Abstract
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→KATP-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 KATP-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.
Highlights
The brain emerges as a regulator of hepatic triglyceride-rich very-low-density lipoproteins (VLDL-TG)
Given that hypothalamic hormone signalling regulates hepatic lipid metabolism while fatty acid sensing regulates feeding and glucose production, we tested whether oleic acid infusion into the mediobasal hypothalamus (MBH) regulates hepatic secretion of VLDL-TG in normal and high-fat diet (HFD)-induced hypertriglyceridemic rodents and characterized the associated MBH-sensing mechanisms and neurocircuitry (Fig. 1a)
In rats fasted for as little as 4 h, chylomicrons were barely detectable compared with fed rats[23], which suggest that chylomicrons do not contribute to the changes in VLDL-TG observed in the present study
Summary
The brain emerges as a regulator of hepatic triglyceride-rich very-low-density lipoproteins (VLDL-TG). The metabolic syndrome includes atherogenic dyslipidemia that is due partly to an overproduction of triglyceride-rich very-low-density lipoproteins (VLDL-TG) by the liver and hypertriglyceridemia[1,2] This disruption in lipid homeostasis manifests in obesity and diabetes[3,4]. The neurocircuitry involved in the central control of lipid homeostasis, as well as the ability of fatty acids to trigger a negative-feedback neuronal network to regulate hepatic VLDLTG secretion, remain largely unknown. Given that hypothalamic hormone signalling regulates hepatic lipid metabolism while fatty acid sensing regulates feeding and glucose production, we tested whether oleic acid infusion into the MBH regulates hepatic secretion of VLDL-TG in normal and high-fat diet (HFD)-induced hypertriglyceridemic rodents and characterized the associated MBH-sensing mechanisms and neurocircuitry (Fig. 1a). We show that MBH oleic acid sensory mechanisms trigger a MBH-DVC-hepatic vagal neuronal relay to regulate hepatic VLDL-TG secretion in vivo
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