Biochemical mechanisms responsible for the attenuation of diabetic and obese conditions in ob/ob mice treated with dopaminergic agonists

Abstract

OBJECTIVE: We previously reported that a two week treatment with SKF 38393 (SKF, a dopamine D 1 receptor agonist), plus bromocriptine (BC, a dopamine D 2 receptor agonist) acted synergistically to normalize hyperphagia, body fat, hyperglycaemia and hyperlipidaemia in obaob mice. The present study further investigates the biochemical mechanisms triggered by this drug treatment. DESIGN: Six week old female C57BLa6J obaob mice were divided into three groups and treated for two weeks with either BC and SKF, vehicle (control), or vehicle and pair fed to match the drug-treated group's daily food intake. RESULTS: BCaSKF treatment reduced food consumption by 55%, and treated mice weighed less than either pair fed or ad libitum fed controls after two weeks of treatment. Moreover, oxygen consumption was increased by 2.4-fold and the respiratory quotient (RQ) decreased from 1.23 to 0.96 (indicating a reduction in de novo lipogenesis) by drug treatment relative to ad libitum fed controls, but these parameters were unaffected by pair feeding control mice. The treatment also reduced blood glucose and free fatty acids (FFA) relative to pair fed and ad libitum fed controls. BCaSKF treatment (but not pair feeding) concurrently reduced lipolysis, lipogenic enzyme activities and hepatic gluconeogenic enzyme activities. Treatment also increased hepatic concentrations of glycogen and xylulose-5-phosphate (X-5-P), a key stimulator of glycolysis. Finally, BCaSKF, but not pair feeding, reduced the circulating concentrations of thyroxine and corticosterone, two hormones known to increase lipolysis, lipogenesis and hyperglycaemia. Drug treatment also increased serum dehydroepiandrosterone (DHEA) sulfate concentrations, an inhibitor of body fat store accumulation. CONCLUSION: These ®ndings demonstrate that BCaSKF treatment not only normalizes hyperphagia of obaob mice, but also redirects several metabolic and endocrine activities, independent of its effects on feeding to improve the obese-diabetic syndrome in obaob mice.

Dopaminergic tone and obesity: an insight from prolactinomas treated with bromocriptine

“…The stimulated area under the oral glucose tolerance test curve was reduced by 46% while the stimulated area under the insulin curve was reduced by 30%. Treatment with SKF 38393 (dopamine D1 receptor agonist) plus BC (dopamine D2 receptor agonist) acted synergistically to normalize hyperphagia, body fat, hyperglycemia and hyperlipidemia in leptin-deficient Ob/Ob mice (12). This treatment not only normalized hyperphagia but redirected several metabolic and endocrine activities independent of its effects on feeding to improve the obese/diabetic syndrome in Ob/Ob mice.…”

Effects of Ovariectomy and 17<i>β</i>-Estradiol Replacement on Dopamine D2 Receptors in Female Rats: Consequences on Sucrose, Alcohol, Water Intakes and Body Weight

“…However, D2 receptors involvement in sucrose intake was not elucidated. On the one hand, previous studies reported that systemic [60] [61] [62] and intracerebral [63] bromocriptine administration in insulin-resistant animals, declined hepatic glucose production and gluconeogenesis, reduced adipose tissue lipolysis, and improved insulin sensitivity [43]. On the other hand, Hajnal et al [15] reported that D2 receptors were involved in heightened sucrose intake observed in the OLETF obese rat.…”

Tesofensine, a Novel Triple Monoamine Reuptake Inhibitor, Induces Appetite Suppression by Indirect Stimulation of α1 Adrenoceptor and Dopamine D1 Receptor Pathways in the Diet-Induced Obese Rat

“…These include reduced DA concentrations, impaired response to electrically evoked accumbal DA release, decreased basal tyrosine hydroxylase and DAT expression, as well as lower levels of D 2 receptor binding (Pothos et al, 1998;Geiger et al, 2008). Correspondingly, striatal D 2 receptor binding is inversely correlated to the degree of obesity in humans (Volkow and Wise, 2005), and D 2 receptor agonists produce hypophagia and weight loss in animal models of obesity (Scislowski et al, 1999;Davis et al, 2008). In addition, mesolimbic D 3 receptor function may also have a role in obesity, as suggested by findings of D 3 receptor agonist-induced hypophagia in DIO mice and increased adiposity in D 3 receptor knockout mice (McQuade et al, 2003;McQuade et al, 2004).…”

“…The finding that positive modulation of D 1 receptor function contributed to the anorexic effect of tesofensine is in agreement with the role of D 1 receptor receptors on feeding behavior. Accordingly, D 1 receptor stimulation reduces food intake and weight gain in mouse models of obesity (Scislowski et al, 1999;Bina and Cincotta, 2000;Kuo, 2002). The inhibitory effect of D 1 receptor activation on feeding is most likely linked to stimulated hypothalamic DA function, which can lead to suppression of hypothalamic orexigenic signaling (Kuo, 2002;Alberto et al, 2006).…”

“…Food intake and food depriviation have opposing effects on extracellular DA levels in the nucleus accumbens, as feeding stimulates DA release and turnover whereas food deprivation causes the opposite effects (Nelson and Gehlert, 2006). Several DA receptors may be effectors of increased DA availability during feeding episodes, as both D 1 , D 2 , and D 3 receptor agonists reduce food intake in animal models of obesity (Scislowski et al, 1999;McQuade et al, 2003;Davis et al, 2008).…”