Abstract
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.
Highlights
Hypothalamic inflammation plays an important role in disrupting feeding behavior and energy homeostasis as well as in the pathogenesis of obesity and diabetes
To investigate whether PDK2 is expressed in neurons differentially, we performed immunostaining of PDK2 and AgRP or POMC in serial brain sections isolated
Our findings demonstrate a critical role that astrocyte-specific PDK2 plays in the hypothalamus in regulating metabolic and inflammatory pathways that contribute to the hypothalamic pathology of altered feeding behavior associated with diabetes
Summary
Hypothalamic inflammation plays an important role in disrupting feeding behavior and energy homeostasis as well as in the pathogenesis of obesity and diabetes. Microglia[5,15], astrocytes[7,16], perivascular macrophages[17], and neurons[18] are the key cell types that contribute to the hypothalamic inflammation associated with metabolic disorders. Microglia, as first-responder cells, play an important role in hypothalamic inflammation and neuronal circuit alterations, promoting obesity and subsequent metabolic complications[5,15,20,21]. Our previous studies have identified PDKs as an important regulator of immune cell metabolism and have suggested its widespread expression[34,35] and critical role in inflammation in the peripheral nervous system. Astrocyte metabolic alterations are critical for their inflammatory activation/phenotype[29,30], the contribution of astrocyte metabolic reprogramming to hypothalamic inflammation and related metabolic disorders, such as diabetes, remains to be explored
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