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      Roles of Fatty Acid Oversupply and Impaired Oxidation in Lipid Accumulation in Tissues of Obese Rats

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          Abstract

          To test the roles of lipid oversupply versus oxidation in causing tissue lipid accumulation associated with insulin resistance/obesity, we studied in vivo fatty acid (FA) metabolism in obese (Obese) and lean (Lean) Zucker rats. Indices of local FA utilization and storage were calculated using the partially metabolizable [9,10- 3H]-(R)-2-bromopalmitate ( 3H-R-BrP) and [U- 14C]-palmitate ( 14C-P) FA tracers, respectively. Whole-body FA appearance ( R a ) was estimated from plasma 14C-P kinetics. Whole-body FA oxidation rate ( R ox) was assessed using 3H 2O production from 3H-palmitate infusion, and tissue FA oxidative capacity was evaluated ex vivo. In the basal fasting state Obese had markedly elevated FA levels and R a , associated with elevated FA utilization and storage in most tissues. Estimated rates of muscle FA oxidation were not lower in obese rats and were similarly enhanced by contraction in both lean and obese groups. At comparable levels of FA availability, achieved by nicotinic acid, R ox was lower in Obese than Lean. In Obese rats, FA oxidative capacity was 35% higher than that in Lean in skeletal muscle, 67% lower in brown fat and comparable in other organs. In conclusion, lipid accumulation in non-adipose tissues of obese Zucker rats appears to result largely from systemic FA oversupply.

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          Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss.

          D Kelley, B Goodpaster, R. R. Wing … (1999)
          The current study was undertaken to investigate fatty acid metabolism by skeletal muscle to examine potential mechanisms that could lead to increased muscle triglyceride in obesity. Sixteen lean and 40 obese research volunteers had leg balance measurement of glucose and free fatty acid (FFA) uptake (fractional extraction of [9,10 (3)H]oleate) and indirect calorimetry across the leg to determine substrate oxidation during fasting and insulin-stimulated conditions. Muscle obtained by percutaneous biopsy had lower carnitine palmitoyl transferase (CPT) activity and oxidative enzyme activity in obesity (P < 0.05). During fasting conditions, obese subjects had an elevated leg respiratory quotient (RQ, 0.83 +/- 0.02 vs. 0.90 +/- 0.01; P < 0.01) and reduced fat oxidation but similar FFA uptake across the leg. During insulin infusions, fat oxidation by leg tissues was suppressed in lean but not obese subjects; rates of FFA uptake were similar. Fasting values for leg RQ correlated with insulin sensitivity (r = -0.57, P < 0.001). Thirty-two of the obese subjects were restudied after weight loss (WL, -14.0 +/- 0.9 kg); insulin sensitivity and insulin suppression of fat oxidation improved (P < 0.01), but fasting leg RQ (0.90 +/- 0.02 vs. 0.90 +/- 0.02, pre-WL vs. post-WL) and muscle CPT activity did not change. The findings suggest that triglyceride accumulation in skeletal muscle in obesity derives from reduced capacity for fat oxidation and that inflexibility in regulating fat oxidation, more than fatty acid uptake, is related to insulin resistance.
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            Minireview: weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndrome.

            Roger Unger (2003)
            The obesity crisis in the United States has been associated with an alarming increase in the prevalence of the metabolic syndrome (MSX) disease cluster. Here we review evidence that the MSX reflects a failure of a system of intracellular lipid homeostasis that prevents lipotoxicity in the organs of overnourished individuals by confining the lipid overload to cells specifically designed to store large quantities of surplus calories, the white adipocytes. Normally, early in obesity, adipocytes increase leptin and adiponectin secretion, hormones that enhance oxidation of surplus liquids in nonadipose tissues by activating AMP-activated protein kinase and reducing the activity and expression of lipogenic enzymes. These events combine to lower malonyl coenzyme A. Deficiency of and/or unresponsiveness to leptin prevents these protective events and results in ectopic accumulation of lipids. Increased de novo ceramide formation is probably the most damaging lipid and is a cause of lipoapoptosis, abetted by a decline in tissue Bcl-2. Pancreatic beta-cells and myocardiocytes are cellular victims of the process, leading to non-insulin-dependent diabetes and lipotoxic cardiomyopathy. The MSX is particularly prevalent in visceral obesity, probably because visceral adipocytes make less leptin than sc adipocytes. Cushing's syndrome, the lipodystrophy associated with protease inhibitor therapy of AIDS, polycystic ovarian disease, as well as diet-induced visceral obesity, all have a high waist/hip ratio, and all exhibit MSX. Increased lipid content in the heart and skeletal muscle organs of such patients is now under study.
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              Malonyl-CoA, a key signaling molecule in mammalian cells.

              David Saggerson (2007)
              Malonyl-CoA can be formed within the mitochondria, peroxisomes, and cytosol of mammalian cells. Besides being an intermediate in the pathways of de novo fatty acid biosynthesis and fatty acid elongation, malonyl-CoA has an important signaling function through its allosteric inhibition of carnitine palmitoyltransferase 1, the enzyme that normally exerts flux control over mitochondrial beta-oxidation. Malonyl-CoA is rapidly turned over in mammalian cells, and the activities of acetyl-CoA carboxylase and malonyl-CoA decarboxylase are important determinants of its cytosolic concentration. It is now recognized that malonyl-CoA participates in a diverse range of physiological or pathological responses and systems. These include the ketogenic response of the liver to fasting and diabetes, carbohydrate versus fat fuel selection in muscle tissues, metabolic changes in muscle during contracture, alterations in fatty acid metabolism during cardiac ischemia and postischemic reperfusion, stimulation of B cell insulin secretion by glucose, and the hypothalamic control of appetite.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Lipids
                Journal ID (iso-abbrev): J Lipids
                Journal ID (publisher-id): JL
                Title: Journal of Lipids
                Publisher: Hindawi Publishing Corporation
                ISSN (Print): 2090-3030
                ISSN (Electronic): 2090-3049
                Publication date (Print): 2013
                Publication date (Electronic): 13 May 2013
                Volume: 2013
                Electronic Location Identifier: 420754
                Affiliations
                1AstraZeneca R&D Mölndal, 431 83 Mölndal, Sweden
                2Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia
                3School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia
                Author notes

                Academic Editor: Philip W. Wertz

                Article
                DOI: 10.1155/2013/420754
                PMC ID: 3666279
                PubMed ID: 23762564
                SO-VID: 04b9d689-c547-4a53-b709-a960fa233933
                Copyright © Copyright © 2013 Nicholas D. Oakes et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 31 January 2013
                Date accepted : 19 April 2013
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Biochemistry
                Data availability:
                ScienceOpen disciplines: Biochemistry

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