503 Stimulation of the Paraventricular Nucleus Activates Brown Adipose Tissue via Local GABA Release: A Novel Target for the Treatment of Obesity

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INTRODUCTION: Sympathetic activation of brown adipose tissue (BAT) has shown significant promise in preclinical studies to elicit long term weight loss and reversal of type 2 diabetes however it is inhibited in obese individuals. METHODS: Rats were anesthetized and monitored for body temperature, BAT temperature, expired CO2, mean arterial pressure, and heart rate. Postganglionic BAT sympathetic nerve activity (SNA) was recorded from the interscapular BAT pad. Stimulating electrode and micropipette were placed steroeotactically in the PVN. Stimulation pulses at an intensity of 100 µA at 100 Hz for 5 minutes were delivered. Changes in BAT SNA and physiology were compared with and without stereotactically injected 500 µM bicuculline, a GABAA receptor antagonist. RESULTS: Stimulation of the PVN increased BAT SNA compared to no stimulation (411.7 ± 75.8% baseline vs 98.18 ± 1.4% baseline n = 5; P < 0.05) along with BAT temperature (35.8 ± 0.8°C vs 34.2 ± 0.7°C, n = 5, P < 0.001), expired CO2 (4.7 ± 0.6% vs 4.2 ± 0.5%, n = 5, P < 0.05) indicating increased metabolic rate. There was no change in blood pressure, body temperature, or paw temperature suggesting no change in sympathetic tone. Heart rate increased (476 ± 21 bpm vs 429 ± 23 bpm, n = 5, P < 0.01) consistent with increased metabolic demand. Microinjection of 500 µM bicuculline into the PVN prevented stimulated activation of BAT SNA. CONCLUSIONS: Stimulation of the PVN increases BAT activation and basal metabolic activity in the absence of cold-stimulus with minimal off-target effects on systemic sympathetic tone and may be a viable therapeutic target for stimulation of BAT activity to treat obesity and type 2 diabetes.

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