oxidative Stress; Salicylates; Tyrosine; Vasodilation

Sedentary lifestyle and a western diet promote subacute-chronic inflammation, obesity, and subsequently dysglycemia. The aim of the current study was to evaluate the efficacy of the anti-inflammatory drug salsalate to improve glycemia by reducing systemic inflammation in obese adults at risk for the development of type 2 diabetes.. In a double-masked, placebo controlled trial, we evaluated 20 obese nondiabetic adults at baseline and after 1 month of salsalate or placebo.. Compared with placebo, salsalate reduced fasting glucose 13% (P < 0.002), glycemic response after an oral glucose challenge 20% (P < 0.004), and glycated albumin 17% (P < 0.0003). Although insulin levels were unchanged, fasting and oral glucose tolerance test C-peptide levels decreased in the salsalate-treated subjects compared with placebo (P < 0.03), consistent with improved insulin sensitivity and a known effect of salicylates to inhibit insulin clearance. Adiponectin increased 57% after salsalate compared with placebo (P < 0.003). Additionally, within the group of salsalate-treated subjects, circulating levels of C-reactive protein were reduced by 34% (P < 0.05).. This proof-of-principle study demonstrates that salsalate reduces glycemia and may improve inflammatory cardiovascular risk indexes in overweight individuals. These data support the hypothesis that subacute-chronic inflammation contributes to the pathogenesis of obesity-related dysglycemia and that targeting inflammation may provide a therapeutic route for diabetes prevention.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Blood Glucose; Dietary Carbohydrates; Double-Blind Method; Exercise; Female; Glycated Serum Albumin; Glycation End Products, Advanced; Humans; Inflammation; Male; Obesity; Placebos; Salicylates; Serum Albumin

Conflicting results on the effects of salicylates on glucose tolerance in subjects with normal glucose tolerance or type 2 diabetes have been reported.. The objective of the study was to investigate the effects of a salicylate derivative (triflusal) on insulin sensitivity and insulin secretion.. This was a double-blind, randomized, crossover study with three treatment periods corresponding to two dose levels of triflusal and placebo in healthy obese subjects.. Insulin sensitivity and insulin secretion, evaluated through frequently sampled iv glucose tolerance test that was performed after each treatment period, were measured. Insulin secretion was also evaluated in vitro in mice and human islets of Langerhans.. The administration of triflusal led to decreased fasting serum glucose concentration in the study subjects. Insulin sensitivity did not significantly change after each treatment period. Insulin secretion, however, significantly increased in a dose-dependent fashion after each triflusal treatment period. The administration of 800 mum of the main triflusal metabolite to whole mice islets of Langerhans led to a sustained increase in intracellular calcium concentration level. This was followed by a significantly increase in insulin secretion. In human islets, 200 mum of 2-hydroxy-4-trifluoromethylbenzoic acid was sufficient to increase insulin release.. The administration of a salicylate compound led to lowering of serum glucose concentration. We suggest that this effect was mediated through increased insulin secretion induced by salicylate directly on the beta-cell.

Topics: Aged; C-Reactive Protein; Calcium; Cross-Over Studies; Cyclooxygenase Inhibitors; Double-Blind Method; Female; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Obesity; Salicylates

Topics: Adult; Aged; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Clinical Trials as Topic; Diet, Reducing; Drug Interactions; Female; Humans; Imidazoles; Indoles; Indomethacin; Male; Middle Aged; Obesity; Osteoarthritis; Placebos; Salicylates; Time Factors

As a worldwide health issue, obesity is associated with the infiltration of monocytes/macrophages into the adipose tissue causing unresolved inflammation. Monocyte chemoattractant protein-1 (MCP-1) exerts a crucial effect on obesity-related monocytes/macrophages infiltration. Clinically, aspirin and salsalate are beneficial for the treatment of metabolic diseases in which adipose tissue inflammation plays an essential role. Herein, we investigated the effect and precise mechanism of their active metabolite salicylate on TNF-α-elevated MCP-1 in adipocytes. The results indicated that salicylate sodium (SAS) could lower the level of MCP-1 in TNF-α-stimulated adipocytes, which resulted from a previously unrecognized target phosphodiesterase (PDE), 3B (PDE3B), rather than its known targets IKKβ and AMPK. The SAS directly bound to the PDE3B to inactivate it, thus elevating the intracellular cAMP level and activating PKA. Subsequently, the expression of MKP-1 was increased, which led to the decrease in p-EKR and p-p38. Both PDE3B silencing and the pharmacological inhibition of cAMP/PKA compromised the suppressive effect of SAS on MCP-1. In addition to PDE3B, the PDE3A and PDE4B activity was also inhibited by SAS. Our findings identify a previously unrecognized pathway through which SAS is capable of attenuating the inflammation of adipocytes.

Topics: Adipocytes; Chemokine CCL2; Cyclic Nucleotide Phosphodiesterases, Type 3; Humans; Inflammation; Obesity; Salicylates; Tumor Necrosis Factor-alpha

Perioperative hyperglycemia is common and is associated with significant morbidity. Although patient characteristics and surgery influence perioperative glucose metabolism, anesthetics have a significant impact. We hypothesized that mice that were obese and insulin-resistant would experience greater hyperglycemia in response to sevoflurane anesthesia compared with lean controls. We further hypothesized that sevoflurane-induced hyperglycemia would be attenuated by salsalate pre-treatment.. Lean and obese male C57BL/6J mice were anesthetized with sevoflurane for 60 min with or without pre-treatment of 62.5 mg·kg. Under sevoflurane anesthesia, obese mice had higher blood glucose compared to lean mice. Increases in blood glucose were attenuated with acute salsalate pre-treatment at 60 min under anesthesia in obese mice (mean ± standard error of the mean [SEM], delta blood glucose; vehicle 5.79 ± 1.09 vs salsalate 1.91 ± 1.32 mM; P = 0.04) but did not reach statistical significance in lean mice (delta blood glucose, vehicle 4.39 ± 0.55 vs salsalate 2.79 ± 0.71 mM; P = 0.10). This effect was independent of changes in insulin but associated with an approx. 1.7-fold increase in glucose uptake into brown adipose tissue (vehicle 45.28 ± 4.57 vs salsalate 76.89 ± 12.23 µmol·g. These data show that salsalate can reduce sevoflurane-induced hyperglycemia in mice. This indicates that salsalate may represent a new class of therapeutics that, in addition to its anti-inflammatory and analgesic properties, may be useful to reduce perioperative hyperglycemia.. RéSUMé: OBJECTIF: L’hyperglycémie périopératoire est fréquente et est associée à une morbidité significative. Bien que les caractéristiques propres au patient et à la chirurgie influencent le métabolisme périopératoire du glucose, les anesthésiques ont un impact significatif. Nous avons émis l’hypothèse que l’hyperglycémie en réponse à une anesthésie à base de sévoflurane serait plus prononcée chez des souris obèses et insulino-résistantes que chez des souris témoins maigres. Nous avons en outre émis l’hypothèse que l’hyperglycémie induite par le sévoflurane serait atténuée par un prétraitement au salsalate. MéTHODE: Des souris mâles C57BL/6J maigres et obèses ont été anesthésiées avec du sévoflurane pendant 60 min avec ou sans prétraitement de 62,5 mg·kg

Topics: Animals; Blood Glucose; Glucose; Hyperglycemia; Insulin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Salicylates; Sevoflurane

Life-style change and anti-inflammatory interventions have only transient effects in obesity. It is not clear how benefits obtained by these treatments can be maintained longer term, especially during sustained high caloric intake. Constitutive ablation of the activin receptor ALK7 in adipose tissue enhances catecholamine signaling and lipolysis in adipocytes, and protects mice from diet-induced obesity. Here, we investigated the consequences of conditional ALK7 ablation in adipocytes of adult mice with pre-existing obesity. Although ALK7 deletion had little effect on its own, it synergized strongly with a transient switch to low-fat diet (life-style change) or anti-inflammatory treatment (Na-salicylate), resulting in enhanced lipolysis, increased energy expenditure, and reduced adipose tissue mass and body weight gain, even under sustained high caloric intake. By themselves, diet-switch and salicylate had only a temporary effect on weight gain. Mechanistically, combination of ALK7 ablation with either treatment strongly enhanced the levels of β3-AR, the main adrenergic receptor for catecholamine stimulation of lipolysis, and C/EBPα, an upstream regulator of β3-AR expression. These results suggest that inhibition of ALK7 can be combined with simple interventions to produce longer-lasting benefits in obesity.

Topics: Activin Receptors, Type I; Adipocytes; Animals; Eating; Lipolysis; Mice; Mice, Transgenic; Obesity; Salicylates

Previously, we reported that Mof was highly expressed in α-cells, and its knockdown led to ameliorated fasting blood glucose (FBG) and glucose tolerance in non-diabetic mice, attributed by reduced total α-cell but enhanced prohormone convertase (PC)1/3-positive α-cell mass. However, how Mof and histone 4 lysine 16 acetylation (H4K16ac) control α-cell and whether Mof inhibition improves glucose handling in type 2 diabetes (T2DM) mice remain unknown.. Mof overexpression and chromatin immunoprecipitation sequence (ChIP-seq) based on H4K16ac were applied to determine the effect of Mof on α-cell transcriptional factors and underlying mechanism. Then we administrated mg149 to α-TC1-6 cell line, wild type, db/db and diet-induced obesity (DIO) mice to observe the impact of Mof inhibition in vitro and in vivo. In vitro, western blotting and TUNEL staining were used to examine α-cell apoptosis and function. In vivo, glucose tolerance, hormone levels, islet population, α-cell ratio and the co-staining of glucagon and PC1/3 or PC2 were examined.. Mof activated α-cell-specific transcriptional network. ChIP-seq results indicated that H4K16ac targeted essential genes regulating α-cell differentiation and function. Mof activity inhibition in vitro caused impaired α-cell function and enhanced apoptosis. In vivo, it contributed to ameliorated glucose intolerance and islet dysfunction, characterized by decreased fasting glucagon and elevated post-challenge insulin levels in T2DM mice.. Mof regulates α-cell differentiation and function via acetylating H4K16ac and H4K16ac binding to Pax6 and Foxa2 promoters. Mof inhibition may be a potential interventional target for T2DM, which led to decreased α-cell ratio but increased PC1/3-positive α-cells.

Topics: Acetylation; Animals; Apoptosis; Cell Line; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet; Gene Regulatory Networks; Glucagon-Secreting Cells; Glucose Intolerance; Histone Acetyltransferases; Histones; Lysine; Mice, Inbred C57BL; Obesity; Proprotein Convertase 1; Salicylates

Obesity is a major worldwide public health issue that increases the risk to develop cardiovascular diseases, type-2 diabetes, and liver diseases. Obesity is characterized by an increase in adipose tissue (AT) mass due to adipocyte hyperplasia and/or hypertrophia, leading to profound remodeling of its three-dimensional structure. Indeed, the maximal capacity of AT to expand during obesity is pivotal to the development of obesity-associated pathologies. This AT expansion is an important homeostatic mechanism to enable adaptation to an excess of energy intake and to avoid deleterious lipid spillover to other metabolic organs, such as muscle and liver. Therefore, understanding the structural remodeling that leads to the failure of AT expansion is a fundamental question with high clinical applicability. In this article, we describe a simple and fast clearing method that is routinely used in our laboratory to explore the morphology of mouse and human white adipose tissue by fluorescent imaging. This optimized AT clearing method is easily performed in any standard laboratory equipped with a chemical hood, a temperature-controlled orbital shaker and a fluorescent microscope. Moreover, the chemical compounds used are readily available. Importantly, this method allows one to resolve the 3D AT structure by staining various markers to specifically visualize the adipocytes, the neuronal and vascular networks, and the innate and adaptive immune cells distribution.

Topics: Adipocytes; Adipose Tissue; Adipose Tissue, White; Animals; Humans; Imaging, Three-Dimensional; Mice; Microscopy, Fluorescence; Obesity; Salicylates

High-fat diets (HFDs) and adiposity increase colorectal cancer risk, in part by elevating pro-inflammatory cytokines that activate pro-cancerous signaling pathways. Curcumin (CUR), a dietary polyphenol and salsalate (SAL), an non-steroidal anti-inflammatory drug (NSAID) lacking the gastrotoxicity of aspirin, each suppress inflammatory signaling, but via different cellular pathways.. A/J mice (n = 110) are fed a low-fat diet (LFD, 10% kcal), a HFD (60% kcal), a HFD containing 0.4% CUR, a HFD containing 0.3% SAL, or a HFD containing both agents (CUR/SAL). All mice receive six injections of azoxymethane. Compared to LFD-fed mice, HFD-fed mice display elevated colonic cytokines, crypt cell proliferation, and increased tumorigenesis (p < 0.05). CUR/SAL significantly reduces colonic cytokines (p < 0.01), suppresses activation of the PI3K/Akt/mTOR/NF-κB/Wnt pathways (p < 0.01), activates AMPK (p < 0.01), attenuates abnormal proliferation of the colonic mucosa (p < 0.05), and reduces tumor multiplicity and burden (p < 0.05), in comparison to the HFD control. In contrast, CUR or SAL alone does not suppress abnormal crypt cell proliferation or tumor multiplicity, and is largely ineffective in modifying activation of these signaling pathways.. These observations demonstrate the superiority of the CUR/SAL over the individual agents and provide a scientific basis for future translational studies in obese subjects and/or those habitually consuming HFDs.

Topics: Adiposity; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Proliferation; Colitis; Colorectal Neoplasms; Curcumin; Diet, High-Fat; Intestinal Mucosa; Male; Mice, Inbred Strains; Obesity; Precancerous Conditions; Salicylates; Signal Transduction

Topics: Adipose Tissue, White; Animals; Body Weight; Cell Line; Diabetes Mellitus, Type 2; Diet, High-Fat; Energy Metabolism; Fatty Liver; Gene Expression; Gluconeogenesis; Glucose; Humans; Insulin; Lipid Metabolism; Liver; Male; Mice; Muscle, Skeletal; Obesity; Pyruvic Acid; Salicylates; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Signal Transduction; Thermogenesis

Topics: Humans; Insulin Resistance; Lipids; Obesity; Overweight; Prediabetic State; Salicylates

Salsalate improves glucose intolerance and dyslipidemia in type 2 diabetes patients, but the mechanism is still unknown. The aim of the current study was to unravel the molecular mechanisms involved in these beneficial metabolic effects of salsalate by treating mice with salsalate during and after development of high-fat diet-induced obesity. We found that salsalate attenuated and reversed high-fat diet-induced weight gain, in particular fat mass accumulation, improved glucose tolerance, and lowered plasma triglyceride levels. Mechanistically, salsalate selectively promoted the uptake of fatty acids from glycerol tri[(3)H]oleate-labeled lipoprotein-like emulsion particles by brown adipose tissue (BAT), decreased the intracellular lipid content in BAT, and increased rectal temperature, all pointing to more active BAT. The treatment of differentiated T37i brown adipocytes with salsalate increased uncoupled respiration. Moreover, salsalate upregulated Ucp1 expression and enhanced glycerol release, a dual effect that was abolished by the inhibition of cAMP-dependent protein kinase (PKA). In conclusion, salsalate activates BAT, presumably by directly activating brown adipocytes via the PKA pathway, suggesting a novel mechanism that may explain its beneficial metabolic effects in type 2 diabetes patients.

Topics: Adipose Tissue, Brown; Animals; Dietary Fats; Drug Administration Schedule; Glucose; Lipid Metabolism; Male; Mice; Mice, Transgenic; Obesity; Salicylates; Weight Gain

Docosahexaenoic acid (DHA 22:6n-3) and salicylate are both known to exert anti-inflammatory effects. This study investigated the effects of a novel bifunctional drug compound consisting of DHA and salicylate linked together by a small molecule that is stable in plasma but hydrolyzed in the cytoplasm. The components of the bifunctional compound acted synergistically to reduce inflammation mediated via nuclear factor κB in cultured macrophages. Notably, oral administration of the bifunctional compound acted in two distinct ways to mitigate hyperglycemia in high-fat diet-induced insulin resistance. In mice with diet-induced obesity, the compound lowered blood glucose by reducing hepatic insulin resistance. It also had an immediate glucose-lowering effect that was secondary to enhanced glucagon-like peptide-1 (GLP-1) secretion and abrogated by the administration of exendin(9-39), a GLP-1 receptor antagonist. These results suggest that the bifunctional compound could be an effective treatment for individuals with type 2 diabetes and insulin resistance. This strategy could also be employed in other disease conditions characterized by chronic inflammation.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Glucose; Cell Line, Transformed; Cell Line, Tumor; Cells, Cultured; Diet, High-Fat; Docosahexaenoic Acids; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin Resistance; Liver; Macrophages; Mice, Inbred C57BL; Obesity; Prediabetic State; Prodrugs; Salicylates; Signal Transduction

Adipose tissue hormone leptin induces endothelium-dependent vasorelaxation mediated by nitric oxide (NO) and endothelium-derived hyperpolarizing factors (EDHF). Previously it has been demonstrated that in short-term obesity the NO-dependent and the EDHF-dependent components of vascular effect of leptin are impaired and up-regulated, respectively. Herein we examined the mechanism of the EDHF-dependent vasodilatory effect of leptin and tested the hypothesis that alterations of acute vascular effects of leptin in obesity are accounted for by chronic hyperleptinemia. The study was performed in 5 groups of rats: (1) control, (2) treated with exogenous leptin for 1 week to induce hyperleptinemia, (3) obese, fed highly-palatable diet for 4 weeks, (4) obese treated with pegylated superactive rat leptin receptor antagonist (PEG-SRLA) for 1 week, (5) fed standard chow and treated with PEG-SRLA. Acute effect of leptin on isometric tension of mesenteric artery segments was measured ex vivo. Leptin relaxed phenylephrine-preconstricted vascular segments in NO- and EDHF-dependent manner. The NO-dependent component was impaired and the EDHF-dependent component was increased in the leptin-treated and obese groups and in the latter group both these effects were abolished by PEG-SRLA. The EDHF-dependent vasodilatory effect of leptin was blocked by either the inhibitor of cystathionine γ-lyase, propargylglycine, or a hydrogen sulfide (H2S) scavenger, bismuth (III) subsalicylate. The results indicate that NO deficiency is compensated by the up-regulation of EDHF in obese rats and both effects are accounted for by chronic hyperleptinemia. The EDHF-dependent component of leptin-induced vasorelaxation is mediated, at least partially, by H2S.

Topics: Adipose Tissue; Alkynes; Animals; Biological Factors; Bismuth; Cystathionine gamma-Lyase; Diet; Endothelium, Vascular; Gene Expression Regulation; Glycine; Hydrogen Sulfide; Leptin; Male; Mesenteric Arteries; Nitric Oxide; Nitric Oxide Synthase Type III; Obesity; Organometallic Compounds; Phenylephrine; Rats; Rats, Wistar; Receptors, Leptin; Salicylates; Signal Transduction; Tissue Culture Techniques; Vasoconstriction; Vasodilation

Gaining understanding of common complex diseases and their treatments are the main drivers for life sciences. As we show here, comprehensive protein set analyses offer new opportunities to decipher functional molecular networks of diseases and assess the efficacy and side-effects of treatments in vivo. Using mass spectrometry, we quantitatively detected several thousands of proteins and observed significant changes in protein pathways that were (dys-) regulated in diet-induced obesity mice. Analysis of the expression and post-translational modifications of proteins in various peripheral metabolic target tissues including adipose, heart, and liver tissue generated functional insights in the regulation of cell and tissue homeostasis during high-fat diet feeding and medication with two antidiabetic compounds. Protein set analyses singled out pathways for functional characterization, and indicated, for example, early-on potential cardiovascular complication of the diabetes drug rosiglitazone. In vivo protein set detection can provide new avenues for monitoring complex disease processes, and for evaluating preclinical drug candidates.

Topics: Adipose Tissue, White; Animals; Diet, High-Fat; Hypoglycemic Agents; Liver; Male; Mice; Mice, Inbred C57BL; Myocardium; Obesity; PPAR gamma; Protein Processing, Post-Translational; Proteomics; Rosiglitazone; Salicylates; Thiazolidinediones

It is increasingly accepted that chronic inflammation participates in obesity-induced insulin resistance and type 2 diabetes (T2D). Salicylates and thiazolidinediones (TZDs) both have anti-inflammatory and anti-hyperglycemic properties. The present study compared the effects of these drugs on obesity-induced inflammation in adipose tissue (AT) and AT macrophages (ATMs), as well as the metabolic and immunological phenotypes of the animal models. Both drugs improved high fat diet (HFD)-induced insulin resistance. However, salicylates did not affect AT and ATM inflammation, whereas Pioglitazone improved these parameters. Interestingly, HFD and the drug treatments all modulated systemic inflammation as assessed by changes in circulating immune cell numbers and activation states. HFD increased the numbers of circulating white blood cells, neutrophils, and a pro-inflammatory monocyte subpopulation (Ly6C(hi)), whereas salicylates and Pioglitazone normalized these cell numbers. The drug treatments also decreased circulating lymphocyte numbers. These data suggest that obesity induces systemic inflammation by regulating circulating immune cell phenotypes and that anti-diabetic interventions suppress systemic inflammation by normalizing circulating immune phenotypes.

Topics: Adipose Tissue; Animals; Cell Count; Diet, High-Fat; Flow Cytometry; Gene Expression Profiling; Gene Expression Regulation; Inflammation; Insulin Resistance; Macrophage Activation; Macrophages; Mice; Multigene Family; Obesity; Oligonucleotide Array Sequence Analysis; Pioglitazone; Salicylates; Thiazolidinediones

Given worldwide increases in the incidence of obesity and type 2 diabetes, new strategies for preventing and treating metabolic diseases are needed. The nuclear receptor PPARγ (peroxisome proliferator-activated receptor gamma) plays a central role in lipid and glucose metabolism; however, current PPARγ-targeting drugs are characterized by undesirable side effects. Natural products from edible biomaterial provide a structurally diverse resource to alleviate complex disorders via tailored nutritional intervention. We identified a family of natural products, the amorfrutins, from edible parts of two legumes, Glycyrrhiza foetida and Amorpha fruticosa, as structurally new and powerful antidiabetics with unprecedented effects for a dietary molecule. Amorfrutins bind to and activate PPARγ, which results in selective gene expression and physiological profiles markedly different from activation by current synthetic PPARγ drugs. In diet-induced obese and db/db mice, amorfrutin treatment strongly improves insulin resistance and other metabolic and inflammatory parameters without concomitant increase of fat storage or other unwanted side effects such as hepatoxicity. These results show that selective PPARγ-activation by diet-derived ligands may constitute a promising approach to combat metabolic disease.

Topics: 3T3-L1 Cells; Animals; Biological Products; Blotting, Western; CHO Cells; Cricetinae; Cricetulus; Crystallography, X-Ray; Diabetes Mellitus, Type 2; Diet, High-Fat; Dietary Supplements; Fabaceae; Gene Expression; Glycyrrhiza; Humans; Hypoglycemic Agents; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Obesity; PPAR gamma; Protein Binding; Reverse Transcriptase Polymerase Chain Reaction; Salicylates

Lipin-1 plays a crucial role in the regulation of lipid metabolism and cell differentiation in adipocytes. Expression of adipose lipin-1 is reduced in obesity, and metabolic syndrome. However, the significance of this reduction remains unclear. This study investigated if and how reduced lipin-1 expression affected metabolism. We assessed mRNA expression levels of various genes related to adipocyte metabolism in lipin-1-depleted 3T3-L1 adipocytes by introducing its specific small interfering RNA. In lipin-1-depleted adipocytes, mRNA and protein expression levels of monocyte chemoattractant protein-1 (MCP-1) were significantly increased, although the other genes tested were not altered. The conditioned media from the cells promoted monocyte chemotaxis. The increase in MCP-1 expression was prevented by treatment with quinazoline or salicylate, inhibitors of nuclear factor-κB activation. Because MCP-1 is related to adipose inflammation and systemic insulin resistance, these results suggest that a reduction in adipose lipin-1 in obesity may exacerbate adipose inflammation and metabolism.

Topics: 3T3-L1 Cells; Adipocytes; Animals; Chemokine CCL2; Chemotaxis; Gene Expression; Insulin Resistance; Mice; NF-kappa B; Nuclear Proteins; Obesity; Phosphatidate Phosphatase; Protein Biosynthesis; Quinazolines; RNA, Messenger; RNA, Small Interfering; Salicylates

Recent findings indicate that endoplasmic reticulum (ER) stress is significantly increased in adipose tissue of obese human subjects and is critical to the initiation and integration of pathways of inflammation and insulin action. But the factors inducing ER stress in human adipose tissue are unknown. The common factors increased in obesity and linked to insulin resistance are hyperglycaemia, hyperlipidemia and also endotoxemia. Therefore, our aims were to investigate: (1) the role of lipopolysaccharide (LPS), high glucose (HG) and saturated fatty acids (SFA) as inducers of ER stress in primary human adipocytes and (2) whether salicylate, a known anti-inflammatory compound, can alleviate this effect. Components of the ER stress pathways were studied in human abdominal subcutaneous (AbSc) adipose tissue (AT) from obese and lean. Following the culture and differentiation of primary human preadipocytes, these adipocytes were treated with LPS, HG, tunicamycin (Tun) and SFA either alone or in combination with sodium salicylate (Sal). Markers of ER stress were significantly increased in AbSc AT of obese. Differentiated human adipocytes treated with LPS, Tun, HG and SFA showed significant activation of eukaryotic translation initiation factor 2alpha (eIF2alpha) and activating transcription factor 6 (ATF6) and their down-stream targets. Sal alleviated this effect and activated AktSer473 phosphorylation. This study presents important evidence that: (1) there is increased ER stress in adipose tissue of obese individuals, (2) LPS, hyperglycaemia and saturated fatty acids induce significant ER stress in primary human adipocytes and (3) this induction is alleviated by salicylate.

Topics: Activating Transcription Factor 6; Adipocytes; Adipose Tissue; Adult; Anti-Inflammatory Agents, Non-Steroidal; Cells, Cultured; Endoplasmic Reticulum; Eukaryotic Initiation Factor-2; Fatty Acids; Glucose; Humans; Lipopolysaccharides; Middle Aged; Obesity; Phosphorylation; Proto-Oncogene Proteins c-akt; Salicylates; Stress, Physiological

Disalicylic acid derivatives with stilbene and bis-styrylbenzene skeleton were synthesized as PTP1B inhibitors. The most potent in this series exhibited a submicromolar IC(50) value. One of the compounds 7b was tested in an animal model for its efficacy as an anti-diabetic or an anti-obesity agent. In feeding compound 7b to diet-induced obese mice, no significant differences in weight gain and food consumption were observed between the drug-treated and the obese control mice. However, 7b significantly lowered the fasting glucose level and improved the glucose tolerance in the obesity-induced diabetic mice.

Topics: Animals; Anti-Obesity Agents; Blood Glucose; Disease Models, Animal; Fasting; Glucose Tolerance Test; Hyperglycemia; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Salicylates; Stilbenes; Structure-Activity Relationship; Styrenes; Weight Gain

Methylenedisalicylic acid derivatives were synthesized and their inhibitory activities against protein tyrosine phosphatases (PTPases) examined. Two of the compounds, 8 and 9, showed K(i) values of 9.4 and 6.3microM against PTP1B, 4- and 7-fold lower values compared to those against TC-PTP. They were reversible and slow-binding inhibitors against PTP1B. When compound 8 was fed to a mouse model, the weight gain and adipocyte fat storage induced by a high-fat-diet were significantly suppressed.

Topics: Adipocytes; Animals; Anti-Obesity Agents; Diet; Disease Models, Animal; Mice; Mice, Inbred C57BL; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases; Salicylates; Weight Gain

A series of compounds containing one or two salicylic acid moieties were synthesized, and their efficacy to inhibit the phosphohydrolase activity of PTP1B examined. Some of the methylenedisalicylic acid derivatives were potent inhibitors of PTP1B. Of those derivatives, 3c exhibited about a 14-fold selectivity against TC-PTP, and this compound was tested in a mouse model for its efficacy to prevent diet-induced obesity. It effectively suppressed the increases in body weight and adipose mass, without any noticeable toxic effect. The compound also prevented increases in the plasma triglyceride, cholesterol, and nonesterified fatty acid concentrations; thus, expanding its therapeutic potential to other related metabolic diseases, such as hyperlipidemia and hypercholesterolemia.

Topics: Animals; Anti-Obesity Agents; Body Weight; Enzyme Inhibitors; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Obesity; Organ Size; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Salicylates; Structure-Activity Relationship

We show that NF-kappaB and transcriptional targets are activated in liver by obesity and high-fat diet (HFD). We have matched this state of chronic, subacute 'inflammation' by low-level activation of NF-kappaB in the liver of transgenic mice, designated LIKK, by selectively expressing constitutively active IKK-b in hepatocytes. These mice exhibit a type 2 diabetes phenotype, characterized by hyperglycemia, profound hepatic insulin resistance, and moderate systemic insulin resistance, including effects in muscle. The hepatic production of proinflammatory cytokines, including IL-6, IL-1beta and TNF-alpha, was increased in LIKK mice to a similar extent as induced by HFD in in wild-type mice. Parallel increases were observed in cytokine signaling in liver and mucscle of LIKK mice. Insulin resistance was improved by systemic neutralization of IL-6 or salicylate inhibition of IKK-beta. Hepatic expression of the IkappaBalpha superrepressor (LISR) reversed the phenotype of both LIKK mice and wild-type mice fed an HFD. These findings indicate that lipid accumulation in the liver leads to subacute hepatic 'inflammation' through NF-kappaB activation and downstream cytokine production. This causes insulin resistance both locally in liver and systemically.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carbohydrate Metabolism; Cytokines; Dietary Fats; Female; Hepatocytes; Humans; I-kappa B Kinase; Insulin; Insulin Resistance; Interleukin-6; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; NF-kappa B; Obesity; Protein Serine-Threonine Kinases; Rats; Salicylates; Signal Transduction

Topics: Alcohol Drinking; Cardiovascular Diseases; Dioxins; Estrogens; Humans; Lipids; Obesity; Risk Factors; Salicylates

Salicylate kinetics following single, 650-mg intravenous and oral doses of aspirin were evaluated in humans in 2 studies. Complete conversion of aspirin to salicylate was assumed. The first study involved 25 young (25-40 years) and 21 elderly (66-89 years) healthy male and female volunteers. Mean salicylate clearance was lower in elderly females compared with that in young females; however, the difference between young men and elderly men was not significant. Salicylate free fraction in plasma increased significantly with age in men and women. After correction for free fraction, unbound mean clearance was reduced in elderly men compared with young men, and in elderly women compared with young women. Peak plasma salicylate concentrations after taking oral aspirin were not significantly influenced by age, and systemic availability of salicylate in all groups was complete. The second study compared 20 obese subjects (mean weight 113 kg) with 20 normal weight controls (mean weight 67 kg) matched for age, sex, height, and smoking habits. Small differences between obese and control groups were observed in total salicylate volume of distribution (Vd), unbound Vd, and mean clearance of total or unbound salicylate. Following normalization for total weight, however, values of total Vd and mean clearance were significantly smaller in obese subjects than in normal weight subjects. Rate and completeness of salicylate absorption were not influenced by obesity when aspirin was ingested, although peak levels were lower in obese subjects. If applied to multiple doses, the reduced unbound clearance of salicylate in the elderly would imply increased accumulation unless doses are appropriately adjusted downward. During long-term therapy, salicylate dosage for obese individuals should not be adjusted upward in proportion to total weight.

Topics: Administration, Oral; Adult; Age Factors; Aged; Aspirin; Body Weight; Female; Humans; Infusions, Parenteral; Kinetics; Male; Obesity; Salicylates; Salicylic Acid; Sex Factors

Topics: Arginine; Blood Glucose; Circadian Rhythm; Diabetes Mellitus; Dietary Fats; Dietary Proteins; Fasting; Fatty Acids, Nonesterified; Glucose; Growth Hormone; Heparin; Humans; Hypopituitarism; Insulin; Nicotinic Acids; Obesity; Salicylates; Sleep; Time Factors