Glia: silent partners in energy homeostasis and obesity pathogenesis

Douglass, John D.; Dorfman, Mauricio D.; Thaler, Joshua P.

doi:10.1007/s00125-016-4181-3

Cited by 79 publications

(63 citation statements)

References 108 publications

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“…HFD consumption and obesity are associated with increased hypothalamic levels of inflammatory mediators and activation and proliferation of MBH glial cells [3]. Given that IKKβ-AKO mice administered TMX prior to HFD feeding show neither decreased hypothalamic gliosis nor altered DIO susceptibility, we investigated whether HFD-TMX IKKβ-AKO mice show reduced astrocyte activation along with their DIO resistance.…”

Section: Resultsmentioning

confidence: 99%

“…Likewise, the central nervous system (CNS) responds to high fat and sugar-rich diets with rapid upregulation of the master inflammatory NF-κB pathway in important brain regions including the hypothalamus, a critical site of energy homeostasis regulation [3], [4], [5], [6], [7]. High-fat diet (HFD) consumption drives hypothalamic cytokine production, neuronal stress, and insulin/leptin resistance that together promote excess weight gain and food intake [4], [8], [9], [10].…”

Section: Introductionmentioning

confidence: 99%

“…Recent evidence suggests that neuronal inflammation may be a downstream event during DIO, with the recruitment and activation of hypothalamic glial cells being a more proximal response to HFD exposure [3], [10], [12], [13], [14]. This gliosis process is characterized by the accumulation and proliferation of activated microglia and astrocytes in the region of the mediobasal hypothalamus (MBH) [10], [12], [13], [14], [15], [16], [17].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Douglass¹,

Dorfman²,

Fasnacht³

et al. 2017

Molecular Metabolism

203

164

View full text Add to dashboard Cite

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“…It has been reported that microglia are responsive to inflammatory signals in the hypothalamus [22]. We therefore tested whether the BV-2 [23] and IMG [28] cell lines are responsive to two common inducers of inflammation LPS and TNFα.…”

Section: Resultsmentioning

confidence: 99%

“…On the contrary, other studies have shown that palmitate may induce an alternative, anti-inflammatory response in microglia, resulting in neuroprotection [20, 21]. It is likely that both are possible given the temporal responses necessary for resolution of an acute inflammatory response versus the chronic neuroinflammation seen with long-term exposure to high fat [22]. Further research is required to determine the role of microglia in neuroinflammation in response to elevated nutrient levels.…”

Section: Introductionmentioning

confidence: 94%

Palmitate Induces an Anti-Inflammatory Response in Immortalized Microglial BV-2 and IMG Cell Lines that Decreases TNFα Levels in mHypoE-46 Hypothalamic Neurons in Co-Culture

et al. 2018

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Background and Objectives: Elevated levels of saturated fatty acids (SFA) induce a state of neuroinflammation in the hypothalamus. It has been suggested that microglia sense palmitate, a prevalent circulating SFA, and act as mediators of this inflammatory process by communicating with neurons, particularly those involved in appetite regulation. In this study, we examined the inflammatory response to palmitate in immortalized microglial cell lines, BV-2 and IMG, and the subsequent effects on inflammatory gene expression in a model of NPY/AgRP neurons, mHypoE-46. Methods: The BV-2 cells were treated with 50 µM palmitate for 4 and 24 h, and the transcriptional regulation of markers for inflammation and cellular stress was assessed using an RT² Profiler PCR Array. Select genes were verified with qRT-PCR. The BV-2 and IMG cells were then co-cultured using 1.0-µm cell culture inserts with an immortalized hypothalamic cell line, mHypoE-46, to investigate potential intercellular communication between microglia and neurons. Results: We found that palmitate increased the mRNA levels of specific inflammatory genes, and a general anti-inflammatory profile was revealed in the microglia cells. The mRNA changes in TNFα at 4 and 24 h in BV-2 cells were abrogated with the toll-like receptor 4 (TLR4) inhibitor, TAK-242, indicating the involvement of TLR4. Co-culture of mHypoE-46 neurons with microglia pre-treated with palmitate resulted in repression of TNFα expression in the hypothalamic neurons. As palmitate significantly increased IL-13 expression in microglia, the effect of this cytokine was tested in mHypoE-46 neurons. The addition of IL-13 to neuronal cultures normalized the palmitate-mediated increase in IL-6 and AgRP expression, suggesting that microglia may protect surrounding neurons, at least in part, through the release of IL-13. Conclusions: These results suggest a potential anti-inflammatory role of microglia towards the palmitate-induced neuroinflammation, and potentially energy homeostasis, in hypothalamic neurons.

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Hypothalamic Gliosis by MRI and Visceral Fat Mass Negatively Correlate with Plasma Testosterone Concentrations in Healthy Men

Berkseth

Rubinow

Melhorn

et al. 2018

Obesity

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Objective: To determine whether a relationship was evident between gliosis in the mediobasal hypothalamus (MBH) and plasma testosterone concentrations in men Methods: 41 adult men (ages 18–50 years) from 23 twin pairs underwent fasting morning blood draw and brain MRI. T2 relaxation time was used to quantify gliosis in the MBH and control areas in the putamen and amygdala. Plasma concentrations of testosterone and 17β-estradiol were measured by LC-MS/MS. Body composition including visceral adiposity was measured by dual X-ray absorptiometry. Results: A negative association was found between MBH T2 relaxation time and plasma concentrations of both free and total testosterone ( r = −0.29, P<0.05 and r = −0.37, P<0.01, respectively). Visceral adiposity exhibited a negative correlation with plasma total testosterone concentration ( r = −0.45, P=0.001) but a positive correlation with MBH T2 relaxation time ( r = 0.24, P=0.03). The negative correlation between plasma total testosterone and MBH T2 relaxation time remained significant after adjustment for visceral adiposity, age, BMI, and insulin resistance. Conclusions: In healthy men across a range of BMIs, MBH gliosis was associated with higher visceral adiposity but lower endogenous testosterone. These findings suggest that MBH gliosis could provide novel mechanistic insights into gonadal dysfunction in men with obesity.

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Glia: silent partners in energy homeostasis and obesity pathogenesis

Cited by 79 publications

References 108 publications

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

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

Palmitate Induces an Anti-Inflammatory Response in Immortalized Microglial BV-2 and IMG Cell Lines that Decreases TNFα Levels in mHypoE-46 Hypothalamic Neurons in Co-Culture

Hypothalamic Gliosis by MRI and Visceral Fat Mass Negatively Correlate with Plasma Testosterone Concentrations in Healthy Men

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