Lipostatic and ischymetric mechanisms originate dexfenfluramine-induced anorexia

Even, Patrick C.; Coulaud, H; Nicolaı̈dis, Stylianos

doi:10.1016/0091-3057(88)90429-7

Cited by 15 publications

(9 citation statements)

References 25 publications

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“…An increase in lipid oxidation and a decrease in carbohydrate oxidation in rats receiving intraperitoneal injections of ≤10 mg dexfenfluramine/kg daily was shown (37). Ruminant studies of fenfluramine have also shown preferential lipid oxidation (63), as have rat studies (34)(35)(36). More recent studies have shown enhanced utilization of fatty acids in humans (38).…”

Section: Discussionmentioning

confidence: 98%

“…In addition to an anorectic effect, dexfenfluramine has been shown to be thermogenic under fasting or postprandial conditions in rats (24)(25)(26)(27)(28), although there is conflicting evidence of serotoninergic thermogenesis in humans (18,(29)(30)(31)(32)(33). Preliminary evidence also shows alterations in oxidative capacity, specifically, an increase in fat oxidation, in both animal models (34)(35)(36)(37) and humans (38).…”

Section: Introductionmentioning

confidence: 99%

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Effect of dietary manipulation on substrate flux and energy balance in obese women taking the appetite suppressant dexfenfluramine

Poppitt

Swann

Murgatroyd

et al. 1998

The American Journal of Clinical Nutrition

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Background: Studies in lean men show poor regulation of energy (EB) and fat balance (FB) during manipulation of dietary ratios of fat to carbohydrate. High-fat (HF), high-energy diets cause hyperphagia and a positive EB and FB. Objective: The protocol was designed to measure substrate flux and EB in obese women taking dexfenfluramine (DF) or placebo (PL) during an HF (50% of energy) or low-fat (25% of energy; LF) diet. We hypothesized that alterations in dietary fat would not be regulated and would lead to a positive EB and FB. Design: The study was double-blind, randomized, and placebocontrolled, with 4 treatments (LF/DF, HF/DF, LF/PL, and HF/PL) and a crossover. Five days of continuous, whole-body calorimetry measurements were made in 6 subjects after 8 d of home DF/PL treatment. Macronutrient balance and EB were measured within the chamber as the cumulative difference between ad libitum intake and oxidation. Conclusions: EB and FB are poorly regulated with HF, energydense diets in obese women, which leads to fat deposition and weight gain.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Effect of dietary manipulation on substrate flux and energy balance in obese women taking the appetite suppressant dexfenfluramine

Poppitt

Swann

Murgatroyd

et al. 1998

The American Journal of Clinical Nutrition

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“…Even and Nicolai'dis [17] and Even et al [ 18] reported that dF increased EE, and rate of glucose oxidation during periods of en hanced LA as compared with pair-fed rats. The data of our pair-feeding experiments showed a similar behavior of both pair-fed dF and saline-injected parallel groups with re spect to EE and glucose and fatty acid oxida tion rates during periods of spontaneous phys ical activity (data not shown).…”

Section: Itmentioning

confidence: 99%

“…In iso lated muscle cells, an insulin-permissive ef fect was found [16]. Even and Nicolaidis [17] and Even et al [18] found an enhanced re lease and utilization of free fatty acids and/or an enhancement of metabolic rate during spontaneous locomotor activity after admin istration of dF to normal rats and postulated the so-called 'lipostatic, ischymetric mecha nism' for body weight reduction. In contrast to that, Scheurink et al [19] found that dF improved both carbohydrate utilization and sensitivity to norepinephrine in normal rats during a 7-day treatment.…”

Section: Introductionmentioning

confidence: 99%

Energy Expenditure and Substrate Oxidation Rates of Obese Rats during a 12-Day Treatment with Dexfenfluramine

Boschmann

Aust²,

Frenz³

et al. 1996

Ann Nutr Metab

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Serotoninergic neuronal networks are included in regulation and modification of eating behavior and energy metabolism. Dexfenfluramine (dF), a serotonin releaser and reuptake inhibitor, was used to investigate changes in food intake, body weight development, energy expenditure, respiratory quotient, and substrate oxidation rates for 12 days. Rats which had been made obese by postnatal overfeeding received an energy-controlled mash diet and water ad libitum and were intraperitoneally injected with either saline or 5 or 10 mg dF/kg. As compared with controls, food intake and energy expenditure were significantly decreased in a dose-dependent manner, especially during the first 6 days. Lipid oxidation was increased, while the oxidation of carbohydrates was decreased. The body weight was only slightly reduced after 2 days of dF treatment. After 4 days, dF-treated rats resumed body weight, but as compared with controls both dF groups exhibited lower body weights at the end of the experiment. After 12 days the plasma glucose concentration was unchanged, whereas plasma free fatty acids were significantly decreased. Plasma insulin levels were unchanged after dF, but 10 mg dF/kg led to increased muscle and, especially, liver glycogen contents, indicating an improved nonoxidative glucose disposal. Muscle pyruvate kinase was slightly but not significantly increased after dF treatment but that of the liver was significantly decreased, indicating a reduced glycolytic activity of the liver. Whereas the renal N excretion was rather decreased, the plasma concentrations of urea, citrulline, arginine, and ornithine were increased, and the liver contents of glutamine and arginine were decreased. Possibly, there is a shift of ammonia removal from glutamine synthesis to production of urea. The sum of all large neutral amino acids in muscle was significantly decreased after dF treatment, indicating a diminished proteolysis. Pair-feeding experiments over 2 days revealed that this was not solely a result of diminished food intake, but also an additional metabolic effect of dF, different from its anorectic effect. It is concluded that both increased oxidation of endogenous fat and reduced food intake could mediate the body weight reducing effect of dF.

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“…Even et al [19,20] found an enhanced release and utilization of free fatty acids and/or an enhanced metabolic rate during spontaneous locomotor activity after DF administration to normal rats and postulated a 'lipostatic, ischymetric mechanism' for body weight reduction. Scheurink et al [21] reported improvements in both carbohydrate utilization and sensitivity to norepinephrine in normal rats during a 7-day treatment with DF.…”

Section: Introductionmentioning

confidence: 99%

In situ Metabolic and Hemodynamic Response to Dexfenfluramine in White Adipose Tissue of Rats

Boschmann

Adams²,

Schimrigk³

2001

Ann Nutr Metab

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Serotonergic neurons are included in the regulation of eating behavior and energy metabolism. Dexfenfluramine (DF), a serotonin releaser and reuptake inhibitor, is known to reduce food intake and body weight and to improve the metabolic profile of obese subjects with and without metabolic complications such as type 2 diabetes. Due to cases of valvular heart diseases, DF was withdrawn from the market in 1997. However, serotonergic drugs are still used in clinical practice. We studied the hemodynamic and metabolic changes induced by in situ perfusion of inguinal subcutaneous adipose tissue (SAT) of normal-weight rats with either 1 µM isoproterenol (IP) or 5 µMDF using the microdialysis technique. Perfusion of SAT with IP resulted in an increase in blood flow (+25%) and lipolysis (+35%) when compared to baseline. In contrast to that, perfusion of SAT with DF resulted in a decrease in blood flow (–25%) and lipolysis (–35%). Additionally, dialysate glucose was decreased and dialysate lactate was increased during perfusion with DF, indicating stimulation of glucose uptake and the glycolytic pathway. It is concluded that DF reduces blood flow and lipolysis whereas it stimulates the glycolytic pathway in SAT and that this could contribute to the positive metabolic outcome, i.e., lowered blood lipids and fat mass of DF-treated obese subjects.

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Lipostatic and ischymetric mechanisms originate dexfenfluramine-induced anorexia

Cited by 15 publications

References 25 publications

Effect of dietary manipulation on substrate flux and energy balance in obese women taking the appetite suppressant dexfenfluramine

Effect of dietary manipulation on substrate flux and energy balance in obese women taking the appetite suppressant dexfenfluramine

Energy Expenditure and Substrate Oxidation Rates of Obese Rats during a 12-Day Treatment with Dexfenfluramine

In situ Metabolic and Hemodynamic Response to Dexfenfluramine in White Adipose Tissue of Rats

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