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      TRC150094 attenuates progression of nontraditional cardiovascular risk factors associated with obesity and type 2 diabetes in obese ZSF1 rats

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          Abstract

          Chronic overnutrition and consequential visceral obesity is associated with a cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus. Moreover, individuals who have a triad of hypertension, dysglycemia, and elevated triglycerides along with reduced high-density lipoprotein cholesterol have a greater residual cardiovascular risk even after factoring for the traditional risk factors such as age, smoking, diabetes, and elevated low-density lipoprotein cholesterol. In our previous study we demonstrated that TRC150094, when administered to rats receiving a high-fat diet, stimulated mitochondrial fatty acid oxidation (FAO) and reduced visceral adiposity, opening an interesting perspective for a possible clinical application. In the present study, oral administration of TRC150094 to obese Zucker spontaneously hypertensive fatty rats (obese ZSF1) improved glucose tolerance and glycemic profile as well as attenuated a rise in blood pressure. Obese ZSF1 rats treated with TRC150094 also showed reduced hepatic steatosis, reduced progression of nephropathy, and improved skeletal muscle function. At the cellular level, TRC150094 induced a significant increase in mitochondrial respiration as well as an increased FAO in liver and skeletal muscle, ultimately resulting in reduced hepatic as well as total body fat accumulation, as evaluated by magnetic resonance spectroscopy and magnetic resonance imaging, respectively. If reproduced in humans, these results could confirm that TRC150094 may represent an attractive therapeutic agent to counteract multiple residual cardiovascular risk components.

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          Most cited references6

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          Effect of 3,3'-diiodothyronine and 3,5-diiodothyronine on rat liver oxidative capacity.

          We report that 3,5,3'-triiodothyronine (T3) as well as two other iodothyronines (3,3'-diiodothyronine and 3,5-diiodothyronine (T2s)) stimulate rat liver oxidative capacity (measured as cytochrome oxidase activity (COX)). In hypothyroid rats COX activity and mitochondrial protein content are significantly lower than in normal control animals. The administration of both T3 and T2s to hypothyroid rats significantly enhances hepatic COX activity with T3 having the greatest effect (+60%); moreover, T3 restores the mitochondrial protein content whereas the T2s are ineffective. Administration of T2s results in a faster stimulation (already significant 1 h after the injection) of hepatic COX activity than T3 injection. Our results suggest that T3 acts on the protein synthesis mechanism involved in the regulation of the mitochondrial mass while T2s would act directly at the mitochondrial level.
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            The insulin gradient phenomenon: a manifestation of the effects of body weight on blood pressure and insulin resistance.

            The relationship between hyperinsulinemia and hypertension is frequently observed in overweight patients; however, population studies have not confirmed an independent association. A population study was conducted to assess whether differences in body mass index and levels of insulinemia modify cardiovascular hemodynamics and arterial pressure. In all, 322 healthy adults underwent a medical evaluation including insulin sensitivity and cardiac performance assessment with echocardiography. A direct relationship between body mass index and blood pressure (r=0.36; P<.01) was shown along with increments in fasting insulin levels. The underlying and progressive rise in insulin levels during blood pressure increase is named the insulin gradient. Left ventricular systolic indexes were significantly greater in the higher-insulin quartile. These findings suggest that body weight increases accompany a rise in systolic pressure and a drop in insulin sensitivity related to the insulin gradient. Increments in ejection fraction and cardiac output with normal total peripheral resistance are related to the blood pressure shift in these persons.
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              Addressing the unmet medical need for safe and effective weight loss therapies.

              Obesity is a significant healthcare problem worldwide and increases the risk of developing debilitating diseases including type 2 diabetes, cardiovascular disease, and cancer. Although the health benefits of weight reduction are well-recognized, weight loss by diet and exercise fail in most patients, and the current marketed drugs have had limited success. It is clear that there is a significant unmet medical need for safe and effective weight-reducing agents. In this review, the current status of potential weight loss approaches that are in development by the pharmaceutical and biotechnology industry are discussed. This should lead to novel treatments that can be used long-term to effectively treat this serious metabolic disorder.
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                Author and article information

                Journal
                Diabetes Metab Syndr Obes
                Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy
                Dove Medical Press
                1178-7007
                2011
                06 January 2011
                : 4
                : 5-16
                Affiliations
                [1 ]Pharmacology
                [2 ]Cellular and Molecular Biology
                [3 ]Pre-clinical and Safety Evaluation, Torrent Research Centre, Torrent Pharmaceuticals Ltd, Gujarat, India;
                [4 ]Dipartimento di Biologia, Universita degli Studi di Napoli Federico II, Naples, Italy;
                [5 ]Dipartimento di Scienze della Vita, Seconda Universita di Napoli, Caserta, Italy;
                [6 ]Dipartimento di Scienze Biologiche ed Ambientali, Universita del Sannio, Benevento, Italy;
                [7 ]Medicinal Chemistry
                [8 ]Discovery Research
                [9 ]Clinical Research, Torrent Research Centre, Torrent Pharmaceuticals Ltd, Gujarat, India
                Author notes
                Correspondence: Chaitanya Dutt, Torrent Research Centre, PO Bhat, Dist Gandhinagar 382428, Gujarat, India, Tel +91 79 2396 9100, Fax +91 79 2396 9135, Email cdutt@ 123456torrentpharma.com
                Article
                dmso-4-005
                10.2147/DMSOTT.S15323
                3064414
                21448317
                bcfa4aea-3eb1-4720-a2d5-3515f618839b
                © 2011 Zambad et al, publisher and licensee Dove Medical Press Ltd.

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                History
                : 31 December 2010
                Categories
                Original Research

                Endocrinology & Diabetes
                obesity,fatty acid oxidation,trc150094,energy expenditure,cv risk factors,type 2 diabetes

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