The Impact of Obesity on Microglial Function: Immune, Metabolic and Endocrine Perspectives

Alexaki, Vasileia Ismini

doi:10.3390/cells10071584

Cited by 39 publications

(44 citation statements)

References 456 publications

(717 reference statements)

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“…LPS treatment leads to increased plasma corticosterone levels (Alexaki, 2021; Kanczkowski et al, 2013c, 2013b). Numerous studies have shown that elevated glucocorticoid levels are primarily driven by activation of the HPA axis, and coincide with increased circulating ACTH levels (Alexaki, 2021; Kanczkowski et al, 2013c, 2013b). This is accompanied by increased expression of genes related to steroid biosynthesis, as previously reported (Chen et al, 2019).…”

Section: Resultsmentioning

confidence: 99%

“…Adrenalectomized rodents show increased mortality after induction of systemic inflammation, while glucocorticoid administration increases survival (Bertini et al ., 1988; Butler et al ., 1989). Similarly to any other stress stimulus, systemic inflammation activates the HPA axis leading to increased glucocorticoid release, which is required to restrain inflammation (Alexaki, 2021; Kanczkowski et al, 2013c, 2013a, 2013b). Adrenocortical cells were also reported to directly respond to inflammation.…”

Section: Introductionmentioning

confidence: 99%

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Succinate mediates inflammation-induced adrenocortical dysfunction

Mateska

Witt

Hagag

et al. 2022

Preprint

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The hypothalamus-pituitary-adrenal (HPA) axis is activated in response to inflammation leading to increased production of glucocorticoids by the adrenal cortex. In turn, glucocorticoids exert potent anti-inflammatory effects. Severe inflammation may reduce adrenal gland responsiveness to adrenocorticotropic hormone (ACTH) although the underlying molecular mechanisms are poorly understood. Here, we show by transcriptomic, proteomics and metabolomics analysis that lipopolysaccharide (LPS)-induced systemic inflammation triggers profound metabolic changes in steroidogenic adrenocortical cells, including downregulation of the tricarboxylic acid (TCA) cycle and oxidative phosphorylation, decreased ATP production and induction of oxidative stress. We demonstrate that although inflammation disrupts the TCA cycle at the levels of succinate dehydrogenase (SDH) and isocitrate dehydrogenase 2 (IDH2) leading to accumulation of succinate and isocitrate, respectively, only reduced SDH activity and increased succinate levels associate with disturbed steroidogenic capacity of adrenocortical cells. Specifically, IL1β reduces Sdhb expression and steroidogenesis in adrenocortical cells. These findings suggest that SDH activity is important for adrenocortical steroidogenesis and provide a link between inflammation and adrenocortical dysfunction through alterations in the TCA cycle.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Succinate mediates inflammation-induced adrenocortical dysfunction

Mateska

Witt

Hagag

et al. 2022

Preprint

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“…on two consecutive days and 1 h after the second dose, they were treated i.p. with LPS for 16 h. We focused on the effects of ENT-A010 in the hippocampus, since the hippocampus is strongly affected by peripheral inflammation and prone to neurodegeneration [61][62][63], and asked whether ENT-A010 affected the phenotype of hippocampal microglia. Staining of brain sections (including the hippocampal formation) from mice treated with ENT-A010, LPS or ENT-A010 + LPS for the microglial marker ionized calcium-binding adaptor molecule 1 (IBA-1) demonstrated that LPS treatment induced thickening of the branches and enlargement of the cell body of microglia, standing in accordance with previous studies [64,65].…”

Section: Ent-a010 Preserves the Homeostatic Phenotype Of Microglia In...mentioning

confidence: 99%

ENT-A010, a Novel Steroid Derivative, Displays Neuroprotective Functions and Modulates Microglial Responses

et al. 2022

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Tackling neurodegeneration and neuroinflammation is particularly challenging due to the complexity of central nervous system (CNS) disorders, as well as the limited drug accessibility to the brain. The activation of tropomyosin-related kinase A (TRKA) receptor signaling by the nerve growth factor (NGF) or the neurosteroid dehydroepiandrosterone (DHEA) may combat neurodegeneration and regulate microglial function. In the present study, we synthesized a C-17-spiro-cyclopropyl DHEA derivative (ENT-A010), which was capable of activating TRKA. ENT-A010 protected PC12 cells against serum starvation-induced cell death, dorsal root ganglia (DRG) neurons against NGF deprivation-induced apoptosis and hippocampal neurons against Aβ-induced apoptosis. In addition, ENT-A010 pretreatment partially restored homeostatic features of microglia in the hippocampus of lipopolysaccharide (LPS)-treated mice, enhanced Aβ phagocytosis, and increased Ngf expression in microglia in vitro. In conclusion, the small molecule ENT-A010 elicited neuroprotective effects and modulated microglial function, thereby emerging as an interesting compound, which merits further study in the treatment of CNS disorders.

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“…While neuroinflammation disrupts insulin sensitivity and leptin resistance (63), obesity reciprocally impairs microglia function (64). Central and peripheral inflammation processes are in constant communication and create feedback signaling that predisposes opioid-exposed individuals to adverse neurological and peripheral effects, i.e., cognitive and cardiometabolic deficits (65,66).…”

Section: Neural and Systemic Inflammation Of Opioidsmentioning

confidence: 99%

Aberrant Feeding and Growth in Neonates With Prenatal Opioid Exposure: Evidence of Neuromodulation and Behavioral Changes

Yen

Maron

2022

Front. Pediatr.

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Opioid use disorder (OUD) among pregnant women over the last decade has led to more than a fivefold increase in the number of neonates born with withdrawal signs known as Neonatal Abstinence Syndrome (NAS) or Neonatal Opioid Withdrawal Syndrome (NOWS). The impact of prenatal opioid exposure on these neonates remains a public health and research priority due to both its short and long-term effects on offspring. Among the adverse long-term effects associated with OUD is a metabolic syndrome with accompanying cardiovascular comorbidities. The susceptibility to metabolic diseases may begin as early as conception. Neonates born in a setting of prenatal opioid exposure are known to have aberrant early growth, e.g., lower birth weight and smaller head size, and dysregulated feeding behavior that ranges from feeding difficulty to hyperphagia which may predispose these neonates to metabolic syndrome in adulthood. However, studies on this topic are lacking. In this article, we describe the reported association between OUD and metabolic syndrome in adults, animal data linking opioid receptors with the development of diet-induced obesity, the inflammatory modulation of opioids and finally, neonatal salivary transcriptomic data from our laboratory that highlighted the sex-specific impact of opioids on the hypothalamic and reward receptors that regulate feeding behavior in opioid-exposed neonates. There is a great need for future research linking opioids with epigenetic and gene expression changes, as well as neuromodulatory effects in the developing brain, that may underlie the dysregulated feeding, growth, and long-term metabolic and cardiovascular risks for these neonates.

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The Impact of Obesity on Microglial Function: Immune, Metabolic and Endocrine Perspectives

Cited by 39 publications

References 456 publications

Succinate mediates inflammation-induced adrenocortical dysfunction

Succinate mediates inflammation-induced adrenocortical dysfunction

ENT-A010, a Novel Steroid Derivative, Displays Neuroprotective Functions and Modulates Microglial Responses

Aberrant Feeding and Growth in Neonates With Prenatal Opioid Exposure: Evidence of Neuromodulation and Behavioral Changes

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