Astrocytic Process Plasticity and IKKβ/NF-κB in Central Control of Blood Glucose, Blood Pressure, and Body Weight

Abstract

Summary Central regulation of metabolic physiology is mediated critically through neuronal functions; however, if astrocytes are also essential remains unclear. Here we show that the high-order processes of astrocytes in the mediobasal hypothalamus displayed shortening in fasting while elongation in fed status. Chronic overnutrition and astrocytic IKKβ/NF-κB upregulation similarly impaired astrocytic plasticity leading to sustained shortening of high-order processes. In physiology, astrocytic IKKβ/NF-κB upregulation resulted in early-onset effects including glucose intolerance and blood pressure rise and late-onset effects including body weight and fat gain. Appropriate inhibition in astrocytic IKKβ/NF-κB protected against chronic overnutrition from impairing astrocytic plasticity and these physiological functions. Mechanistically, astrocytic regulation of hypothalamic extracellular GABA level and therefore BDNF expression were found partly accountable. Hence, astrocytic process plasticity and IKKβ/NF-κB play significant roles in central control of blood glucose, blood pressure and body weight as well as the central induction of these physiological disorders leading to disease.

Deletion of astrocytic BMAL1 results in metabolic imbalance and shorter lifespan in mice

“…Our findings that the administration of a GABAA receptor antagonist normalized the glutamate levels, delayed the reactive gliosis and the metabolic phenotypes and increased the lifespan of Bmal1cKO mice, suggest that the altered GABA and/or glutamate astrocyte–neuron coupling underlie the phenotypes of our mutants. This hypothesis is supported by previous reports showing that astrocytes critically modulate hypothalamic neural circuits controlling energy homeostasis (Chen et al, ; Zhang, Reichel, Han, Zuniga‐Hertz, & Cai, ) by modulating extracellular GABA bioavailability (Zhang et al, ). Additionally, astrocytes can impact the molecular clock in cortical, hippocampal, SCN (Barca‐Mayo et al, ; Barca‐Mayo, Berdondini, & De Pietri Tonelli, ; Tso et al, ; Duhart et al, ) and hypothalamic neurons (present study).…”

Astrocytes in neuroendocrine systems: An overview

“…Further evidence for a role of astrocytes in the physiological response to energy imbalance comes from experiments where mice are pushed out of homeostasis into negative energy balance by fasting. In common with acute energy excess associated with feeding a high‐fat diet, fasting impacts hypothalamic astrocyte signalling . Taken together, these studies indicate that hypothalamic astrocytes are sensitive to acute deviations in energy homeostasis.…”

“…Returning DIO mice to a standard chow diet results in weight loss and reversal of the astrogliosis, highlighting the plastic nature of this response. The physiological significance of these changes is reinforced by studies indicating that inducing inflammatory signalling in astrocytes results in obesity, whereas preventing inflammation preserves astrocytic plasticity protecting against DIO . Supporting this supposition, brain‐wide deletion of astrocyte IKK β during the induction of DIO is protective against hypothalamic inflammation and prevents subsequent weight gain .…”

“…Glucose intolerance driven by high‐fat diet challenge also has an astrocytic component. For example, astrocyte‐specific inducible knockout of the NF‐κB activating molecule IKK β improves glucose intolerance caused by DIO, restoring glucose handling and insulin sensitivity in addition to reducing astrogliosis in the medial basal hypothalamus/ARC . Additionally, astrocyte‐specific constitutive activation of IKK β causes glucose intolerance in chow fed mice via a mechanism involving increased extracellular GABA preventing the release of the growth hormone brain‐derived neurotrophic factor (BDNF) .…”

Physiological and pathophysiological roles of hypothalamic astrocytes in metabolism

“…Astrocytes can also metabolise many of the peripheral signals that they transport, such as glucose to lactate, thus controlling and modifying external messages reaching the surrounding neurones and directly influencing their responses. Although many of these functions have been discovered and studied in regard to astrocytic functions in disease process such as Alzheimer's or Parkinson's diseases, they have also come into the limelight in the field of neuroendocrinology for their implication in the perpetuation of weight gain and development of complications of obesity . Indeed, a better understanding of the role of these glial cells in the physiological control of metabolism would undoubtedly lead to a clearer vision of the processes that lead to comorbidities such as type 2 diabetes and cardiovascular dysfunction in obesity.…”