Nutrient infusion in the dorsal vagal complex controls hepatic lipid and glucose metabolism in rats

Abstract

Summary Hypothalamic regulation of lipid and glucose homeostasis is emerging, but whether the dorsal vagal complex (DVC) senses nutrients and regulates hepatic nutrient metabolism remains unclear. Here, we found in rats DVC oleic acid infusion suppressed hepatic secretion of triglyceride-rich very-low-density lipoprotein (VLDL-TG), which was disrupted by inhibiting DVC long-chain fatty acyl-CoA synthetase that in parallel disturbed lipid homeostasis during intravenous lipid infusion. DVC glucose infusion elevated local glucose levels similarly as intravenous glucose infusion and suppressed hepatic glucose production. This was independent of lactate metabolism as inhibiting lactate dehydrogenase failed to disrupt glucose sensing and neither could DVC lactate infusion recapitulate glucose effect. DVC oleic acid and glucose infusion failed to lower VLDL-TG secretion and glucose production in high-fat fed rats, while inhibiting DVC farnesoid X receptor enhanced oleic acid but not glucose sensing. Thus, an impairment of DVC nutrient sensing may lead to the disruption of lipid and glucose homeostasis in metabolic syndrome.

A glucose-sensing mechanism with glucose transporter 1 and pyruvate kinase in the area postrema regulates hepatic glucose production in rats

“…We detected a lack of glucoregulatory effect when glucose was infused into the NTS of 3 days HF-fed rats as well ( Fig. 5 , D – F ) as previously reported ( 10 ).

Figure 5 Short-term high fat feeding downregulates GLUT1 expression and disrupts AP and NTS glucose sensing mechanism.

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“…In the presence of LV-shMM injection, NTS-targeted glucose versus saline infusion increased glucose infusion rate during the clamps by suppressing glucose production ( Fig. 2 , C – E and Table S1 ), and these glucoregulatory effect of NTS glucose infusion was comparable in nonviral-injected rats ( 10 ). NTS glucose infusion failed to increase glucose infusion rate and lower glucose production in LV-shGLUT1–injected rats with GLUT1 knocked down in the NTS ( Fig.…”

“…The dosage of glucose (2 mM) infused into the AP is documented to activate NTS and hypothalamic glucose sensing to a comparable extent as systemic hyperglycemia ( 10 , 22 ). Herein, we found that glucose (2 mM) versus saline infusion into the AP increased the exogenous glucose infusion rate required to maintain euglycemia during the pancreatic (basal-insulin) clamps ( Fig.…”

“…In parallel, glucoprivic signals in the NTS increase food intake ( 8 ) but also activate counterregulatory responses to elevate plasma glucose levels ( 9 ). NTS glucose infusion that increases local glucose levels to a similar extent as seen with systemic hyperglycemia suppresses glucose production in rats as well ( 10 ). Similarly, the hypothalamus detects changes in glucose and fatty acid levels to not only regulate food intake but also hepatic glucose production ( 11 , 12 , 13 , 14 , 15 ).…”

“…Upon cellular uptake of glucose, subsequent metabolism to lactate -> pyruvate -> acetyl-CoA is sufficient and necessary for hypothalamic glucose-sensing to inhibit glucose production in chow male rats ( 11 ). In contrast, neither lactate infusion nor the disruption of lactate metabolism in the presence of glucose in the NTS alter glucose production ( 10 ). However, whether GLUT1 or pyruvate metabolism is required for NTS and/or potentially AP glucose-sensing mechanism to regulate glucose homeostasis remains to be investigated.…”