title: Glycine normalizes hepatic triglyceride-rich VLDL secretion by triggering the CNS in high-fat fed rats.
abstract: BACKGROUND
  Dysregulation of hepatic triglyceride (TG)-rich very low-density lipoproteins (VLDL-TG) in obesity and 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.
  
  
  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.
  
  
  CONCLUSIONS
  Molecular and pharmacological inhibition of the NR1-containing NMDA receptors in the DVC negated the ability of glycine to inhibit hepatic secretion of VLDL-TG in vivo. Importantly, the hypersecretion of VLDL-TG from the liver induced by a model of high-fat feeding was restored by the hepatic lipid control of CNS glycine sensing. These findings collectively suggest that glycine or glycine analogues may have therapeutic benefits in lowering plasma lipid levels in diabetes and obesity by triggering the CNS.
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, ON, Canada.
authors.forename: Jessica T Y
authors.initials: JT
authors.lastname: Yue
authors.forename: Patricia I
authors.initials: PI
authors.lastname: Mighiu
authors.forename: Mark
authors.initials: M
authors.lastname: Naples
authors.forename: Khosrow
authors.initials: K
authors.lastname: Adeli
authors.forename: Tony K T
authors.initials: TK
authors.lastname: Lam
mesh_terms: D052242:Adiponectin / Q000097:blood; D000818:Animals; D015243:Cholesterol, VLDL / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D004041:Dietary Fats / Q000494:pharmacology; D050171:Dyslipidemias / Q000188:drug therapy / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005998:Glycine / Q000378:metabolism* / Q000494:pharmacology; D007031:Hypothalamus / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000097:blood; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism*; D014628:Vagotomy
chemical_list: D052242:Adiponectin; D015243:Cholesterol, VLDL; D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D020738:Leptin; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D014280:Triglycerides; D013230:Stearoyl-CoA Desaturase; D005998:Glycine