The online version of this article (doi:10.1186/1758-5996-6-104) contains supplementary material, which is available to authorized users.
An erratum to this article is available at http://dx.doi.org/10.1186/s13098-015-0056-x.
Michael Ezrokhi, Shuqin Luo, Yelena Trubitsyna, and Anthony H. Cincotta are all employees of VeroScience, a company that developed and via partnership markets Cycloset, the active agent of which is bromocriptine, for the treatment of type 2 diabetes in the U.S. Anthony H. Cincotta serves as the President and Chief Scientific Officer and is a shareholder of VeroScience. VeroScience holds patents relating to the metabolic effects of bromocriptine.
ME made substantial contributions to 1) conception and design, acquisition of data, analysis and interpretation of data; 2) was involved in drafting the manuscript and revising it critically for important intellectual content; 3) gave final approval of the version to be published; and 4) agrees to be accountable for all aspects of the work. SL made substantial contributions to 1) conception and design, acquisition of data, analysis and interpretation of data; 2) was involved in drafting the manuscript and revising it critically for important intellectual content; 3) gave final approval of the version to be published; and 4) agrees to be accountable for all aspects of the work. YT made substantial contributions to 1) acquisition of data, analysis of data; 2) was involved in drafting the manuscript and revising it critically for important intellectual content; 3) gave final approval of the version to be published; and 4) agrees to be accountable for all aspects of the work. AHC made substantial contributions to 1) conception and design, acquisition of data, analysis and interpretation of data; 2) was involved in drafting the manuscript and revising it critically for important intellectual content; 3) gave final approval of the version to be published; and 4) agrees to be accountable for all aspects of the work. All authors read and approved the final manuscript.
The hypertensive, pro-inflammatory, obese state is strongly coupled to peripheral and hepatic insulin resistance (in composite termed metabolic syndrome [MS]). Hepatic pro-inflammatory pathways have been demonstrated to initiate or exacerbate hepatic insulin resistance and contribute to fatty liver, a correlate of MS. Previous studies in seasonally obese animals have implicated an important role for circadian phase-dependent increases in hypothalamic dopaminergic tone in the maintenance of the lean, insulin sensitive condition. However, mechanisms driving this dopaminergic effect have not been fully delineated and the impact of such dopaminergic function upon the above mentioned parameters of MS, particularly upon key intra-hepatic regulators of liver inflammation and lipid and glucose metabolism have never been investigated.
This study therefore investigated the effects of timed daily administration of bromocriptine, a potent dopamine D2 receptor agonist, on a) ventromedial hypothalamic catecholamine activity, b) MS and c) hepatic protein levels of key regulators of liver inflammation and glucose and lipid metabolism in a non-seasonal model of MS - the hypertensive, obese SHR rat.
Sixteen week old SHR rats maintained on 14 hour daily photoperiods were treated daily for 16 days with bromocriptine (10 mg/kg, i.p.) or vehicle at 1 hour before light offset and, subsequent to blood pressure recordings on day 14, were then utilized for in vivo microdialysis of ventromedial hypothalamic catecholamine activity or sacrificed for the analyses of MS factors and regulators of hepatic metabolism. Normal Wistar rats served as wild-type controls for hypothalamic activity, body fat levels, and insulin sensitivity.
Bromocriptine treatment significantly reduced ventromedial hypothalamic norepinephrine and serotonin levels to the normal range and systolic and diastolic blood pressures, retroperitoneal body fat level, plasma insulin and glucose levels and HOMA-IR relative to vehicle treated SHR controls. Such treatment also reduced plasma levels of C-reactive protein, leptin, and norepinephrine and increased that of plasma adiponectin significantly relative to SHR controls. Finally, bromocriptine treatment significantly reduced hepatic levels of several pro-inflammatory pathway proteins and of the master transcriptional activators of lipogenesis, gluconeogenesis, and free fatty acid oxidation versus control SHR rats.
These findings indicate that in SHR rats, timed daily dopamine agonist treatment improves hypothalamic and neuroendocrine pathologies associated with MS and such neuroendocrine events are coupled to a transformation of liver metabolism potentiating a reduction of elevated lipogenic and gluconeogenic capacity. This liver effect may be driven in part by concurrent reductions in hyperinsulinemia and sympathetic tone as well as by reductions in intra-hepatic inflammation.
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- Neuroendocrine and metabolic components of dopamine agonist amelioration of metabolic syndrome in SHR rats
Anthony H Cincotta
- BioMed Central
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