A brain-liver circuit regulates glucose homeostasis

Pocai, Alessandro; Obici, Silvana; Schwartz, Gary J.; Rossetti, Luciano

doi:10.1016/j.cmet.2004.11.001

Cited by 347 publications

(320 citation statements)

References 39 publications

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“…Capsaicin-induced lesion of vagal afferents in the common hepatic branch prevented these effects, suggesting that vagal afferent information from the liver may protect against metabolic consequences induced by excessive energy storage in the liver (Uno et al, 2006). Since vagal efferents in the common hepatic branch are important for the suppression of hepatic glucose production when the hypothalamic nutrient sensor is stimulated by nutrient repletion signals such as insulin or fatty acid oxidation (Pocai et al, 2005b;Pocai et al, 2005a), ablation of vagal efferents innervating the liver could play an additional supportive role in the development of obesity. In support of this, rats with selective common hepatic branch vagotomies where slightly hyperphagic and gained weight more rapidly when fed sweet milk (Kraly et al, 1986).…”

Section: Role Of Vagal Innervation Of Pancreas Liver and Other Abdomentioning

confidence: 99%

The vagus nerve, food intake and obesity

Berthoud

2008

Regulatory Peptides

259

197

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Food interacts with sensors all along the alimentary canal to provide the brain with information regarding its composition, energy content, and beneficial effect. Vagal afferents innervating the gastrointestinal tract, pancreas, and liver provide a rapid and discrete account of digestible food in the alimentary canal, as well as circulating and stored fuels, while vagal efferents together with the sympathetic nervous system and hormonal mechanisms codetermine the rate of nutrient absorption, partitioning, storage, and mobilization. Although vagal sensory mechanisms play a crucial role in the neural mechanism of satiation, there is little evidence suggesting a significant role in long-term energy homeostasis. However, increasing recognition of vagal involvement in the putative mechanisms making bariatric surgeries the most effective treatment for obesity should greatly stimulate future research to uncover the many details regarding the specific transduction mechanisms in the periphery and the inter-and intra-neuronal signaling cascades disseminating vagal information across the neuraxis.

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Section: Role Of Vagal Innervation Of Pancreas Liver and Other Abdomentioning

confidence: 99%

The vagus nerve, food intake and obesity

Berthoud

2008

Regulatory Peptides

259

197

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“…Neurons in the mediobasal hypothalamus respond to nutrients, insulin and leptin, and modulate peripheral glucose metabolism through innervation of the liver (Pocai et al, 2005). More recently, Muse et al (2007) demonstrated that injection of resistin injection into the cerebral ventricle in rat blunted insulin action in the liver; however, the mediators of resistin in the brain were not determined.…”

Section: Introductionmentioning

confidence: 99%

Central Resistin Induces Hepatic Insulin Resistance via Neuropeptide Y

Singhal¹,

Lazar²,

Ahima³

2007

J. Neurosci.

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“…Furthermore, in rats, hypothalamic K ATP channels are activated by central lipid fluxes, and efferent vagal input from the brainstem to the liver is required for hypothalamic lipids to impact expression of gluconeogenic enzymes and EGP (50). A key study integrating the above findings confirmed in rats that physiologic increases in circulating LCFAs lead to suppression of EGP, and blocking hypothalamic K ATP channels with ICV glibenclamide abolishes this effect, as does inhibition of fatty acid esterification by ICV infusion of an acyl-CoA synthetase inhibitor, genetic deletion of hypothalamic K ATP channels, or hepatic vagotomy (51).…”

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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A brain-liver circuit regulates glucose homeostasis

Cited by 347 publications

References 39 publications

The vagus nerve, food intake and obesity

The vagus nerve, food intake and obesity

Central Resistin Induces Hepatic Insulin Resistance via Neuropeptide Y

Evidence for Central Regulation of Glucose Metabolism

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