Hypothalamic perineuronal net assembly is required for sustained diabetes remission induced by fibroblast growth factor 1 in rats

Alonge, Kimberly M.; Mirzadeh, Zaman; Scarlett, Jarrad; Logsdon, Aric F.; Brown, Jenny; Cabrales, Elaine; Chan, Christina K.; Kaiyala, Karl J.; Bentsen, Marie A.; Banks, William A.; Guttman, Miklós; Wight, Thomas N.; Morton, Gregory J.; Schwartz, Michael W.

doi:10.1038/s42255-020-00275-6

Cited by 33 publications

(51 citation statements)

References 40 publications

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“…While mechanisms underlying the sustained glucoselowering action of FGF1 in the MBH await additional study, our recent work points to a role for glia-neuron interactions [55] and associations with FGF1-induced changes in the extracellular matrix [56]. Whatever the mechanism, the data collectively suggest that in rodent models of type 2 diabetes, hyperglycaemia arises from pathological processes that can be corrected (or overridden) through the hypothalamic action of FGF1.…”

Section: Targeting the Brain To Restore Normoglycaemia In Rodent Modementioning

confidence: 76%

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: Targeting the Brain To Restore Normoglycaemia In Rodent Modementioning

confidence: 76%

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

2020

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“…Also reminiscent of the current findings is our recent report that hypothalamic perineuronal nets (PNNs, defined as extracellular matrix specializations combined of proteoglycans and hyaluronan), which were recently shown to enmesh neurons in the ARC-ME 28 , are also targets for the glucose-lowering action of FGF1. Indeed, PNN formation increases rapidly in the ARC-ME following icv FGF1 injection and, in a rat model of T2D, disruption of this PNN response blocks the sustained antidiabetic action induced by icv FGF1 injection, while having no impact on the acute, transient effects of FGF1 on food intake, body weight, and glycemia 8 . These observations once again parallel those observed when hypothalamic MAPK/ERK signaling either is not induced or is blocked in a sustained manner.…”

Section: Discussionmentioning

confidence: 98%

“…Representative western blot (left panel) showing phosphorylated (red) and total ERK1/2 (green) and total protein (red), and data quantitation (right panel) from hypothalamic punches from adult male C57Bl6J mice at 20 min after a injection into the lateral ventricle of the inhibitor of MAPK signaling U0126 (5 µg) or DMSO, followed by injection of either vehicle or FGF1 (n=5/group, one-way ANOVA F(2-5.27)= 20.1692 p=0.00339). Effects of the same treatments on levels of B) food intake, C) body weight (n=7- 8 As an alternative test of the hypothesis that diabetes remission induced by icv FGF1 injection requires sustained ERK1/2 activation in the hypothalamus, we repeated these studies in mice using FGF1 R50E, a FGF1 mutant in which arginine at the amino acid position 50 is substituted with glutamate 11 . In cell culture studies, FGF1 R50E retains the ability to bind to and activate FGFRs and induce transient activation of ERK1/2, but the effect is not sustained 11,12,18 .…”

Section: Figure 2-prolonged Mapk Signaling In the Mbh Is Required Formentioning

confidence: 99%

“…Since the effect of icv FGF1 administration to normalize diabetic hyperglycemia in a sustained manner is recapitulated by microinjection of a lower dose of FGF1 directly into mediobasal hypothalamus (MBH), this brain area is implicated as a key target for this sustained antidiabetic response 5 . While recent work points to a role for glia-neuron interactions leading to increased melanocortin signaling 7 , as well as to FGF1-induced changes in MBH extracellular matrix 8 , the signal transduction mechanisms by which FGF1 action in the MBH induces sustained remission of diabetic hyperglycemia is unknown.…”

Section: Introductionmentioning

confidence: 99%

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Role of hypothalamic MAPK/ERK signaling in diabetes remission induced by the central action of fibroblast growth factor 1

Brown

Bentsen

Rausch

et al. 2020

Preprint

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SummaryThe capacity of the brain to elicit sustained remission of hyperglycemia in rodent models of type 2 diabetes following intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) is well established. Here, we show that following icv FGF1 injection, hypothalamic signaling by extracellular signal-regulated kinases 1 and 2 (ERK1/2), members of the mitogen-activated protein kinase (MAPK) family is induced for at least 24h. Further, we show that in diabetic Lepob/ob mice, this prolonged response is required for the sustained antidiabetic action of FGF1, since it is abolished by sustained (but not acute) pharmacologic blockade of hypothalamic MAPK/ERK signaling. We also demonstrate that FGF1 R50E, a FGF1 mutant that activates FGF receptors but induces only transient hypothalamic MAPK/ERK signaling, fails to mimic the sustained glucose lowering induced by FGF1. These data identify sustained activation of hypothalamic MAPK/ERK signaling as playing an essential role in the mechanism underlying diabetes remission induced by icv FGF1 administration.

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“…the cortex and the hippocampus, and 50 the PNNs levels in these regions can be regulated by animals' experience, and have been implicated in 51 various neurobiological disorders such as schizophrenia, bipolar disorder, Alzheimer's disease and addictions. Recent evidence indicates that chemical disruption of PNNs in the mediobasal hypothalamus significantly blunts the glucose-lowering effects of central action of fibroblast growth factor (FGF1) in obese Zucker diabetic fatty (ZDF) rats (10). Thus, hypothalamic PNNs may also play important roles in the regulation of energy and/or glucose homeostasis.…”

mentioning

confidence: 99%

Hypothalamic perineuronal nets are regulated by sex and dietary interventions

Zhang

Yan

Liu

et al. 2021

Preprint

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Perineuronal nets (PNNs) are widely present in the hypothalamus, and are thought to provide physical protection and ion buffering for neurons, and regulate their synaptic plasticity and intracellular signaling. Recent evidence indicates that PNNs in the mediobasal hypothalamus plays an important role in the regulation of glucose homeostasis. However, whether and how hypothalamic PNNs are regulated are not fully understood. In the present study, we examined whether PNNs in various hypothalamic regions in mice can be regulated by sex, gonadal hormones, dietary interventions, or their interactions. We demonstrated that gonadal hormones are required to maintain normal PNNs in the arcuate nucleus of hypothalamus in both male and female mice. In addition, PNNs in the terete hypothalamic nucleus display a sexual dimorphism with females higher than males, and high-fat diet feeding increases terete PNNs only in female mice but not in male mice. On the other hand, PNNs in other hypothalamic regions are not influenced by sex, gonadal hormones or dietary interventions. In summary, we demonstrated that hypothalamic PNNs are regulated in a region-specific manner and these results provide a framework to further investigate the potential functions of PNNs in regulating energy/glucose homeostasis at the interplay of sex, gonadal hormones and diets.

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Hypothalamic perineuronal net assembly is required for sustained diabetes remission induced by fibroblast growth factor 1 in rats

Cited by 33 publications

References 40 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

Role of hypothalamic MAPK/ERK signaling in diabetes remission induced by the central action of fibroblast growth factor 1

Hypothalamic perineuronal nets are regulated by sex and dietary interventions

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