Evidence for a novel functional role of astrocytes in the acute homeostatic response to high-fat diet intake in mice

Buckman, Laura B.; Thompson, Misty M.; Lippert, Rachel N.; Blackwell, Timothy S.; Yull, Fiona E.; Ellacott, Kate L. J.

doi:10.1016/j.molmet.2014.10.001

Cited by 113 publications

(135 citation statements)

References 33 publications

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“…Notably, in the brain ANKK1 is highly represented, if not uniquely expressed in astrocytes [111, 112]. Astrocytes can be targets for saturated fat-induced inflammatory responses and endoplasmic reticulum (ER) stress mediated through toll-like receptor ( TLR ) and IKK/NF-κB [113, 114] signaling pathways. In addition, eicosanoids derived from lipids are potent inducers of neural growth factor secretion by astrocytes, which also directly regulates DRD2 expression through an NF-κB dependent mechanism [115].…”

Section: Taqia Polymorphism (Rs1800497)mentioning

confidence: 99%

DRD2: Bridging the Genome and Ingestive Behavior

Sun

Luquet

2017

Trends in Cognitive Sciences

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Recent work highlights the importance of genetic variants that influence brain structure and function in conferring risk for polygenic obesity. The neurotransmitter dopamine (DA) plays a pivotal role in energy balance by integrating metabolic signals with circuits supporting cognitive, perceptual and appetitive functions that guide feeding. It has also been established that diet and obesity alter DA signaling leading to compulsive-like feeding and neurocognitive impairments. This raises the possibility that genetic variants that influence DA signaling and adaptation confer risk for overeating and cognitive decline. We consider the role of two common gene variants, FTO and TaqIA rs1800497 in driving gene * environment interactions promoting obesity, metabolic dysfunction, and cognitive change via their influence on dopamine receptor subtype 2 signaling.

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Section: Taqia Polymorphism (Rs1800497)mentioning

confidence: 99%

DRD2: Bridging the Genome and Ingestive Behavior

Sun

Luquet

2017

Trends in Cognitive Sciences

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“…Once activated, however, astrocytes may perpetuate DIO through a variety of mechanisms, including loss of BBB integrity [80], enhancement of diet reward properties in the mesolimbic system [81] and glial ensheathment of melanocortin synapses that are restructured by HFD intake [82]. Surprisingly, however, inhibition of astrocyte inflammatory signalling has only minimal effects on DIO, paradoxically potentiating the early hyperphagic response to HFD [75]. These data are consistent with the possibility that astrocytic inflammation initially serves as an adaptive response to HFD feeding, limiting neuronal stress and restraining energy intake.…”

Section: Astrocyte–neuron Interactions In Energy Homeostasismentioning

confidence: 99%

Glia: silent partners in energy homeostasis and obesity pathogenesis

2016

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Body weight stability requires homeostatic regulation to balance energy intake and energy expenditure. Research on this system and how it is affected by obesity has largely focussed on the role of hypothalamic neurons as integrators of information about long-term fuel storage, short-term nutrient availability and metabolic demand. Recent studies have uncovered glial cells as additional contributors to energy balance regulation and obesity pathogenesis. Beginning with early work on leptin signalling in astrocytes, this area of research rapidly emerged after the discovery of hypothalamic inflammation and gliosis in obese rodents and humans. Current studies have revealed the involvement of a wide variety of glial cell types in the modulation of neuronal activity, regulation of hormone and nutrient availability, and participation in the physiological regulation of feeding behaviour. In addition, one glial type, microglia, has recently been implicated in susceptibility to diet-induced obesity. Together, these exciting new findings deepen our understanding of energy homeostasis regulation and raise the possibility of identifying novel mechanisms that contribute to the pathogenesis of obesity.

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“…While several studies have implicated microglia in the generation of diet-induced inflammatory signals and metabolic dysfunction [17], [18], a similar role for astrocytes remains unclear. One study demonstrated a modest contribution of astrocyte inflammation to caloric intake on the first day of HFD feeding, but no analysis of DIO susceptibility was reported [19].…”

Section: Introductionmentioning

confidence: 99%

Astrocyte IKKβ/NF-κB signaling is required for diet-induced obesity and hypothalamic inflammation

Douglass¹,

Dorfman²,

Fasnacht³

et al. 2017

Molecular Metabolism

203

164

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ObjectiveObesity and high fat diet (HFD) consumption in rodents is associated with hypothalamic inflammation and reactive gliosis. While neuronal inflammation promotes HFD-induced metabolic dysfunction, the role of astrocyte activation in susceptibility to hypothalamic inflammation and diet-induced obesity (DIO) remains uncertain.MethodsMetabolic phenotyping, immunohistochemical analyses, and biochemical analyses were performed on HFD-fed mice with a tamoxifen-inducible astrocyte-specific knockout of IKKβ (GfapCreERIkbkbfl/fl, IKKβ-AKO), an essential cofactor of NF-κB-mediated inflammation.ResultsIKKβ-AKO mice with tamoxifen-induced IKKβ deletion prior to HFD exposure showed equivalent HFD-induced weight gain and glucose intolerance as Ikbkbfl/fl littermate controls. In GfapCreERTdTomato marker mice treated using the same protocol, minimal Cre-mediated recombination was observed in the mediobasal hypothalamus (MBH). By contrast, mice pretreated with 6 weeks of HFD exposure prior to tamoxifen administration showed substantially increased recombination throughout the MBH. Remarkably, this treatment approach protected IKKβ-AKO mice from further weight gain through an immediate reduction of food intake and increase of energy expenditure. Astrocyte IKKβ deletion after HFD exposure—but not before—also reduced glucose intolerance and insulin resistance, likely as a consequence of lower adiposity. Finally, both hypothalamic inflammation and astrocytosis were reduced in HFD-fed IKKβ-AKO mice.ConclusionsThese data support a requirement for astrocytic inflammatory signaling in HFD-induced hyperphagia and DIO susceptibility that may provide a novel target for obesity therapeutics.

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Evidence for a novel functional role of astrocytes in the acute homeostatic response to high-fat diet intake in mice

Cited by 113 publications

References 33 publications

DRD2: Bridging the Genome and Ingestive Behavior

DRD2: Bridging the Genome and Ingestive Behavior

Glia: silent partners in energy homeostasis and obesity pathogenesis

Astrocyte IKKβ/NF-κB signaling is required for diet-induced obesity and hypothalamic inflammation

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