Silencing of Supramammillary Nucleus (SuMN) Dopaminergic Neuronal Activity Induces the Obese Glucose Intolerant State

The “westernized” diet reduces brain dopamine synthesis and low brain striatal dopamine function has been associated with and implicated in potentiation of metabolic syndrome in animals and humans. However, hypothalamic dopamine function may be a more dominant regulator of peripheral fuel metabolism. The hypothalamic SuMN dopaminergic neurons project to the lateral septum, medial preoptic area, and suprachiasmatic nucleus, areas that prominently regulate both peripheral metabolism and striatal dopamine function. However, a causal role for such hypothalamic dopaminergic circuitry in modulating peripheral metabolism under normal feeding conditions has never been explored. This study therefore tested the impact of SuMN-selective knock-down of tyrosine hydroxylase (TH, the rate-limiting enzyme for dopamine synthesis) gene expression using AAV-mediated shRNA targeting TH (AAV-TH shRNA) on peripheral fuel metabolism in 14 weeks old rats fed standard low fat rodent chow (RC). Rats were micro-infused at the SuMN with either AAV-TH shRNA (N=12) or AAV-scrambled shRNA [control] (N=10) and maintained on RC ad lib for 77 days to assess changes in body weight (BW), glucose tolerance and fat metabolism. SuMN-selective TH knock down increased BW gain (54%, p=0.0005), total white adipose tissue mass (43%, p=0.012), feed efficiency (BW gain /g food) (25%, p= 0.048) and cumulative food consumption (15%, p= 0.0001) vs. control. SuMN-selective TH knock down increased glucose tolerance test glucose area under curve (AUC) by 27% (p=0.009) with no change in insulin AUC (p=0.99) vs. control. Such knock down also reduced adipose tissue mitochondrial fatty acid oxidation (FAO) rate (basal oxygen consumption rate 51%, p< 0.0001; endogenous FAO rate 58%, p< 0.0001; and exogenous FAO 54%, p=0.024). These findings indicate that reduced SuMN dopaminergic neuronal activity facilitates dysglycemia and obesity while reducing fat energy expenditure and increasing food consumption.