Hypothalamic Protein Kinase C Regulates Glucose Production

Ross, Rachel; Wang, Penny Y.T.; Chari, Madhu; Lam, Carol K.L.; Caspi, Liora; Ono, Hiraku; Muse, Evan D.; Li, Xiaosong; Gutiérrez‐Juárez, Roger; Light, Peter E.; Schwartz, Gary J.; Rossetti, Luciano; Lam, Tony K.T.

doi:10.2337/db08-0206

Cited by 50 publications

(41 citation statements)

References 31 publications

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“…Concurrent DVC infusion (0.33 ml per h) in one study consisted of (xi) saline, (xii) MK-801 (0.06 ng min À 1 ) or (xiii) glycine (10 mmol l À 1 ) with MBH vehicle or MBH oleic acid (1 mmol l À 1 ) infusion. These infusate doses were used based on studies involving glucose regulation and/or feeding 28,33,43,54 . Infusions of inhibitors, when used, or saline as a control, commenced at t ¼ À 20 min, and infusions of other reagents commenced at t ¼ À 10 min and were maintained until the end of the experiment at t ¼ 150 min.…”

Section: Methodsmentioning

confidence: 99%

“…2a,b). MBH PKC-d was first tested since the activation of MBH PKC-d is necessary for lipids to lower glucose production 33 and glucagon-like peptide 1 to regulate insulin sensitivity 34 . Further, oleic acid directly activates PKC-d in hepatocytes 35 .…”

Section: Mbh Oleic Acid Infusion Lowers Vldl-tg Secretionmentioning

confidence: 99%

“…Given that the activation of MBH K ATP -channels is necessary for lipid-PKC activation to lower glucose production 33 , we addressed the role of MBH K ATP -channels in the VLDL-TG lowering effect of MBH oleic acid-PKC-d signalling via chemical and molecular loss-of-function approaches (Fig. 4a,b).…”

Section: Mbh K Atp -Channel Activation Lowers Vldl-tg Secretionmentioning

confidence: 99%

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

et al. 2015

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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-d-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-d 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.

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Section: Methodsmentioning

confidence: 99%

Section: Mbh Oleic Acid Infusion Lowers Vldl-tg Secretionmentioning

confidence: 99%

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

et al. 2015

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“…Thus, hypothalamic K ATP channels were established as a common pathway for central insulin, glucose, and fatty acid sensing in rat models. Some of the molecular mechanisms of hypothalamic K ATP channel lipid sensing were later clarified; hypothalamic protein kinase C (PKC) activation was necessary for central lipid administration to modulate EGP in rats (52). Conversely, central insulin also seems to modulate peripheral lipid metabolism because central insulin administration restrains lipolysis in white adipose tissue, whereas mice lacking central insulin receptors have unrestrained white adipose tissue lipolysis (53).…”

Section: Evidence For Cns Nutrient and Hormone Sensing In Animalsmentioning

confidence: 99%

Evidence for Central Regulation of Glucose Metabolism

Carey

Kehlenbrink

Hawkins

2013

Journal of Biological Chemistry

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Evidence for central regulation of glucose homeostasis is accumulating from both animal and human studies. Central nutrient and hormone sensing in the hypothalamus appears to coordinate regulation of whole body metabolism. Central signals activate ATP-sensitive potassium (K ATP ) channels, thereby down-regulating glucose production, likely through vagal efferent signals. Recent human studies are consistent with this hypothesis. The contributions of direct and central inputs to metabolic regulation are likely of comparable magnitude, with somewhat delayed central effects and more rapid peripheral effects. Understanding central regulation of glucose metabolism could promote the development of novel therapeutic approaches for such metabolic conditions as diabetes mellitus.The estimated global prevalence of Type 2 diabetes (T2DM) 2 is 347 million (1). Because glycemic control is achieved in only ϳ40% of patients, additional therapeutic strategies are needed (2). Increased endogenous glucose production (EGP) is the main source of fasting hyperglycemia (3, 4), contributing ϳ80% of diurnal hyperglycemia in T2DM (5). Apart from insulin, there is no treatment targeting basal EGP. Better understanding its regulation would have important therapeutic implications. We will examine the evidence for central sensing of nutritional and hormonal signals in animal models and humans, focusing on CNS regulation of glucose metabolism. Evidence for CNS Nutrient and Hormone Sensing in AnimalsUnlike other organs, the brain is an obligate consumer of glucose (6). Central regulation of EGP would therefore be teleologically advantageous. Since the first demonstration by Claude Bernard (7) that lesions in the floor of the fourth ventricle altered blood glucose levels, the ability of central glucose sensing to regulate peripheral glucose homeostasis has been extensively examined in animal models. There are glucosesensing neurons in many areas of the brain (8), particularly the hypothalamus (9). Specifically, the ventromedial hypothalamus (VMH) and arcuate nucleus (10) integrate hormonal and nutrient signals impacting peripheral metabolism (Fig. 1). Central signals appear to activate hypothalamic ATP-sensitive potassium (K ATP ) channels (9,11,12) composed of an inward rectifier potassium ion channel Kir6.2 subunit and a sulfonylurea receptor (SUR) subunit. Pharmacologic compounds including diazoxide activate and thereby close hypothalamic K ATP channels, whereas sulfonylureas inhibit and thereby open them, ultimately modulating EGP (12).Glucose-Elegant studies in rats showed that direct infusion of D-glucose into the VMH inhibited counterregulatory hormonal responses to systemic hypoglycemia during a hypoglycemic clamp, indicating that VMH glucose sensing is needed for the systemic response to peripheral hypoglycemia (13). VMH infusion of L-lactate, a byproduct of glucose metabolism and an alternate fuel source for neurons in conditions of glucose deficiency, produced similar suppression of the counterregulatory hormonal response to systemic...

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“…1b). The use of the pancreatic-euglycemic clamp technique and tracer-dilution methodology allows for the assessment of the effects that treatments have on the rate of hepatic glucose production and peripheral glucose uptake independent of differences among groups in peripheral circulating insulin and glucose levels (7,18,24). During the pancreatic clamp, when circulating insulin and glucose were maintained at near basal levels (supplemental Table S1), DVC glycine administration mark-FIGURE 2.…”

Section: Dvc Glycinementioning

confidence: 99%

Activation of N-Methyl-d-aspartate (NMDA) Receptors in the Dorsal Vagal Complex Lowers Glucose Production

Lam

Chari

et al. 2010

Journal of Biological Chemistry

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Diabetes is characterized by hyperglycemia due partly to increased hepatic glucose production. The hypothalamus regulates hepatic glucose production in rodents. However, it is currently unknown whether other regions of the brain are sufficient in glucose production regulation. The N-methyl-D-aspartate (NMDA) receptor is composed of NR1 and NR2 subunits, which are activated by co-agonist glycine and glutamate or aspartate, respectively. Here we report that direct administration of either co-agonist glycine or NMDA into the dorsal vagal complex (DVC), targeting the nucleus of the solitary tract, lowered glucose production in vivo. Direct infusion of the NMDA receptor blocker MK-801 into the DVC negated the metabolic effect of glycine. To evaluate whether NR1 subunit of the NMDA receptor mediates the effect of glycine, NR1 in the DVC was inhibited by DVC NR1 antagonist 7-chlorokynurenic acid or DVC shRNA-NR1. Pharmacological and molecular inhibition of DVC NR1 negated the metabolic effect of glycine. To evaluate whether the NMDA receptors mediate the effects of NR2 agonist NMDA, DVC NMDA receptors were inhibited by antagonist D-2-amino-5-phosphonovaleric acid (D-APV). DVC D-APV fully negated the ability of DVC NMDA to lower glucose production. Finally, hepatic vagotomy negated the DVC glycine ability to lower glucose production. These findings demonstrate that activation of NR1 and NR2 subunits of the NMDA receptors in the DVC is sufficient to trigger a brain-liver axis to lower glucose production, and suggest that DVC NMDA receptors serve as a therapeutic target for diabetes and obesity.Diabetes and obesity are partly characterized by a disruption in glucose homeostasis. An elevation of glucose production and/or a decrease in glucose uptake lead to a rise in plasma glucose levels and the breakdown of gluco-regulatory homeostatic mechanisms. In fact, an increased production of glucose by the liver is determined to be the major contributing factor to fasting hyperglycemia in type 2 diabetes (1).To date, the mechanisms underlying the regulation of hepatic glucose production and homeostasis in healthy and obese/diabetic conditions remain to be elucidated. In this regard, the hypothalamus detects a rise in nutrients and hormones to regulate peripheral glucose homeostasis and specifically lower glucose production (2-14). However, the neuronal network that controls glucose homeostasis remains unclear.The N-methyl-D-aspartate (NMDA) 5 receptor is composed of NR1 and NR2 subunits, which are activated by co-agonist glycine and glutamate or aspartate, respectively (15). NMDA is a selective agonist of NMDA receptors and NMDA receptors are fundamental to excitatory neurotransmission (Fig. 1a). In the CNS, the NMDA receptors have important roles in synaptic plasticity and neuronal development (16). In addition, direct administration of NMDA receptor blocker into the DVC negates the ability of lipid/cholecystokinin-sensing mechanisms in the gut to regulate glucose production (17, 18). However, it remains unknown whether direct a...

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Hypothalamic Protein Kinase C Regulates Glucose Production

Cited by 50 publications

References 31 publications

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

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

Evidence for Central Regulation of Glucose Metabolism

Activation of N-Methyl-d-aspartate (NMDA) Receptors in the Dorsal Vagal Complex Lowers Glucose Production

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