Update on Hypothalamic Inflammation and Gliosis: Expanding Evidence of Relevance Beyond Obesity

Abstract

Purpose of review: To evaluate the role of hypothalamic inflammation and gliosis in human obesity pathogenesis and other disease processes influenced by obesity.

Recent findings: Recent studies using established and novel magnetic resonance imaging (MRI) techniques to assess alterations in hypothalamic microarchitecture in humans support the presence of hypothalamic inflammation and gliosis in adults and children with obesity. Studies also identify prenatal exposure to maternal obesity or diabetes as a risk factor for hypothalamic inflammation and gliosis and increased obesity risk in offspring. Hypothalamic inflammation and gliosis have been further implicated in reproductive dysfunction (specifically polycystic ovarian syndrome and male hypogonadism), cardiovascular disease namely hypertension, and alterations in the gut microbiome, and may also accelerate neurocognitive aging. The most recent translational studies support the link between hypothalamic inflammation and gliosis and obesity pathogenesis in humans and expand our understanding of its influence on broader aspects of human health.

Keywords: Cardiovascular disease; Hypothalamic gliosis; Hypothalamic inflammation; Neurocognitive aging; Obesity; Prenatal exposures.

Figure 1.. Role of hypothalamic inflammation and gliosis in neurocognitive aging

Neurocognitive aging may be exacerbated by hypothalamic inflammation and gliosis through 1) direct effects on the brain, via perturbations in cognitive processes under hypothalamic control and dampened neurogenesis, and 2) systemic effect, mediated by autonomic dysregulation and neuroendocrine dysfunction, which lead to further dysfunction in energy homeostasis, glucose metabolism, and circadian rhythm, and may promote systemic inflammation. These ultimately feedback to the central nervous system contributing to neurodegeneration, neuroinflammation (including in the hypothalamus), and vascular disease – all of which are catalysts for neurocognitive aging. Created in BioRender.com.

Figure 2.. Theoretical model of pathogenic hypothalamic inflammation and gliosis and downstream effects

Dietary and prenatal exposures predispose humans to the development of hypothalamic inflammation and gliosis. Hypothalamic inflammation and gliosis subsequently lead to autonomic dysfunction, disrupted energy homeostasis, adipose expansion, peripheral inflammation, dysregulated glucose metabolism, and neuroendocrine dysfunction. These represent indirect pathways whereby hypothalamic inflammation and gliosis affect end organ function but there remains the possibility of direct pathways. For example, hypothalamic inflammation and gliosis may have direct effects on neurocognition and aging. EDCs endocrine disrupting chemicals, ACEs adverse childhood events, GDM gestational diabetes, FFAs free fatty acids, PCOS polycystic ovarian syndrome. Created in BioRender.com.