Microglia are glial cells residing in the central nervous system (CNS), recognized as the main immune modulator cells of the CNS with roles similar to those of tissue macrophages. They are crucial for preserving the CNS’s health since they coordinate neuroinflammatory responses and help to get rid of infections and damaged neurons. Additionally, microglia play a significant role in other physiological processes including synaptic pruning and neurogenesis, which aid in the remodelling of synaptic networks. Microglial cells act as sentinels in a healthy physiological situation, always keeping an eye on their surroundings. When the brain’s equilibrium is upset, microglia activate, which is evidenced by changes in cellular shape, expression of various immunomodulatory mediators, and increased phagocytic activity. Once the problem is solved and homeostasis is restored, they usually revert to the surveillance or resting state. However, sometimes microglial cells retain a memory of past inflammatory episodes, thus acquiring a “primed” state. Primed microglia have a significantly higher capability for responding to subsequent stimuli and are also more sensitive to them, so they may even deploy neurotoxic responses.
Many different stimuli can trigger inflammation within the CNS. Thus, a high-fat diet (HFD) is an inflammatory stimulus; even after just a few days of HFD intake, signs of moderate inflammation may be seen in brain areas such as the hypothalamus. It has been demonstrated that hypothalamic inflammation alters the hypothalamus circuitry and causes body weight dysregulation, including obesity, by interfering with the control of food and energy balance.
In a new study published in the peer-reviewed journal GLIA, Spanish researchers at University of Malaga, Professor María D. López-Ávalos and co-workers designed a new model that depicted an acute neuroinflammatory process triggered by neuraminidase administered within the brain ventricles, followed by a short-term HFD a few months later. The primed condition of hypothalamic microglia and their reaction to the pro-inflammatory HFD were studied in this context where animals remained lean. A second experimental design envisioned obesity, provoked by sustained HFD feeding, months following the acute neuroinflammatory process triggered by neuraminidase. Diet-induced obesity (DIO) provides a challenge to the hypothalamus, which regulates food intake, body weight, and energy balance. In obese mice, the effects of hypothalamic microglial priming on eating and body weight regulation were examined.
The research team discovered that neuraminidase -induced inflammation causes long-term changes in the basal hypothalamus, including microglia and neurons that compose the energy balancing circuitry in this region. They postulated that microglial priming could be an underlying mechanism for hypothalamic disregulation. Indeed, morphological features of hypothalamic microglia suggest that these cells respond more strongly to HFD and to DIO when are primed by neuraminidase -induced inflammation. Such long-term hypothalamic abnormalities caused by previous inflammation may account for a distorted response to any future dietary or inflammatory stimulus, as with obesity caused by HFDs. The potential that these hyperactive microglia are involved in modifying the neuronal populations in charge of controlling eating and energy balance is intriguing, but more research is needed. The authors suggested that a previous neuroinflammatory event, even if it was transient, may affect the outcome of subsequent episodes of inflammation. The subsequent inflammatory stimulation does not have to be severe or related to infections, as does the DIO paradigm that they employed. The basal hypothalamus, a critical hub for the regulation of autonomous activities, was found to be particularly vulnerable to inflammation-induced long-term changes in this study. Aside from the ensuing disruption in energy balance regulation, the influence of such changes on other autonomous or neuroendocrine reflexes should be investigated.
Obesity is a major health problem reaching worldwide pandemic proportions. It is associated with the development of chronic inflammation in the adipose tissue which gradually becomes systemic and may affect other organs, including the brain. Microglia can respond to various peripheral inflammatory signals, such as HFD or inflammation linked to obesity, and drive neuroinflammation. If this happens when microglia is primed by previous events, the neuroinflammation will be enhanced. In conclusion, Professor María D. López-Ávalos and colleagues showed that a single acute neuroinflammatory event may induce a prolonged state of priming in microglial cells, particularly those in the hypothalamus, with implications for hypothalamic cytoarchitecture and its regulatory role in response to dietary stressors. The authors’ study is important since it could lead to the identification of targets for the management of neuroinflammation in metabolic disease.
Fernández‐Arjona MD, León‐Rodríguez A, Grondona JM, López‐Ávalos MD. Long‐term priming of hypothalamic microglia is associated with energy balance disturbances under diet‐induced obesity. Glia. 2022 May 23.