174-OR: Dorsal Vagal Complex Is a Site for Brain Lipid Sensing to Regulate Lipid Homeostasis

Abstract

Obesity and diabetes are characterized by dyslipidemia due partly to an overproduction of hepatic triglyceride-rich very-low-density lipoproteins (VLDL-TG). The hypothalamus regulates whole-body lipid homeostasis in rodents but whether extra-hypothalamic brain regions can impact lipid homeostasis remain unclear. We here assessed whether the dorsal vagal complex (DVC), a region in the brainstem which contains a circumventricular organ termed the area postrema, as well as the nucleus of the solitary tract and the dorsal motor nucleus of the vagus, senses oleic acids to regulate whole-body lipid homeostasis. We first surgically implanted a guide cannula into the DVC of male 280-300g rats for vehicle (3% cyclodextrin in saline) or oleic acid (1 mM dissolved in vehicle) infusion, followed by catheter placements (7 days after) in the left carotid artery and right jugular vein for sampling and infusion. After an additional 5 days of recovery, 10h-fasted rats received either vehicle or oleic acid pre-infusion to the DVC for 10 min, and DVC infusion was maintained for an additional 150 min after an i.v. injection of poloxamer (600 mg/kg; a lipoprotein lipase inhibitor), while plasma samples were collected every 15 min for TG measurement. The rate of plasma TG appearance as a function of time (slope) reflects the rate of VLDL-TG secretion in the current experimental context. DVC oleic acid vs. vehicle infusion (0.33 ul/h) lowered VLDL-TG secretion (mM/min) in healthy rats (0.032±0.003, n=7 vs. 0.049±0.006, n=5; p<0.001), but interestingly failed to do so in high-fat fed rats. Taken together, our findings indicate that: (i) the DVC is a novel site of fatty acid sensing that impacts whole-body lipid homeostasis by regulating hepatic VLDL-TG secretion, and (ii) a disruption in DVC fatty acid sensing may contribute to the overproduction of hepatic VLDL-TG and a disruption in lipid homeostasis in obesity and diabetes. Disclosure B. Batchuluun: None. T. Waise: None. J.T. Yue: None. T.K. Lam: None. Funding Canadian Institutes of Health Research