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Metabolic abnormalities linked to obesity: Effects of dexfenfluramine in the corpulent rat

  • David N. Brindley
    Correspondence
    Address reprint requests to David N. Brindley, PhD, Lipid and Lipoprotein Research Group, 332 Heritage Medical Research Centre, Edmonton, Alberta, T6G 2S2 Canada.
    Affiliations
    Departments of Biochemistry and Surgery, Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada

    Lipid and Lipoprotein Research Group, Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada
    Search for articles by this author
  • James C. Russell
    Affiliations
    Departments of Biochemistry and Surgery, Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada

    Lipid and Lipoprotein Research Group, Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada
    Search for articles by this author
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      Abstract

      The JCR:LA-corpulent rat is a useful experimental model for the obese-diabetic-dyslipidemic syndrome that mimics the human condition and exhibits spontaneous development of atherosclerosis and myocardial lesions. A 30-day treatment of 6-month-old rats with dexfenfluramine 1, 2.5, and 5 mg per kilogram decreased body weight through loss of adipose tissue mass. The effect is caused primarily by the ability of dexfenfluramine to reduce food intake. The maximum depression of food intake and greatest weight loss is seen during the first 10 days of treatment in this experimental model; thereafter, body weight stabilizes. However, during this period, there is a marked decrease in serum concentrations of triglycerides, cholesterol, and insulin. Corpulent male rats were also treated from 6 to 37 weeks of age with dexfenfluramine 2.5 mg/kg. This also produces a sustained decrease in body weight and a decrease in circulating insulin concentrations. Preliminary evidence demonstrates a substantial decrease in the incidence of necrotic myocardial lesions produced by ischemic events. This study establishes that dexfenfluramine treatment can decrease the severity of associated risk factors for cardiovascular disease, namely obesity, diabetes, and dyslipidemias. Furthermore, we report the first evidence that long-term treatment with dexfenfluramine can largely prevent the occurrence of myocardial lesions and end-stage cardiovascular disease in this animal model prone to atherosclerosis.
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      References

        • Garratini S
        Central anorectic effects of phenylethylamines.
        in: Curtis-Prior PB Biochemical Pharmacology of Obesity. Elsevier, Amsterdam, The Netherlands1983: 243-262
        • Brindley DN
        Phenylethylamines and their effects on the synthesis of fatty acids, triacylglycerols and phospholipids.
        in: Curtis-Prior PB Biochemical Pharmacology of Obesity. Elsevier, Amsterdam, The Netherlands1983: 285-308
        • Brindley DN
        • Saxton J
        • Shahidullah A
        • et al.
        Possible relationships between changes in body weight set-point and stress metabolism after treating rats chronically with d-fenfluramine.
        Biochem Pharmacol. 1985; 34: 1265-1271
        • Storlien LH
        • Thornburn AW
        • Smyth GA
        • et al.
        Effect of d-fenfluramine on basal glucose turnover and fat-feeding—induced insulin resistance in rats.
        Diabetes. 1989; 38: 499-503
        • Arnaud O
        • Nathan C
        Antiobesity and lipid lowering agents with antidiabetic activity.
        in: Bailey CJ Flatt RP New Anti-Diabetic Drugs. Smith Gordon, London, UK1990: 133-142 (Miigata, Japan, Nishimura)
        • Brindley DN
        • Hales P
        • Al-Sieni All
        • et al.
        Sustained decreases in weight and serum insulin, glucose, triacylglycerol and cholesterol in JCR:LA-corpulent rats treated with d-fenfluramine.
        Br J Pharmacol. 1992; 105: 679-685
        • Vague J
        Different forms of human obesity.
        in: Curtis-Prior PB Biochemical Pharmacology of Obesity. Elsevier, Amsterdam, The Netherlands1983: 13-66
        • Bjorntorp P
        Classification of obese patients and complications related to the distribution of surplus fat.
        Nutrition. 1990; 6: 131-137
        • Després J-P
        • Moorjani S
        • Lupien PJ
        • et al.
        Regional distribution of body fat, plasma lipoproteins and cardiovascular disease.
        Arteriosclerosis. 1990; 10: 497-511
        • Reaven GM
        Role of insulin resistance in human disease.
        Diabetes. 1988; 37: 1595-1607
        • Pederson RA
        • Campos RV
        • Buchan AMJ
        • et al.
        Comparison of the enteroinsular axis in two strains of obese rat, the fatty Zucker and JCR:LA-corpulent.
        Int J Obes. 1991; 15: 461-470
        • Amy RM
        • Dolphin PJ
        • Pederson RA
        • et al.
        Atherogenesis in two strains of obese rats.
        in: The fatty Zucker and LA/N-corpulent. Atherosclerosis. 69. 1988: 199-209
        • Russell JC
        • Amy RM
        Early atherosclerotic lesions in a susceptible rat model: The LA/N-corpulent rat.
        Atherosclerosis. 1986; 60: 119-129
        • Russell JC
        • Amy RM
        Myocardial and vascular lesions in the LA/N-corpulent rat.
        Can J Physiol Pharmacol. 1986; 64: 1270-1280
        • Russell JC
        • Amy RM
        • Michaelis IV, OE
        • et al.
        Myocardial disease in the corpulent strains of rats.
        in: Sharfir E Frontiers in Diabetes Research. Lessons From Animal Diabetes. vol 4. Smith Gordon, London, UK1990: 402-407
        • Russell JC
        • Amy RM
        • Dolphin PJ
        Effect of dietary n-3 fatty acids on atherosclerosis prone JCR:LA-corpulent rats.
        Exp Mol Pathol. 1991; 55: 285-293
        • Russell JC
        • Koeslag DG
        • Amy RM
        • et al.
        Independence of myocardial disease in the JCR:LA-corpulent rat on plasma cholesterol concentration.
        Clin Invest Med. 1991; 14: 288-295
        • Russell JC
        • Amy RM
        • Manickavel V
        • et al.
        Prevention of myocardial disease in JCR:LA-corpulent rats by running.
        J Appl Physiol. 1989; 66: 1649-1655
        • Russell JC
        • Amy RM
        • Manickavel V
        • et al.
        Effects of chronic ethanol consumption in atherosclerosis-prone JCR:LA-corpulent rat.
        Arteriosclerosis. 1989; 9: 122-128
        • Russell JC
        • Koselag DG
        • Manickavel V
        • et al.
        Effects of advancing age and severe food restriction on pathological processes in the insulin resistant JCR:LA-corpulent rat.
        Diabetes Res. 1990; 15: 53-62
        • Samanin R
        Drugs affecting serotonin and feeding.
        in: Curtis-Prior PB Biochemical Pharmacology of Obesity. Elsevier, Amsterdam, The Netherlands1983: 339-356
        • Brindley DN
        Neuroendocrine regulation and obesity.
        Int J Obes. 1992; 16: S73-S79
        • Amatruda JM
        • Danahy SA
        • Cheng CL
        The effects of glucocorticoids on insulin-stimulated lipogenesis in primary cultures of rat hepatocytes.
        Biochem J. 1983; 212: 135-141
        • Plested CP
        • Taylor E
        • Brindley DN
        • et al.
        Interaction of insulin and dexamethasone in the control of pyruvate kinase activity and glucose metabolism in sheep adipose tissue.
        Biochem J. 1987; 247: 459-465
        • Brindley DN
        • Rolland Y
        Possible connections between stress, diabetes, obesity, hypertension and altered lipoprotein metabolism that may result in atherosclerosis.
        Clin Sci. 1989; 77: 453-461
        • Stojanovska L
        • Rosella G
        • Proietto J
        Evolution of dexamethasone-induced insulin resistance.
        Am J Physiol. 1990; 258: E748-E756
        • Randle PJ
        • Garland PB
        • Hales CN
        • et al.
        The glucose fatty acid cycle.
        in: Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1. 1963: 785-789
        • Bevilacqua S
        • Bonadonna R
        • Buzzigoli G
        • et al.
        Acute elevation of free fatty acid levels leads to hepatic insulin resistance in obese subjects.
        Metabolism. 1987; 36: 502-506
        • Hennes MMI
        • Shrago E
        • Kissebah AH
        Mechanism of free fatty acid effects on hepatocyte insulin receptor binding and processing.
        Obes Res. 1993; 1: 18-28
        • Brindley DN
        • Salter AM
        Hormonal regulation of the hepatic low density lipoprotein receptor: Relationship with the secretion of very low density lipoproteins.
        Prog Lipid Res. 1991; 30: 349-360
        • Brindley DN
        • McCann BS
        • Niaura R
        • et al.
        Stress and lipoprotein metabolism: Modulators and mechanisms.
        Metabolism. 1993; 42: 3-15
        • Rivera MP
        • Svec F
        Is cortisol involved in upper body obesity?.
        Med Hypotheses. 1989; 30: 95-100
        • Langley SC
        • York DA
        Glucocorticoid receptor numbers in the brain and liver of the obese Zucker rat.
        Int J Obes. 1992; 16: 135-143
        • York DA
        Central regulation of appetite and autonomic activity by CRH, glucocorticoids and stress.
        Prog Neuroendocrinol Immunol. 1992; 5: 153-165
        • Bray GA
        • York DA
        Hypothalamic and genetic obesity in experimental animals: An autonomic and endocrine hypothesis.
        Physiol Rev. 1979; 59: 719-809
        • Baulieu EE
        Contragestion and other clinical applications of RU486, an antiprogesterone, at the receptor.
        Science. 1989; 245: 1351-1357
        • Langley SC
        • York DA
        Effects of antiglucocorticoid RU486 on development of obesity in obese Math Eq Zucker rats.
        Am J Physiol. 1990; 259: R539-R544
        • Okada S
        • York DA
        • Bray GA
        Mifepristone (RU 486), a blocker of type II glucocorticoid and progestin receptors, reverses a dietary form of obesity.
        Am J Physiol. 1992; 262: R1106-R1110
        • Troxler RG
        • Sprague EA
        • Albanese RA
        • et al.
        The association of elevated plasma cortisol, and early atherosclerosis as demonstrated by coronary angiography.
        Atherosclerosis. 1977; 26: 151-162
        • Kaplan JR
        • Nanuck SB
        • Adams MR
        Plaque changes and arterial enlargement in atherosclerotic monkeys after manipulation of diet and social environment.
        Arterioscler Thromb. 1993; 26: 151-162
        • Haynes SG
        • Feinlieb M
        • Kannel WB
        The relationship of psychological factors to coronary heart disease in The Framingham Study. III. Eight year incidence of coronary heart disease.
        Am J Epidemiol. 1980; 111: 37-58