Hypothalamic inflammation in metabolic disorders and aging

Abstract

The hypothalamus is a critical brain region for the regulation of energy homeostasis. Over the years, studies on energy metabolism primarily focused on the neuronal component of the hypothalamus. Studies have recently uncovered the vital role of glial cells as an additional player in energy balance regulation. However, their inflammatory activation under metabolic stress condition contributes to various metabolic diseases. The recruitment of monocytes and macrophages in the hypothalamus helps sustain such inflammation and worsens the disease state. Neurons were found to actively participate in hypothalamic inflammatory response by transmitting signals to the surrounding non-neuronal cells. This activation of different cell types in the hypothalamus leads to chronic, low-grade inflammation, impairing energy balance and contributing to defective feeding habits, thermogenesis, and insulin and leptin signaling, eventually leading to metabolic disorders (i.e., diabetes, obesity, and hypertension). The hypothalamus is also responsible for the causation of systemic aging under metabolic stress. A better understanding of the multiple factors contributing to hypothalamic inflammation, the role of the different hypothalamic cells, and their crosstalks may help identify new therapeutic targets. In this review, we focus on the role of glial cells in establishing a cause-effect relationship between hypothalamic inflammation and the development of metabolic diseases. We also cover the role of other cell types and discuss the possibilities and challenges of targeting hypothalamic inflammation as a valid therapeutic approach.

Hordeum vulgare ethanolic extract mitigates high salt-induced cerebellum damage via attenuation of oxidative stress, neuroinflammation, and neurochemical alterations in hypertensive rats

“…Additionally, this research's results revealed that the HSD reduced NOx production in the cerebellum (Zheng et The results of this study con rmed that the high-salt diet caused neuroin ammation manifested by the signi cant rise in the levels of TNF-α and IL-1β in the cerebellum, which is consistent with previous ndings that revealed a signi cant elevation in IL-1, IL-6, and TNF-α tissue levels in the PVN of Ang IIinduced hypertensive rats (Knoll et al 2017;Yu et al 2021;Bhusal et al 2021). Intracerebroventricular and PVN injections of IL-1 β increased the blood pressure of normotensive Sprague-Dawley rats (Shi et al 2010), and infusion of an IL-1 inhibitor into the PVN of salt-sensitive hypertension rats attenuated hypertensive responses by reinstating the balance between pro-and anti-in ammatory cytokines and decreasing oxidative stress in the PVN (Qi et al 2016).…”

“…Many studies have found that a high salt diet produces an excessive amount of reactive oxygen species (ROS) that is essential in modulating blood pressure and sympathetic nerve activity in hypertension (Gao et al 2017;Yu et al 2021). Additionally, substantial evidence demonstrates that high salt intake increased pro-in ammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and the IL-6, decreased anti-in ammatory cytokines, such as IL-10, in the PVN (Qi et al 2016; Knoll et al 2017;Bhusal et al 2021). Thus, restoring the balance between the excitatory and inhibitory neurotransmitters and reducing the production of ROS and pro-in ammatory cytokines in the brain is bene cial in treating hypertension.…”

Anthocyanins in Chronic Diseases: The Power of Purple

“…The role of the hypothalamus in the regulation of energy homeostasis is well-known. The inflammatory activation of glial cells in the hypothalamus leads to changes in feeding habits, thermogenesis and adipokine signalling, leading to metabolic disorders [ 141 ]. Further, maternal obesity and inflammation may lead to metabolic reprogramming in the foetus, which could influence both childhood and adult body weight and composition, thus increasing the risk of transgenerational transmission of obesity [ 142 ].…”

Identifying of immune‐associated genes for assessing the obesity‐associated risk to the offspring in maternal obesity: A bioinformatics and machine learning

“…The arcuate (Arc) nucleus of the hypothalamus comprises anorexigenic neuropeptide Y (NPY)/agouti‐related protein (AgRP) neurons and anorexigenic proopiomelanocortin (POMC) neurons, which subtly regulate the energy balance 7 . Recent evidence suggests that although neurons are fundamental to the physical functions of the hypothalamus, their proper function and systemic metabolic regulation largely rely on the surrounding non‐neuronal cells, such as glia, epithelial cells, pericytes, and endothelia 8 . Aberrant nutritional elements, including fatty acids and glucose, transported into the hypothalamus primarily through the permeable blood–brain barrier (BBB), can induce glial activation and metaflammation within the hypothalamus 9 .…”

“…Aberrant nutritional elements, including fatty acids and glucose, transported into the hypothalamus primarily through the permeable blood–brain barrier (BBB), can induce glial activation and metaflammation within the hypothalamus 9 . Hypothalamic inflammation is increasingly appreciated as an important mechanism for obesity and other metabolic disorders 8,9 …”