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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.

Whole body fuel metabolism and energy balance are controlled by an interactive brain neuronal circuitry involving multiple brain centers regulating cognition, circadian rhythms, reward, feeding and peripheral biochemical metabolism. The hypothalamic supramammillary nucleus (SuMN) comprises an integral node having connections with these metabolically relevant centers, and thus could be a key central coordination center for regulating peripheral energy balance. This study investigated the effect of chronically diminishing or increasing SuMN neuronal activity on body composition and peripheral fuel metabolism. The influence of neuronal activity level at the SuMN area on peripheral metabolism was investigated via chronic (2-4 week) direct SuMN treatment with agents that inhibit neuronal activity (GABAa receptor agonist [Muscimol] and AMPA plus NMDA glutamate receptor antagonists [CNQX plus dAP5, respectively]) in high fat fed animals refractory to the obesogenic effects of high fat diet. Such treatment reduced SuMN neuronal activity and induced metabolic syndrome, and likewise did so in animals fed low fat diet including inducement of glucose intolerance, insulin resistance, hyperinsulinemia, hyperleptinemia, and increased body weight gain and fat mass coupled with both increased food consumption and feed efficiency. Consistent with these results, circadian-timed activation of neuronal activity at the SuMN area with daily local infusion of glutamate receptor agonists, AMPA or NMDA at the natural daily peak of SuMN neuronal activity improved insulin resistance and obesity in high fat diet-induced insulin resistant animals. These studies are the first of their kind to identify the SuMN area as a novel brain locus that regulates peripheral fuel metabolism.

Bromocriptine mesylate treatment was examined in dogs fed a high fat diet (HFD) for 8 wk. After 4 wk on HFD, daily bromocriptine (Bromo; n = 6) or vehicle (CTR; n = 5) injections were administered. Oral glucose tolerance tests were performed before beginning HFD (OGTT1), 4 wk after HFD began (Bromo only), and after 7.5 wk on HFD (OGTT3). After 8 wk on HFD, clamp studies were performed, with infusion of somatostatin and intraportal replacement of insulin (4× basal) and glucagon (basal). From 0 to 90 min (P1), glucose was infused via peripheral vein to double the hepatic glucose load; and from 90 to 180 min (P2), glucose was infused via the hepatic portal vein at 4 mg·kg−1·min−1, with the HGL maintained at 2× basal. Bromo decreased the OGTT glucose ΔAUC0–30and ΔAUC0–120by 62 and 27%, respectively, P < 0.05 for both) without significantly altering the insulin response. Bromo dogs exhibited enhanced net hepatic glucose uptake (NHGU) compared with CTR (~33 and 21% greater, P1 and P2, respectively, P < 0.05). Nonhepatic glucose uptake (non-HGU) was increased ~38% in Bromo in P2 ( P < 0.05). Bromo vs. CTR had higher ( P < 0.05) rates of glucose infusion (36 and 30%) and non-HGU (~40 and 27%) than CTR during P1 and P2, respectively. In Bromo vs. CTR, hepatic 18:0/16:0 and 16:1/16:0 ratios tended to be elevated in triglycerides and were higher ( P < 0.05) in phospholipids, consistent with a beneficial effect of bromocriptine on liver fat accumulation. Thus, bromocriptine treatment improved glucose disposal in a glucose-intolerant model, enhancing both NHGU and non-HGU.