Insulin and IGF-1 elicit robust transcriptional regulation to modulate autophagy in astrocytes

Insulin is a principal metabolic hormone. It regulates a plethora of metabolic pathways in peripheral tissues. Recent studies have shown that insulin signaling plays fundamental roles in the brain. Loss of insulin action in astrocytes leads to impaired brain glucose sensing and behavioral abnormalities in mice. How insulin signaling modulates astrocyte function and neural circuits is not completely known. Overall design: Using next-generation RNA sequencing, we show that insulin significantly regulates the expression of over 1,200 genes involved in multiple functional processes in primary astrocytes. The closely related insulin-like growth factor 1 (IGF-1) triggers similar robust transcriptional reprogramming in astrocytes. Thus, over 50% of the significantly regulated genes are regulated by both ligands. As expected, these commonly regulated genes are highly enriched in pathways involved in lipid and cholesterol biosynthesis. Additionally, insulin and IGF-1 induce the expression of genes involved in ribosomal biogenesis, while suppressing the expression of genes involved in autophagy, indicating a common role of insulin and IGF-1 on protein homeostasis in astrocytes. By comparing insulin responsiveness in astrocytes without endogenous IR, IGF1R or both, we show that only IR/IGF1R double knockout astrocytes display blunted insulin-dependent suppression of autophagy genes, including p62, Ulk1/2, and several Atg genes, indicating both IR and IGF1R can elicit insulin-dependent transcriptional regulation on autophagy. In summary, insulin/IGF-1 potently suppresses autophagy in astrocytes through transcriptional regulation, indicating a potential important role of astrocytic insulin/IGF-1 signaling on proteostasis. Impairment of this regulation in insulin resistance and diabetes may contribute to neurological complications related to diabetes.