Insulin actions on hypothalamic glucose‐sensing neurones

Garcia, Stephanie; Hirschberg, Pamela R.; Sarkar, Pallabi; Siegel, Dashiel M.; Teegala, Suraj B.; Vail, Gwyndolin M.; Routh, Vanessa H.

doi:10.1111/jne.12937

Cited by 10 publications

(7 citation statements)

References 175 publications

(287 reference statements)

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“…Obesity impairs brain function and synapse formation by impairing insulin signaling [ 73 ]. In neurons, insulin receptor signaling-related genes, such as Irs1 and Slc2a4 , could affect the secretion of excitatory glutamate neurotransmitters [ 74 ], neuroinflammation [ 75 ], and memory formation [ 76 ]. Moreover, in neurons, synaptic formation-related genes, such as Map2 and Syp , are related to memory consolidation and synaptic plasticity [ 77 ].…”

Section: Discussionmentioning

confidence: 99%

Profiling and Cellular Analyses of Obesity-Related circRNAs in Neurons and Glia under Obesity-like In Vitro Conditions

Yoon

Lim

et al. 2023

IJMS

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Recent evidence indicates that the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease, is associated with metabolic disorders such as diabetes and obesity. Various circular RNAs (circRNAs) have been found in brain tissues and recent studies have suggested that circRNAs are related to neuropathological mechanisms in the brain. However, there is a lack of interest in the involvement of circRNAs in metabolic imbalance-related neuropathological problems until now. Herein we profiled and analyzed diverse circRNAs in mouse brain cell lines (Neuro-2A neurons, BV-2 microglia, and C8-D1a astrocytes) exposed to obesity-related in vitro conditions (high glucose, high insulin, and high levels of tumor necrosis factor-alpha, interleukin 6, palmitic acid, linoleic acid, and cholesterol). We observed that various circRNAs were differentially expressed according to cell types with many of these circRNAs conserved in humans. After suppressing the expression of these circRNAs using siRNAs, we observed that these circRNAs regulate genes related to inflammatory responses, formation of synaptic vesicles, synaptic density, and fatty acid oxidation in neurons; scavenger receptors in microglia; and fatty acid signaling, inflammatory signaling cyto that may play important roles in metabolic disorders associated with neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 99%

Profiling and Cellular Analyses of Obesity-Related circRNAs in Neurons and Glia under Obesity-like In Vitro Conditions

Yoon

Lim

et al. 2023

IJMS

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“…Using a recent review of brain insulin signaling and glucose sensing we designed a list of key genes of interest involved in either of these functions (Figure S1). 3,8,[20][21][22][23][24] Previously-published RNA sequencing data was retrieved from Okaty et al 25 with R software version 4.0.3. The dataset was directly extracted from the available Supplementary materials from Okaty et al, 25 which initially included 18 pooled fractions and 56 single neuron fractions.…”

Section: Bioinformatic Analysis Of Genes Involved In Glucose-sensing ...mentioning

confidence: 99%

“…8 VMH neurons also present the ability to detect insulin. [8][9][10] The effect of insulin in the regulation of the CRR also seems to be a key in view of studies showing that insulin regulates VMH GSNs 11 and that NIRKO mice lacking the insulin receptor in brain neurons present impaired CRR to insulin-hypoglycemia. 12 While the VMH plays an essential role in the control of the CRR in response to insulin-induced hypoglycemia, it receives projections from other brain areas which could modulate the activity of GSNs and consequently the CRR.…”

Section: Introductionmentioning

confidence: 99%

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Serotonergic neurons are involved in the counter‐regulatory response to hypoglycemia

Martin,

Coursan,

Lallement

et al. 2023

J Neuroendocrinology

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ObjectivesIntensive insulin therapy provides optimal glycemic control in patients with diabetes. However, intensive insulin therapy causes so‐called iatrogenic hypoglycemia as a major adverse effect. The ventromedial hypothalamus (VMH) has been described as the primary brain area initiating the counter‐regulatory response (CRR). Nevertheless, the VMH receives projections from other brain areas which could participate in the regulation of the CRR. In particular, studies suggest a potential role of the serotonin (5‐HT) network. Thus, the objective of this work is to determine the contribution of 5‐HT neurons in CRR control.MethodsComplementary approaches have been used to test this hypothesis in quantifying the level of 5‐HT in several brain areas by HPLC in response to insulin‐induced hypoglycemia, measuring the electrical activity of dorsal Raphe (DR) 5‐HT neurons in response to insulin or decreased glucose level by patch‐clamp electrophysiology; and measuring the CRR hormone glucagon as an index of the CRR to the modulation of the activity of 5‐HT neurons using pharmacological or pharmacogenetic approaches.ResultsHPLC measurements show that the 5HIAA/5HT ratio is increased in several brain regions including the VMH in response to insulin‐induced hypoglycemia. Patch‐clamp electrophysiological recordings show that insulin, but not decreased glucose level, increases the firing frequency of DR 5‐HT neurons in the DR. In vivo, both the pharmacological inhibition of 5‐HT neurons by intraperitoneal injection of the 5‐HT1A receptor agonist 8‐OH‐DPAT or the chemogenetic inhibition of these neurons reduce glucagon secretion, suggesting an impaired CRR.ConclusionTaken together, these data highlight a new neuronal network involved in the regulation of the CRR. In particular, this study shows that DR 5‐HT neurons detect iatrogenic hypoglycemia in response to the increased insulin level and may play an important role in the regulation of CRR.This article is protected by copyright. All rights reserved.

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“…Of note, it has been reported that insulin resistance, lack of insulin or hypoglycemia associated automimic failure would affect glucose sensitivity of glucose-sensing neurons, thereby whole-body glucose homeostasis (see the review Ref. [ 33 ]). Obviously, the major glucoregulatory effect of insulin is to promote glucose utilization in the peripheral tissues (e.g., liver, skeletal muscle and adipose tissue).…”

Section: Central Regulation Of Glucose Homeostasismentioning

confidence: 99%

The ventromedial hypothalamic nucleus: watchdog of whole-body glucose homeostasis

Fukuda

Tong

et al. 2022

Cell Biosci

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The brain, particularly the ventromedial hypothalamic nucleus (VMH), has been long known for its involvement in glucose sensing and whole-body glucose homeostasis. However, it is still not fully understood how the brain detects and responds to the changes in the circulating glucose levels, as well as brain-body coordinated control of glucose homeostasis. In this review, we address the growing evidence implicating the brain in glucose homeostasis, especially in the contexts of hypoglycemia and diabetes. In addition to neurons, we emphasize the potential roles played by non-neuronal cells, as well as extracellular matrix in the hypothalamus in whole-body glucose homeostasis. Further, we review the ionic mechanisms by which glucose-sensing neurons sense fluctuations of ambient glucose levels. We also introduce the significant implications of heterogeneous neurons in the VMH upon glucose sensing and whole-body glucose homeostasis, in which sex difference is also addressed. Meanwhile, research gaps have also been identified, which necessities further mechanistic studies in future.

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Insulin actions on hypothalamic glucose‐sensing neurones

Cited by 10 publications

References 175 publications

Profiling and Cellular Analyses of Obesity-Related circRNAs in Neurons and Glia under Obesity-like In Vitro Conditions

Profiling and Cellular Analyses of Obesity-Related circRNAs in Neurons and Glia under Obesity-like In Vitro Conditions

Serotonergic neurons are involved in the counter‐regulatory response to hypoglycemia

The ventromedial hypothalamic nucleus: watchdog of whole-body glucose homeostasis

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