Experimental dopaminergic neuron lesion at the area of the biological clock pacemaker, suprachiasmatic nuclei (SCN) induces metabolic syndrome in rats.

BACKGROUND: The daily peak in dopaminergic neuronal activity at the area of the biological clock (hypothalamic suprachiasmatic nuclei [SCN]) is diminished in obese/insulin resistant vs lean/insulin sensitive animals. The impact of targeted lesioning of dopamine (DA) neurons specifically at the area surrounding (and that communicate with) the SCN (but not within the SCN itself) upon glucose metabolism, adipose and liver lipid gene expression, and cardiovascular biology in normal laboratory animals has not been investigated and was the focus of this study. METHODS: Female Sprague-Dawley rats received either DA neuron neurotoxic lesion by bilateral intra-cannula injection of 6-hydroxydopamine (2-4 µg/side) or vehicle treatment at the area surrounding the SCN at 20 min post protriptyline ip injection (20 mg/kg) to protect against damage to noradrenergic and serotonergic neurons. RESULTS: At 16 weeks post-lesion relative to vehicle treatment, peri-SCN area DA neuron lesioning increased weight gain (34.8%, P < 0.005), parametrial and retroperitoneal fat weight (45% and 90% respectively, P < 0.05), fasting plasma insulin, leptin and norepinephrine levels (180%, 71%, and 40% respectively, P < 0.05), glucose tolerance test area under the curve (AUC) insulin (112.5%, P < 0.05), and insulin resistance (44%-Matsuda Index, P < 0.05) without altering food consumption during the test period. Such lesion also induced the expression of several lipid synthesis genes in adipose and liver and the adipose lipolytic gene, hormone sensitive lipase in adipose (P < 0.05 for all). Liver monocyte chemoattractant protein 1 (a proinflammatory protein associated with metabolic syndrome) gene expression was also significantly elevated in peri-SCN area dopaminergic lesioned rats. Peri-SCN area dopaminergic neuron lesioned rats were also hypertensive (systolic BP rose from 157 ± 5 to 175 ± 5 mmHg, P < 0.01; diastolic BP rose from 109 ± 4 to 120 ± 3 mmHg, P < 0.05 and heart rate increase from 368 ± 12 to 406 ± 12 BPM, P < 0.05) and had elevated plasma norepinephrine levels (40% increased, P < 0.05) relative to controls. CONCLUSIONS: These findings indicate that reduced dopaminergic neuronal activity in neurons at the area of and communicating with the SCN contributes significantly to increased sympathetic tone and the development of metabolic syndrome, without effect on feeding.

Erratum: Neuroendocrine and metabolic components of dopamine agonist amelioration of metabolic syndrome in SHR rats.

[This corrects the article DOI: 10.1186/1758-5996-6-104.].

Neuroendocrine and metabolic components of dopamine agonist amelioration of metabolic syndrome in SHR rats.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.