Short-term inhibition of peroxisome proliferator-activated receptor-γ coactivator-1α expression reverses diet-induced diabetes mellitus and hepatic steatosis in mice

Aims/hypothesis The coactivator of nuclear receptors, peroxisome proliferator-activated receptor- coactivator-1 (PGC-1) has been implicated in a series of events that contribute to the control of glucose metabolism. We have recently reported the use of a PGC-1 antisense oligonucleotide (PGC-1AS) that inhibits up to 60% of PGC-1 expression in pancreatic islets, leading to increased insulin secretion. This oligonucleotide was used in this study to try to ameliorate diet-induced type 2 diabetes in a genetically predisposed mouse strain (Swiss mice).Materials and methods Glucose and insulin tolerance tests, euglycaemic–hyperinsulinaemic clamp, immunoprecipitation assays, immunoblotting assays and immunohistochemistry were used in this investigation.Results Swiss mice became obese and overtly diabetic after 8 weeks of feeding with chow containing 24% saturated fat. One daily dose (1.0 nmol) of PGC-1AS significantly reduced glucose and increased insulin blood levels without affecting food intake and body weight. These effects were accompanied by a reduced area under the glucose curve during an intraperitoneal glucose tolerance test, an increased constant of glucose decay (K_itt) during an insulin tolerance test, and an increased glucose consumption rate during a euglycaemic–hyperinsulinaemic clamp. Moreover, mice treated with PGC-1AS presented an outstanding reduction of macroscopic and microscopic features of hepatic steatosis. These effects were accompanied by reduced expression or function of a series of proteins involved in lipogenesis.Conclusions/interpretation PGC-1 is an attractive target for pharmacological therapeutics in type 2 diabetes mellitus and diet-induced hepatic steatosis.     

Peroxisome proliferator-activated receptor-α agonists modulate CXCL9 and CXCL11 chemokines in Graves' ophthalmopathy fibroblasts and preadipocytes

Peroxisome proliferator-activated receptors (PPAR)α have been shown to exert immunomodulatory effects in autoimmune disorders; no study evaluated the effect of PPARα activation in Graves’ ophthalmopathy (GO).We show the presence of PPARα, δ and γ in GO fibroblasts and preadipocytes. PPARα activators have a potent inhibitory action on the secretion of CXCL9 and CXCL11 chemokines (induced by IFNγ and TNFα) in fibroblasts and preadipocytes. The potency of the used PPARα agonists was maximum on the secretion of CXCL11 (67% inhibition by fenofibrate) in fibroblasts. The relative potency of the compounds in GO fibroblasts was different with each chemokine. PPARα agonists were stronger inhibitors of CXCL9 and CXCL11 (in GO fibroblasts and preadipocytes) than PPARγ activators.This study first shows that PPARα activators inhibit CXCL9 and CXCL11 chemokines in normal and GO fibroblasts and preadipocytes, suggesting that PPARα may be involved in the modulation of the immune response in GO.     

Peroxisome proliferator-activated receptor-γ activation with angiotensin II type 1 receptor blockade is pivotal for the prevention of blood-brain barrier impairment and cognitive decline in type 2 diabetic mice

We reported previously that an angiotensin II type 1 receptor blocker, telmisartan, improved cognitive decline with peroxisome proliferator-activated receptor-γ activation; however, the detailed mechanisms are unclear. Enhanced blood-brain barrier (BBB) permeability with alteration of tight junctions is suggested to be related to diabetes mellitus. Therefore, we examined the possibility that telmisartan could attenuate BBB impairment with peroxisome proliferator-activated receptor-γ activation to improve diabetes mellitus-induced cognitive decline. Type 2 diabetic mice KKA(y) exhibited impairment of cognitive function, and telmisartan treatment attenuated this. Cotreatment with GW9662, a peroxisome proliferator-activated receptor-γ antagonist, interfered with these protective effects of telmisartan against cognitive function. BBB permeability was increased in both the cortex and hippocampus in KKA(y) mice. Administration of telmisartan attenuated this increased BBB permeability. Coadministration of GW9662 reduced this effect of telmisartan. Significant decreases in expression of tight junction proteins and increases in matrix metalloproteinase expression, oxidative stress, and proinflammatory cytokine production were observed in the brain, and treatment with telmisartan restored these changes. Swollen astroglial end-feet in BBB were observed in KKA(y) mice, and this change in BBB ultrastructure was decreased in telmisartan. These effects of telmisartan were weakened by cotreatment with GW9662. In contrast, administration of another angiotensin II type 1 receptor blocker, losartan, was less effective compared with telmisartan in terms of preventing BBB permeability and astroglial end-foot swelling, and coadministration of GW9662 did not affect the effects of losartan. These findings are consistent with the possibility that, in type 2 diabetic mice, angiotensin II type 1 receptor blockade with peroxisome proliferator-activated receptor-γ activation by telmisartan may help with protection against cognitive decline by preserving the integrity of the BBB.     

Tesaglitazar, a novel dual peroxisome proliferator-activated receptor α/γ agonist, dose-dependently improves the metabolic abnormalities associated with insulin resistance in a non-diabetic population

Aims/hypothesis Insulin resistance is associated with abnormalities in lipid and glucose metabolism, which are major components of metabolic syndrome and risk factors for vascular disease. This study examined the effect of tesaglitazar (Galida), a novel, dual-acting peroxisome proliferator-activated receptor / agonist, on lipid and glucose metabolism in patients with evidence of insulin resistance.Methods A 12-week, multicentre, randomised, double-blind, placebo-controlled, dose-finding study compared the efficacy and safety of oral tesaglitazar (0.1, 0.25, 0.5 and 1.0 mg/day) and placebo in 390 non-diabetic patients with hypertriglyceridaemia (plasma triglyceride concentration >1.7 mmol/l) and abdominal obesity (waist-to-hip ratio >0.90 for men and >0.85 for women).Results A 1.0-mg dose of tesaglitazar reduced fasting triglycerides (the primary endpoint) by 37% (95% CI: –43% to –30%; p<0.0001), non-HDL-cholesterol by 15% (95% CI: –20% to –10%; p<0.0001) and NEFA by 40% (95% CI: –51% to –27%; p<0.0001), and increased HDL-cholesterol by 16% (95% CI: 8 to –24%; p<0.0001). At the end of treatment there was a dose-dependent increase in patients with pattern A LDL particle diameter (40% at baseline vs 87% at 12 weeks for tesaglitazar 1.0 mg). Tesaglitazar produced significant reductions in fasting insulin concentration (–35%; p<0.0001) and plasma glucose concentration (–0.47 mmol/l; p<0.0001). Respiratory infection and gastrointestinal symptoms were the most common adverse events and were similarly frequent in all groups.Conclusions/interpretation Tesaglitazar was well tolerated and produced significant, dose-dependent improvements in lipid and glucose metabolism and insulin sensitivity. Tesaglitazar may have the potential to prevent vascular complications and delay progression to diabetes in these patients.     

Peroxisome proliferator-activated receptor-γ agonist rosiglitazone reduces circulating platelet activity in patients without diabetes mellitus who have coronary artery disease

Background

Rosiglitazone, a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, is used in the treatment of type 2 diabetes mellitus, and in vitro data has shown that it may have anti-platelet effects independent of its hypoglycemic effects. The aim of this study was to assess the effect of rosiglitazone on circulating platelet activity in patients without diabetes mellitus who had coronary artery disease.

Methods

Ninety-two patients with stable, documented coronary artery disease without diabetes mellitus were studied. Patients were randomized (double-blind) to receive placebo or rosiglitazone for 12 weeks. Circulating platelet activity was measured at baseline and after 12 weeks of therapy with whole blood flow cytometry to quantify platelet P-selectin expression.

Results

The percentage of P-selectin positive platelets was significantly reduced by rosiglitazone treatment compared with placebo (P = .04). In the rosiglitazone group, the percentage of P-selectin positive platelets (median with interquartile range) decreased from 0.1 % (0.05-0.24) to 0.05 % (0.01-0.15). Rosiglitazone treatment significantly reduced the insulin resistance index (HOMA-R) compared with placebo (P = .02). No significant correlation was observed between change in platelet activity and change in HOMA-R.

Conclusions

Rosiglitazone significantly reduces circulating platelet activity in patients without diabetes mellitus who have coronary artery disease. This effect appears to be independent of any insulin-sensitising effect.     

Peroxisome proliferator-activated receptor α (PPARα) activation advances locomotor activity and feeding daily rhythms in mice

Peroxisome proliferator-activated receptors (PPARs) are key mediators of energy homeostasis, and lipid and glucose metabolism that exhibit circadian expression. PPAR activating drugs are used clinically as lipid and glucose-lowering drugs. We evaluated the effect of long-term (11 weeks) PPARα and PPARγ activation using bezafibrate and rosiglitazone, respectively, on metabolism, locomotor activity and feeding rhythms of non-obese mice. We found that bezafibrate, but not rosiglitazone, led to no weight gain and a slight weight loss with reduced epididymal fat pads. Although rosiglitazone had a minor effect on 24-h food intake rhythm, bezafibrate treatment was accompanied by increased amplitude and an advanced acrophase of the 24-h feeding rhythm. Similarly, unlike rosiglitazone, bezafibrate treatment was accompanied by a significantly advanced acrophase of locomotor activity rhythm under constant darkness conditions. As disrupted circadian rhythms lead to obesity, PPARα activation can serve as a clinical target for the modulation of both circadian rhythms and metabolism.     

Expression and significance of HIF-1α and VEGF in rats with diabetic retinopathy

Objective:To investigate the expression of hypoxia inducible iaclor-1α(HIF-1α)and vascular endothelial growth factor(VECF)in diabelic retinopathy(DR)rats and its effect on the DR occurrence and development.Methods:A total of 120 SD rats were randomly divided into trial group and control group with 60 in each.STZ.i.p.was used in the trial group to establish the DM model,citrate buffer salt of same amount was used up.to the control group.1,3 and 6 months after injection,respective 20 rats were sacrificed in each group to observe expression of HIF-1αand VEGF in the rat retina tissue at different lime points.Results:Expression of HIF-1αand VEGF were negative in the control group;expression of HIF-1αand VKGF protein in retinal tissue were weak after 1 month of DR mold formation.It showed progressive enhancement along with the progression in different organizations,differences between groups were significant(P0.05).Conclusions:Expressions of HIF-1αand VF.GF were;correlated with disease progression in early diabelic relinopathy.Retinal oxygen can induce over-expression of HIF-1αand VEGF.It shows that HIF-1αand VEGF play an important role in the pathogenesis of DR.     

TNF-α inhibitors and tocilizumab do not influence hepatic steatosis in patients with rheumatoid arthritis

AIM: To investigate the influence, if any, of tumor necrosis factor(TNF)-α inihibitors and Tocilizumab, on hepatic steatosis(HS) in rheumatoid arthritis(RA) patients in the light of the known role of TNF-α and interleukin-6, which are key-cytokines in the pathogenesis of RA, in inducing HS in general population.METHODS: We retrospectively reviewed the clinical charts of 36 RA patients, out of whom 12 had been treated with Methotrexate(MTX), 12 with TNF inhibitors ± MTX and 12 with Tocilizumab ± MTX. The 3 subgroups of patients matched each other for sex, age, body mass index, metabolic syndrome(MS) and other risk factors for atherosclerosis. At baseline and after 12 mo each patient underwent an abdominal ultrasonog-raphy for the assessment of presence of HS and the evaluation of its grade.RESULTS: No difference was detected either in the prevalence of HS or in that of its distinct grades between the 3 groups of patients at baseline. After 12 mo, the HS grade unchanged in 20 patients(7 subjects treated with MTX, 7 with TNF-α inhibitors ± MTX and 6 Tocilizumab ± MTX); increased in 12 patients(4 subjects treated with MTX, 4 TNF-α blockers ± MTX and 4 Tocilizumab ± MTX); decreased in 4(1 treated with MTX, 1 with anti-TNF-α + MTX and 2 with TCZ ± MTX(P = 0.75). No correlation was found between getting remission or low disease activity and the course of either MS or HS.CONCLUSION: We failed to detect any influence of MTX ± TNF-α inhibitors or Tocilizumab in reducing MS and HS. A prospective study is needed to clarify the topic.     

A new, highly selective murine peroxisome proliferator-activated receptor δ agonist increases responsiveness to thermogenic stimuli and glucose uptake in skeletal muscle in obese mice

Aim: We investigated how GW800644, the first pharmacologically selective murine peroxisome proliferator‐activated receptor δ (PPARδ) agonist, affects energy balance, glucose homeostasis and fuel utilization by muscle in obese mice. Methods: Potencies were determined in transactivation assays. Oral glucose tolerance was determined after 14 and 22 days' administration (10 mg/kg body weight, twice daily) to Lep^ob/Lep^ob mice. Food intake and energy expenditure were measured during a 26‐day experiment, and plasma metabolites and 2‐deoxyglucose uptake in vivo at termination. Palmitate oxidation and 2‐deoxyglucose uptake by isolated soleus muscles were measured after 14 (in lean and obese mice) and 26 days. Results: GW800644 activated murine PPARδ (EC₅₀ 2 nM), but caused little to no activation of PPARα or PPARγ up to 10 µM. It did not increase liver weight. GW800644 reduced food intake and body weight in obese mice after 8 days. It did not affect resting energy expenditure, but, compared to pair‐fed mice, it increased the response to a β₃‐adrenoceptor agonist. It improved glucose tolerance. GW800644, but not pair‐feeding, reduced plasma glucose, insulin and triglyceride concentrations. It increased 2‐deoxyglucose uptake in vivo in adipose tissue, soleus muscle, heart, brain and liver, and doubled 2‐deoxyglucose uptake and palmitate oxidation in isolated soleus muscle from obese but not lean mice. Conclusions: PPARδ agonism reduced food intake and independently elicited metabolic effects that included increased responsiveness to β₃‐adrenoceptor stimulation, increased glucose utilization and fat oxidation in soleus muscle of Lep^ob/Lep^ob but not lean mice and increased glucose utilization in vivo in Lep^ob/Lep^ob mice.