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.
Among vertebrate species of the major vertebrate classes in the wild, a seasonal rhythm of whole body fuel metabolism, oscillating from a lean to obese condition, is a common biological phenomenon. This annual cycle is driven in part by annual changes in the circadian dopaminergic signalling at the suprachiasmatic nuclei (SCN), with diminution of circadian peak dopaminergic activity at the SCN facilitating development of the seasonal obese insulin-resistant condition. The present study investigated whether such an ancient circadian dopamine-SCN activity system for expression of the seasonal obese, insulin-resistant phenotype may be operative in animals made obese amd insulin resistant by high-fat feeding and, if so, whether reinstatement of the circadian dopaminergic peak at the SCN would be sufficient to reverse the adverse metabolic impact of the high-fat diet without any alteration of caloric intake. First, we identified the supramammillary nucleus as a novel site providing the majority of dopaminergic neuronal input to the SCN. We further identified dopamine D2 receptors within the peri-SCN region as being functional in mediating SCN responsiveness to local dopamine. In lean, insulin-sensitive rats, the peak in the circadian rhythm of dopamine release at the peri-SCN coincided with the daily peak in SCN electrophysiological responsiveness to local dopamine administration. However, in rats made obese and insulin resistant by high-fat diet (HFD) feeding, these coincident circadian peak activities were both markedly attenuated or abolished. Reinstatement of the circadian peak in dopamine level at the peri-SCN by its appropriate circadian-timed daily microinjection to this area (but not outside this circadian time-interval) abrogated the obese, insulin-resistant condition without altering the consumption of the HFD. These findings suggest that the circadian peak of dopaminergic activity at the peri-SCN/SCN is a key modulator of metabolism and the responsiveness to adverse metabolic consequences of HFD consumption. K E Y W O R D Scircadian, diabetes, dopamine, insulin sensitivity, suprachiasmatic nucleiThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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