The role of insulin at brain-liver axis in the control of glucose production

Ribeiro, Izabela Martina Ramos; Antunes, Vagner Roberto

doi:10.1152/ajpgi.00290.2017

Cited by 10 publications

(6 citation statements)

References 32 publications

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“…Furthermore, brain insulin action is associated with the autonomic outflow through the hepatic vagal innervation, and it can modulate gluconeogenesis in the liver through the brain-liver axis. 59 Insulin stimulation in the brain is mainly reported to suppress hepatic glucose production in lean persons and animals. 60,61 Moreover, brain insulin resistance can inactivate insulin and leptin signaling pathways to suppress the KATP in the hypothalamus and also induce neuroinflammation pathways through potentiating the Toll-like receptor (TLR)-4 to increase endoplasmic reticulum stress.…”

Section: Luteolin Protection Against Ad Pathology By Modulation Of mentioning

confidence: 99%

“…Luteolin also increases BDNF in the cortex and hippocampus to alleviate cognitive impairment in high‐fat induced obese mice, 58 suggesting that luteolin suppresses the accelerated pathologies. Furthermore, brain insulin action is associated with the autonomic outflow through the hepatic vagal innervation, and it can modulate gluconeogenesis in the liver through the brain‐liver axis 59 . Insulin stimulation in the brain is mainly reported to suppress hepatic glucose production in lean persons and animals 60,61 .…”

Section: Luteolin Protection Against Ad Pathology By Modulation Of Systemic and Brain Glucose Metabolismmentioning

confidence: 99%

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Protection against Alzheimer's disease by luteolin: Role of brain glucose regulation, anti‐inflammatory activity, and the gut microbiota‐liver‐brain axis

Daily¹,

Kang

Park

2020

BioFactors

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Luteolin is a widely distributed flavone herbs and vegetables. It has antioxidant and anti-inflammatory activities and improves glucose metabolism by potentiating insulin sensitivity and improving β-cell function and mass.Alzheimer's disease (AD) is induced by the deposition of amyloid-beta (Aβ) in the hippocampus and the formation of neurotoxic Aβ plaques. The Aβ deposition is associated with increased formation of Aβ from amyloid precursor protein by up-regulation of β-secretase and β-site amyloid precursor proteincleaving enzyme 1 (BACE1). Furthermore, Aβ accumulation is increased by brain insulin resistance. The impairment of insulin/IGF-1 signaling mainly in the hippocampus and brain insulin resistance is connected to signals originating in the liver and gut microbiota, known as the gut microbiota-liver-brain axis. This indicates that the changes in the production of short-chain fatty acids by the gut microbiota and pro-inflammatory cytokines can alter insulin resistance in the liver and brain. Luteolin is detected in the brain tissues after passing through the blood-brain barrier, where it can directly influence neuroinflammation and brain insulin resistance and modulate Aβ deposition. Luteolin (10-70 mg/kg bw for rodents) can modulate the systemic and brain insulin resistance, and it suppresses AD development directly, and it influences Aβ deposition by activation of the gut microbiota-liver-brain axis. In this review, we evaluate the potential of luteolin to mitigate two potential causes of AD, neuroinflammatory processes, and disruption of glucose metabolism in the brain. This review suggests that luteolin intake can enhance brain insulin resistance and neuroinflammation, directly and indirectly, to protect against the development of Alzheimer's-like disease, and the gut microbiota-liver-

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Section: Luteolin Protection Against Ad Pathology By Modulation Of mentioning

confidence: 99%

Section: Luteolin Protection Against Ad Pathology By Modulation Of Systemic and Brain Glucose Metabolismmentioning

confidence: 99%

Protection against Alzheimer's disease by luteolin: Role of brain glucose regulation, anti‐inflammatory activity, and the gut microbiota‐liver‐brain axis

Daily¹,

Kang

Park

2020

BioFactors

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“…Thus, preventing hepatic fat accumulation is a promising strategy to prevent age-associated metabolic disease. The autonomic nervous system (ANS) plays a key role in regulating hepatic metabolism (5), and is therefore an attractive target for the treatment of metabolic disease. Metabolic signals from the hypothalamus reach the liver via neuronal pathways that include the brain stem, sympathetic nerves, and vagus nerve.…”

Section: Introductionmentioning

confidence: 99%

Neuronal Lipoprotein Lipase Deficiency alters Neuronal Function and Hepatic Metabolism

Bruce

Wang

Dobrinskikh

et al. 2020

Preprint

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Background: The autonomic regulation of hepatic metabolism offers a novel target for the treatment of non-alcoholic fatty liver disease (NAFLD). However, the molecular characteristics of neurons that regulate the brain-liver axis remain unclear. Since mice lacking neuronal lipoprotein lipase (LPL) develop perturbations in neuronal lipid-sensing and systemic energy balance, we reasoned that LPL may be a component of pre-autonomic neurons involved in the regulation of hepatic metabolism. Methods: Measures of glucose homeostasis in mice homozygous (NEXLPL-/-) and heterozygous (NEXLPL+/-) for neuronal LPL deficiency were compared to that of WT mice. A detailed analysis of hepatic glucose and lipid metabolism was also determined in NEXLPL+/- at 6-18 mo. To determine the effect of neuronal LPL deficiency on neuronal physiology, liver-related neurons were identified in the paraventricular nucleus (PVN) of the hypothalamus using the transsynaptic retrograde tracer PRV-152. In addition, we used Fluorescence Lifetime Imaging Microscopy (FLIM) as a novel method to visualize changes in neuronal metabolism following LPL-depletion directly in the PVN. Results: Here we show that despite obesity, mice with reduced neuronal LPL also show improved glucose tolerance and reduced hepatic lipid accumulation with aging, concomitant with reduced hepatic lipogenic gene expression (e.g. SCD1 and FADS2). Retroviral tracing and patch clamp studies revealed reduced inhibitory post-synaptic currents in liver-related neurons lacking LPL. Quantification of the free versus bound Nicotinamide Adenine Dinucleotide (NADH) and Flavin Adenine Dinucleotide (FAD), revealed that LPL loss resulted in altered substrate utilization characterized by increased glucose utilization and TCA cycle flux. These findings were recapitulated by analysis of global metabolites from hypothalamic cell lines either deficient in, or over-expressing, LPL. Conclusions: Our data suggest that LPL is a novel feature of liver–related preautonomic neurons in the PVN. Moreover, LPL loss is sufficient to alter neuronal metabolism and function, leading to changes in systemic glucose metabolism including improved hepatic function with age.

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“…Thus, preventing hepatic fat accumulation is a promising strategy to prevent age-associated metabolic disease. The autonomic nervous system (ANS) plays a key role in regulating hepatic metabolism [ 5 ] and is, therefore, an attractive target for the treatment of metabolic disease. Metabolic signals from the hypothalamus reach the liver via neuronal pathways that include the brain stem, the sympathetic nerves, and the vagus nerve.…”

Section: Introductionmentioning

confidence: 99%

Neuronal Lipoprotein Lipase Deficiency Alters Neuronal Function and Hepatic Metabolism

et al. 2020

View full text Add to dashboard Cite

The autonomic regulation of hepatic metabolism offers a novel target for the treatment of non-alcoholic fatty liver disease (NAFLD). However, the molecular characteristics of neurons that regulate the brain-liver axis remain unclear. Since mice lacking neuronal lipoprotein lipase (LPL) develop perturbations in neuronal lipid-sensing and systemic energy balance, we reasoned that LPL might be a component of pre-autonomic neurons involved in the regulation of hepatic metabolism. Here, we show that, despite obesity, mice with reduced neuronal LPL (NEXCreLPLflox (LPL KD)) show improved glucose tolerance and reduced hepatic lipid accumulation with aging compared to wilt type (WT) controls (LPLflox). To determine the effect of LPL deficiency on neuronal physiology, liver-related neurons were identified in the paraventricular nucleus (PVN) of the hypothalamus using the transsynaptic retrograde tracer PRV-152. Patch-clamp studies revealed reduced inhibitory post-synaptic currents in liver-related neurons of LPL KD mice. Fluorescence lifetime imaging microscopy (FLIM) was used to visualize metabolic changes in LPL-depleted neurons. Quantification of free vs. bound nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) revealed increased glucose utilization and TCA cycle flux in LPL-depleted neurons compared to controls. Global metabolomics from hypothalamic cell lines either deficient in or over-expressing LPL recapitulated these findings. Our data suggest that LPL is a novel feature of liver-related preautonomic neurons in the PVN. Moreover, LPL loss is sufficient to cause changes in neuronal substrate utilization and function, which may precede changes in hepatic metabolism.

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The role of insulin at brain-liver axis in the control of glucose production

Cited by 10 publications

References 32 publications

Protection against Alzheimer's disease by luteolin: Role of brain glucose regulation, anti‐inflammatory activity, and the gut microbiota‐liver‐brain axis

Protection against Alzheimer's disease by luteolin: Role of brain glucose regulation, anti‐inflammatory activity, and the gut microbiota‐liver‐brain axis

Neuronal Lipoprotein Lipase Deficiency alters Neuronal Function and Hepatic Metabolism

Neuronal Lipoprotein Lipase Deficiency Alters Neuronal Function and Hepatic Metabolism

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