Hypothalamic inflammation in metabolic disorders and aging.

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.

Astrocytic pyruvate dehydrogenase kinase-2 is involved in hypothalamic inflammation in mouse models of diabetes.

Hypothalamic inflammation plays an important role in disrupting feeding behavior and energy homeostasis as well as in the pathogenesis of obesity and diabetes. Here, we show that pyruvate dehydrogenase kinase (PDK)-2 plays a role in hypothalamic inflammation and its sequelae in mouse models of diabetes. Cell type-specific genetic ablation and pharmacological inhibition of PDK2 in hypothalamic astrocytes suggest that hypothalamic astrocytes are involved in the diabetic phenotype. We also show that the PDK2-lactic acid axis plays a regulatory role in the observed metabolic imbalance and hypothalamic inflammation in mouse primary astrocyte and organotypic cultures, through the AMPK signaling pathway and neuropeptidergic circuitry governing feeding behavior. Our findings reveal that PDK2 ablation or inhibition in mouse astrocytes attenuates diabetes-induced hypothalamic inflammation and subsequent alterations in feeding behavior.

Hypothalamic inflammation and malfunctioning glia in the pathophysiology of obesity and diabetes: Translational significance.

Preclinical studies have suggested that chronic inflammation in the brain might be associated with multiple metabolic disorders, including obesity and diabetes. In particular, hypothalamic inflammation interferes with the endocrine system and modulates nutritional homeostasis, leading to metabolic alterations and consequent pathologies. With regard to the mechanisms underlying molecular and cellular pathogenesis, neurons, non-neuronal cells, and the crosstalk between them have gained particular attention. Specifically, malfunctioning glia have recently been implicated as an important component of pathological hypothalamic inflammation. Hypothalamic inflammation modulates food intake, energy expenditure, insulin secretion, hepatic glucose production, and glucose and fatty acid metabolism. Moreover, growing evidence suggests that hypothalamic inflammation is intrinsically associated with the pathogenesis of obesity, diabetes, and their dysfunctional consequences. However, the translational significance of hypothalamic inflammation has not yet been fully explored. In this review, we cover recent advances suggesting that hypothalamic inflammation and glia play a central role in the ontology of obesity, diabetes, and their complications. Finally, we explore the possibilities and challenges of targeting hypothalamic inflammation as a potential therapeutic strategy.