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

Abstract

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.

Microglial Inflammatory Signaling Orchestrates the Hypothalamic Immune Response to Dietary Excess and Mediates Obesity Susceptibility

“…On the whole, hypothalamic inflammation promotes overconsumption and weight gain in mice. For example, deleting or inhibiting the inflammatory master regulator NF-κB in neurons or astrocytes mitigated DIO while stimulating inflammation in the MBH impaired leptin and insulin signaling (Benzler et al, 2015; Douglass et al, 2017a; Zhang et al, 2008). However, these studies have not addressed the potential role of microglia in this process.…”

Physiological and pathophysiological roles of hypothalamic astrocytes in metabolism

“…This observation is similar to that described above when synaptic reorganisation is blocked. In another study where inhibitor of kappa kinase (IKK)β was specifically knocked out in astrocytes to limit their inflammatory response a very different role for astrocyte activation in long‐term weight gain was demonstrated . Douglass et al reported that deletion of this signalling pathway in astrocytes before HFD exposure had no significant effect on weight gain or glucose tolerance.…”

“…In another study where inhibitor of kappa kinase (IKK)β was specifically knocked out in astrocytes to limit their inflammatory response a very different role for astrocyte activation in long‐term weight gain was demonstrated . Douglass et al reported that deletion of this signalling pathway in astrocytes before HFD exposure had no significant effect on weight gain or glucose tolerance. However, if this mechanism is deleted in astrocytes of diet‐induced obese mice, a rapid reduction in food intake and an increase in energy expenditure is observed, with this resulting in reduced weight gain.…”

“…Although microglia are involved in this central inflammatory response, astrocytes also participate. Indeed, inhibition of inflammatory signalling specifically in astrocytes of HFD‐induced obese mice was shown to improve glucose tolerance and reduce insulin resistance, although this could be the result of the reduction in body weight that was also induced by the reduction in hypothalamic inflammation …”

“…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.…”