A fatty acid-dependent hypothalamic–DVC neurocircuitry that regulates hepatic secretion of triglyceride-rich lipoproteins

• Published in: Nature communications 2015-01, Vol.6 (1), p.5970-5970, Article 5970
• Main Authors: Yue, Jessica T. Y., Abraham, Mona A., LaPierre, Mary P., Mighiu, Patricia I., Light, Peter E., Filippi, Beatrice M., Lam, Tony K. T.
• Format: Article
• Language: English
• Subjects: 631/378/3920; 631/45/287/1191; 692/308; Adenoviridae - metabolism; Animals; Apolipoproteins B - metabolism; Brain - metabolism; Fatty Acids - chemistry; Green Fluorescent Proteins - metabolism; Homeostasis; Humanities and Social Sciences; Hypothalamus - metabolism; Lipoproteins - secretion; Lipoproteins, VLDL; Liver - innervation; Liver - secretion; Male; multidisciplinary; Neurons - physiology; Oleic Acid - chemistry; Potassium Channels - metabolism; Protein Kinase C - metabolism; Rats; Rats, Sprague-Dawley; Science; Science (multidisciplinary); Triglycerides - metabolism; Triglycerides - secretion; Vagus Nerve - physiology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms6970

The brain emerges as a regulator of hepatic triglyceride-rich very-low-density lipoproteins (VLDL-TG). The neurocircuitry involved as well as the ability of fatty acids to trigger a neuronal network to regulate VLDL-TG remain unknown. Here we demonstrate that infusion of oleic acid into the mediobasal hypothalamus (MBH) activates a MBH PKC-δ→K ATP -channel signalling axis to suppress VLDL-TG secretion in rats. Both NMDA receptor-mediated transmissions in the dorsal vagal complex (DVC) and hepatic innervation are required for lowering VLDL-TG, illustrating a MBH-DVC-hepatic vagal neurocircuitry that mediates MBH fatty acid sensing. High-fat diet (HFD)-feeding elevates plasma TG and VLDL-TG secretion and abolishes MBH oleic acid sensing to lower VLDL-TG. Importantly, HFD-induced dysregulation is restored with direct activation of either MBH PKC-δ or K ATP -channels via the hepatic vagus. Thus, targeting a fatty acid sensing-dependent hypothalamic–DVC neurocircuitry may have therapeutic potential to lower hepatic VLDL-TG and restore lipid homeostasis in obesity and diabetes. The brain has a central role in the regulation of organismal energy homeostasis. Here the authors show that neurons in the mediobasal hypothalamus respond to fatty acids by generating neuronal signals, relayed to the liver via vagal nerves that mediate secretion of very-low-density lipoproteins.