Glial adaptations to high-fat diet in the mediobasal hypothalamus and effects on metabolic control

Obesity represents a global health issue and major socioeconomic burden. As a multifactorial disease, obesity is influenced by genetic and environmental factors, with maladaptive eating habits and high-fat, high-sugar diets (HFD, HFHS) overconsumption being major contributors. While traditionally studied in the context of adipose tissue and peripheral metabolism, the brain is at the centre of this pathology. In the central nervous system, circulating free fatty acids (FAs) are taken up directly, while brain lipoprotein lipases break down triglyceride-rich particles, providing an additional source of fatty acids. Growing evidence supports the idea that both neuronal and glial cells in the hypothalamus undergo significant changes in response to increased HFD consumption. These alterations may play a key role in the wide range of dysfunctions associated with obesity. The review at hand explores how FAs are utilised by the brain and how excessive intake of FAs during HFD feeding impacts glial cell function. We focus on glial cells within the mediobasal hypothalamus (MBH), one of the key brain subregions regulating energy balance. Microglia, the brain's resident immune cells, are activated by HFD exposure, leading to morphological changes and inflammation in the hypothalamus, which likely contributes to neuronal dysfunction. Microglial depletion in the MBH can significantly limit HFD-induced metabolic alterations by reducing food intake, weight gain and brain inflammation. Astrocytes respond to HFD intake by utilising its nutrients for energy production. Unlike neurons, astrocytes actively perform β-oxidation and ketogenesis, which influence feeding behaviour. HFD-induced ketone production by hypothalamic astrocytes has been shown to acutely trigger an anorectic response in rats. Like microglia, they also undergo significant morphological changes and increase cytokine release in response to HFD, leading to altered synaptic and neurotransmitter regulation, which may in turn impair hypothalamic control of energy homeostasis. This review highlights the critical role of glial cells in mediating the effects of dietary FAs on brain function, emphasising their contribution to obesity-related neuroinflammation, hypothalamic dysfunction and energy balance.