Glycine Normalizes Hepatic Triglyceride-Rich VLDL Secretion by Triggering the CNS in High-Fat Fed Rats

Abstract

Rationale: Dysregulation of hepatic triglyceride (TG)-rich very low-density lipoproteins (VLDL-TG) in obesityand type 2 diabetes contributes to the dyslipidemia that leads to cardiovascular morbidity. The central nervous system (CNS), particularly the hypothalamus, regulates hepatic lipid metabolism. Although the underlying neurocircuitry remains elusive, glycine has been documented to enhance CNS N-methyl-D-aspartate (NMDA) receptor-mediated transmission.Objective: We tested the hypothesis that glycine regulates hepatic VLDL-TG secretion by potentiating NMDA receptor-mediated transmission in the CNS. Methods and Results:Using 10-hour fasted male Sprague-Dawley rats implanted with stereotaxic cannulae into an extrahypothalamic region termed the dorsal vagal complex (DVC) and vascular catheters to enable direct DVC infusion and blood sampling, respectively, the rate of hepatic VLDL-TG secretion was measured following tyloxapol (an inhibitor of lipoprotein lipase) injection. Direct DVC infusion of glycine lowered VLDL-TG secretion, whereas NMDA receptor blocker MK-801 fully negated glycine's effect. NR1 subunit of NMDA receptor antagonist 7-chlorokynurenic acid, adenoviral injection of NR1 short hairpin RNA (shRNA), and hepatic vagotomy also nullified glycine's effect. Finally, DVC glycine normalized the hypersecretion of VLDL-TG induced by high-fat feeding. Key Words: glycine Ⅲ NMDA receptors Ⅲ CNS Ⅲ hepatic lipid metabolism Ⅲ obesity H ypertriglyceridemia and overproduction and secretion of VLDL-TG are key contributors to the metabolic syndrome and atherogenic dyslipidemia. 1-3 Although circulating insulin and free fatty acids (FFA) regulate hepatic VLDL-TG secretion, 4,5 the underlying regulatory mechanisms remain unclear. Given that diabetes and obesity are associated with hypertriglyceridemia and increased hepatic secretion and production of VLDL-TG, 1-3 it is important to elucidate the regulatory mechanisms of hepatic VLDL-TG secretion in a normal setting with the hope to discover novel therapeutic molecules to lower blood lipid levels in obesity and diabetes. Conclusions:In addition to the array of circulating factors that directly regulate hepatic lipid metabolism, the hypothalamic region of the brain senses circulating nutrients and hormones to regulate peripheral lipid homeostasis 6 -10 and blood pressure. 11 For example, nutrients such as glucose signal within the hypothalamus to inhibit VLDL-TG secretion through the hepatic vagus. 12 Consistent with the fact that nutrients in the brain lowers appetite through the suppression of neuropeptide Y, 13 direct administration of neuropeptide Y into the hypothalamus conversely stimulates VLDL-TG secretion. 9 Central neuropeptide Y signaling also negates the ability of circulating insulin to inhibit VLDL-TG secretion, 6 whereas hormones such as insulin, 8 ghrelin, 7 melanocortins, 14,15 and leptin 16,17 trigger hypothalamic signaling cascades to modulate peripheral lipid profiles. In spite of the fact that the hypothalamus regulates peripheral lipid metabolism, ...

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

“…N-methyl-D-aspartate (NMDA) receptor-mediated transmission in the DVC is sufficient and necessary for MBH nutrient sensing to lower glucose production 42,43 and is also sufficient to lower hepatic VLDL-TG secretion 27 . To begin delineating the neurocircuitry that mediates the lipid-lowering effect of MBH oleic acid sensing (Fig.…”

“…Hypothalamic neuropeptide Y infusion augments VLDL-TG secretion 23,24 and impairs the ability of insulin to inhibit VLDL-TG secretion 25 . In contrast, glucose sensing in the mediobasal hypothalamus (MBH) 26 and glycine in the dorsal vagal complex (DVC) 27 suppress hepatic secretion of VLDL-TG. To date, 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 VLDL-TG secretion, remain largely unknown.…”

Evidence for Central Regulation of Glucose Metabolism

“…Thus, the above work defined the role of hypothalamic SUR1-containing K ATP channels in modulating hepatic gluconeogenesis and suggested that central insulin mediates its effect on EGP via vagal nerve efferent signaling to the liver (12). Recent work has also implicated extra-hypotha- http://www.jbc.org/ Downloaded from lamic brain regions, such as the dorsal vagal complex, in regulating whole body glucose and lipid handling, and identified novel signaling pathways (26,27).…”

“…Thus, the above work defined the role of hypothalamic SUR1-containing K ATP channels in modulating hepatic gluconeogenesis and suggested that central insulin mediates its effect on EGP via vagal nerve efferent signaling to the liver (12). Recent work has also implicated extra-hypotha- http://www.jbc.org/ Downloaded from lamic brain regions, such as the dorsal vagal complex, in regulating whole body glucose and lipid handling, and identified novel signaling pathways (26,27).The mechanism whereby central insulin suppresses EGP appears to be via phosphorylation of hepatic signal transducer and activator of transcription 3 (STAT3) (28 -30). Mice with liver-specific STAT3 deficiency are insulin-resistant with increased gluconeogenic enzyme expression, whereas constitutive hepatic STAT3 activation improves glucose tolerance in diabetic mice (29).…”

Increasing Angiotensin-(1–7) Levels in the Brain Attenuates Metabolic Syndrome–Related Risks in Fructose-Fed Rats

“…16 Emerging evidence has also suggested that the sympathoinhibitor neurotransmitter nitric oxide (NO) [17][18][19] and the sympathoexcitatory neurotransmitter glutamate, through N-methyl-d-aspartate receptor (NMDAr), [20][21][22][23] play a role on energy metabolism. Recent data have shown that central lipid infusion by the carotid artery deregulates hepatic insulin signaling in rats, in part, by increasing neuronal NO synthase (nNOS) activity in hypothalamus, suggesting that nNOS in the hypothalamus might be involved with the development of insulin resistance.…”