Ventromedial hypothalamic nucleus neuronal subset regulates blood glucose independently of insulin

Flak, Jonathan N.; Goforth, Paulette B.; Dell’Orco, James M.; Sabatini, Paul V.; Li, Chien; Bozadjieva, Nadejda; Sorensen, Matthew J.; Valenta, Alec C.; Rupp, Alan C.; Affinati, Alison H.; Cras-Méneur, Corentin; Ansari, Ahsan; Sacksner, Jamie; Kodur, Nandan; Sandoval, Darleen A.; Kennedy, Robert T.; Olson, David P.; Myers, Martin G.

doi:10.1172/jci134135

Cited by 54 publications

(73 citation statements)

References 42 publications

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“…The brain's response to this stimulus mimics that induced by hypoglycaemia: increased glucose production combined with decreased peripheral glucose utilisation drives blood glucose levels upwards to a stable, hyperglycaemic plateau sufficient to overcome the underlying defect in neuronal glucose sensing. This hyperglycaemia is fully recapitulated in rodents by optogenetic or chemogenetic activation of subsets of neurons in the CRR circuit activated by hypoglycaemia that are situated in the hypothalamic ventromedial nucleus (VMN) [19][20][21]. The expected increase in insulin secretion in response to this neurocircuit-induced hyperglycaemia is suppressed as part of the brain response to reduced glucose availability.…”

Section: Brain Control Of Glucose Homeostasis During Hypoglycaemiamentioning

confidence: 99%

“…The brain's contribution to diabetic hyperglycaemia is also illustrated by studies in rodents wherein subsets of the CRR glucoregulatory neurons in the VMN are inactivated, providing information on what the neurons actually do (as opposed to what they are capable of doing when activated). In a recent study by Flak and colleagues [21], silencing a subset of glutamatergic CRR neurons in the VMN (marked by expression of the cholecystokinin B [CCK-B] receptor) of otherwise normal mice caused a~25% reduction in blood glucose levels. Implicit in this finding is the intriguing concept that a specific subset of VMN neurons participating in the CRR is also a physiological determinant of the defended blood glucose level.…”

Section: Brain Control Of Glucose Homeostasis During Hypoglycaemiamentioning

confidence: 99%

“…Implicit in this finding is the intriguing concept that a specific subset of VMN neurons participating in the CRR is also a physiological determinant of the defended blood glucose level. More important is the observation that inactivation of these neurons not only impairs the ability to mount CRRs in response to neuroglycopenia [24,25] but also ameliorates hyperglycaemia in diabetic mice [21]. Thus, neurons in the circuit responsible for mounting the brain response to reduced glucose availability are key contributors to hyperglycaemia in diabetic animals.…”

Section: Brain Control Of Glucose Homeostasis During Hypoglycaemiamentioning

confidence: 99%

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Brain control of blood glucose levels: implications for the pathogenesis of type 2 diabetes

2020

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Despite a rapidly growing literature, the role played by the brain in both normal glucose homeostasis and in type 2 diabetes pathogenesis remains poorly understood. In this review, we introduce a framework for understanding the brain's essential role in these processes based on evidence that the brain, like the pancreas, is equipped to sense and respond to changes in the circulating glucose level. Further, we review evidence that glucose sensing by the brain plays a fundamental role in establishing the defended level of blood glucose, and that defects in this control system contribute to type 2 diabetes pathogenesis. We also consider the possibility that the close association between obesity and type 2 diabetes arises from a shared defect in the highly integrated neurocircuitry governing energy homeostasis and glucose homeostasis. Thus, whereas obesity is characterised by an increase in the defended level of the body's fuel stores (e.g. adipose mass), type 2 diabetes is characterised by an increase in the defended level of the body's available fuel (e.g. circulating glucose), with the underlying pathogenesis in each case involving impaired sensing of (or responsiveness to) relevant humoral negative feedback signals. This perspective is strengthened by growing preclinical evidence that in type 2 diabetes the defended level of blood glucose can be restored to normal by therapies that restore the brain's ability to properly sense the circulating glucose level.

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Section: Brain Control Of Glucose Homeostasis During Hypoglycaemiamentioning

confidence: 99%

Section: Brain Control Of Glucose Homeostasis During Hypoglycaemiamentioning

confidence: 99%

Section: Brain Control Of Glucose Homeostasis During Hypoglycaemiamentioning

confidence: 99%

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Brain control of blood glucose levels: implications for the pathogenesis of type 2 diabetes

2020

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“…the transmembrane form of fibrinogen-like protein 2 (mFgl2), while Fgl2 protein also has a soluble cleaved form (sFgl2), which is a negative regulator of immunity 7 - 9 . Our recent study identified that the sFgl2 ameliorates sepsis by increasing n-3 docosapentaenoic acid-derived resolvin D5 (RvD5 n-3 DPA , also named RvDp5) 10 , a specialized pro-resolving lipid mediator (SPM) derived from n-3 docosapentaenoic acid (DPA) by 15-lipoxygenase (15-LOX or ALOX15) catalyzation 11 - 13 . Here, we report the correlation of mFgl2 and sFgl2 with coagulation and peripheral blood mononuclear cells (PBMC), as well as explore the differential roles of anticoagulants heparin, warfarin and dabigatran on inflammation resolution.…”

Section: Introductionmentioning

confidence: 99%

Dabigatran activates inflammation resolution by promoting fibrinogen-like protein 2 shedding and RvD5_{n-3 DPA} production

et al. 2021

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Rationale: The interaction between coagulation and inflammation resolution remains elusive. We recently highlighted a link between fibrinogen-like protein 2 (Fgl2) and a specialized pro-resolving mediator (SPM)-n-3 docosapentaenoic acid-derived resolvin D5 (RvD5 n-3 DPA ) in sepsis. This study aimed to investigate the functions of commonly used anticoagulants warfarin, dabigatran and heparin in regulating inflammation resolution. Methods: Peripheral blood was collected from clinical sepsis patients and healthy control for the determination of indicated indexes. Mouse sepsis models of zymosan-induced peritonitis and cecal ligation and puncture (CLP) were employed for the measurement of inflammation- and coagulation-related indexes. Western-blotting, ELISA and flow cytometry were applied to assess proteins. UPLC-MS/MS was used to evaluate lipid metabolites. Results: Here we report that the transmembrane Fgl2 (mFgl2) was positively associated with coagulation, while soluble Fgl2 (sFgl2) level correlated with the enhanced number of peripheral blood mononuclear cells in the sepsis patients. The anticoagulants dabigatran and warfarin attenuated zymosan-induced peritonitis, which was not shared by heparin, while only dabigatran significantly improved sepsis survival in the CLP sepsis mouse model. Although these anticoagulants consistently inhibited pro-inflammatory mediators including prostaglandin E 2 and leukotriene B 4 , only dabigatran increased sFgl2 at both the initiation and resolution phases of inflammation. Mechanistically, dabigatran elicited the shedding of sFgl2 via prothrombin-related metalloproteases, thereby enhanced the subsequent biosynthesis of RvD5 n-3 DPA via STAT6-ALOX15 axis. Blocking metalloproteases or ALOX15 significantly impaired dabigatran-enhanced macrophage efferocytosis in vitro , as well as delayed the dabigatran-accelerated inflammation resolution in vivo . Conclusions: Our findings identify the dual anti-inflammatory and pro-resolving actions of dabigatran, through promoting sFgl2-triggered RvD5 n-3 DPA production, which has important implications for promoting tissue homeostasis of sepsis.

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“…Each VMH subdivision mediates a variety of outputs and thus presumably contains multiple functionally-distinct cell types. For example, activating adult Nr5a1expressing VMH neurons (which includes most cells in the VMH DM and VMH C ) promotes panic-related behaviors, augments hepatic glucose output to increase blood glucose, and elevates energy expenditure (Meek et al 2016, 201;Flak et al 2020;Kunwar et al 2015). In contrast, activating the subset of VMH DM cells that expresses leptin receptor (Lepr, which encodes the receptor for the adipose-derived, energy balance-controlling hormone, leptin (H. Chen et al 1996;Tartaglia et al 1995)) promotes energy expenditure without altering these other parameters (Sabatini et al 2021;Meek et al 2013;.…”

Section: Introductionmentioning

confidence: 99%

Cross-Species Analysis Defines the Conservation of Anatomically-Segregated VMH Neuron Populations

Affinati

Sabatini

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et al. 2021

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The ventromedial hypothalamic nucleus (VMH) controls diverse behaviors and physiologic functions, suggesting the existence of multiple VMH neural subtypes with distinct functions. Combing Translating Ribosome Affinity Purification with RNA sequencing (TRAP-seq) data with snRNA-seq data, we identified 24 mouse VMH neuron clusters. Further analysis, including snRNA-seq data from macaque tissue, defined a more tractable VMH parceling scheme consisting of 6 major genetically- and anatomically-differentiated VMH neuron classes with good cross-species conservation. In addition to two major ventrolateral classes, we identified three distinct classes of dorsomedial VMH neurons. Consistent with previously-suggested unique roles for leptin receptor (Lepr)-expressing VMH neurons, Lepr expression marked a single dorsomedial class. We also identified a class of glutamatergic VMH neurons that resides in the tuberal region, anterolateral to the neuroanatomical core of the VMH. This atlas of conserved VMH neuron populations provides an unbiased starting point for the analysis of VMH circuitry and function.

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Ventromedial hypothalamic nucleus neuronal subset regulates blood glucose independently of insulin

Cited by 54 publications

References 42 publications

Brain control of blood glucose levels: implications for the pathogenesis of type 2 diabetes

Brain control of blood glucose levels: implications for the pathogenesis of type 2 diabetes

Dabigatran activates inflammation resolution by promoting fibrinogen-like protein 2 shedding and RvD5_{n-3 DPA} production

Cross-Species Analysis Defines the Conservation of Anatomically-Segregated VMH Neuron Populations

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Ventromedial hypothalamic nucleus neuronal subset regulates blood glucose independently of insulin

Cited by 54 publications

References 42 publications

Brain control of blood glucose levels: implications for the pathogenesis of type 2 diabetes

Brain control of blood glucose levels: implications for the pathogenesis of type 2 diabetes

Dabigatran activates inflammation resolution by promoting fibrinogen-like protein 2 shedding and RvD5n-3 DPA production

Cross-Species Analysis Defines the Conservation of Anatomically-Segregated VMH Neuron Populations

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Dabigatran activates inflammation resolution by promoting fibrinogen-like protein 2 shedding and RvD5_{n-3 DPA} production