Tyrosine Hydroxylase Knockdown at the Hypothalamic Supramammillary Nucleus Area Induces Obesity and Glucose Intolerance

Introduction: The supramammillary nucleus (SuMN) exerts influences on a wide range of brain functions including feeding and feeding-independent fuel metabolism. However, which specific neuronal type(s) within the SuMN manifest this influence has not been delineated. This study investigated the effect of SuMN tyrosine hydroxylase (TH) (rate-limiting enzyme in dopamine synthesis) knockdown (THx) on peripheral fuel metabolism. Methods: SuMN-THx was accomplished using a virus-mediated shRNA to locally knockdown TH gene expression at the SuMN. The impact of SuMN-THx was examined over 35-72 days in rats least prone to developing metabolic syndrome (MS) - female Sprague-Dawley rats resistant to the obesogenic effect of high fat diet (HFDr) and fed regular chow (RC) - upon body weight/fat, feeding, glucose tolerance, and insulin sensitivity. The influence of HFD, gender, and long-term response of SuMN-THx was subsequently investigated in female HFDr rats fed HFD, male HFDr rats fed RC, and female HFD-sensitive rats fed RC over 1 year, respectively. Results: SuMN-THx induced obesity and glucose intolerance, elevated plasma leptin and triglycerides, increased hepatic mRNA levels of gluconeogenic, lipogenic, and pro-inflammatory genes, reduced white adipose fatty acid oxidation rate, and altered plasma corticosterone level and hepatic circadian gene expression. Moreover, SuMN-THx increased feeding during the natural resting/fasting period and altered ghrelin feeding response suggesting ghrelin resistance. This MS-inducing effect was enhanced by HFD feeding, similarly observed in male rats and persisted over 1 year. Discussion/Conclusion: SuMN-THx induced long-term, gender-nonspecific, multiple pathophysiological changes leading to MS suggesting SuMN dopaminergic circuits communicating with other brain metabolism and behavior control centers modulate peripheral fuel metabolism.