Insulin Signaling Suppresses Autophagy in Astrocytes

Abstract

Insulin is a peptide hormone produced in the pancreas that is crucial in regulating systemic glucose homeostasis and energy balance. Diabetes mellitus is an endocrine disease that can be broken down into two subtypes. Type I diabetes is low to non‐measurable amounts of insulin being produced by the pancreas consequent to cellular damage. Type II diabetes is caused by insulin resistance and later, decreased insulin secretion. Both conditions lead to hyperglycemia and impaired insulin signaling throughout the body if left untreated. Numerous studies have shown that insulin signaling controls several metabolic pathways in peripheral insulin‐sensitive tissues, such as liver, adipose tissue, and muscle. Among them, autophagy is one of the most potent pathways suppressed by insulin. Autophagy is a molecular mechanism by which cells recycle the damaged or outdated components, including proteins and lipids, to alleviate cellular stresses. In addition, during the fasting state, autophagy acts as a “metabolic rescuing” pathway to degrade non‐essential proteins, providing free amino acids for the synthesis of essential proteins. Conversely, when nutrients are abundant postprandially, insulin potently suppresses this “self‐eating” process in cells. While studies have demonstrated the important role of insulin signaling on the autophagic pathway in peripheral tissues, whether insulin signaling contributes to the regulation of the autophagic pathway in the central nervous system remains elusive. Here, we investigate the role of insulin stimulation on autophagy in mouse astrocytes, the most abundant glial cells in the brain. We show that following insulin stimulation (100 nM, 6 h), the transcription of the critical genes involved in autophagic pathway, including p62, Ulk1/2, several Atg genes, are all dramatically decreased. Consistently, the protein levels of p62, Ulk1/2, as well as LC3, are all reduced following insulin stimulation, indicating suppression of the autophagic process. The effect of insulin signaling on the transcriptional regulation is potent, since 1 nM of insulin is sufficient to suppress many of the critical autophagic genes. To confirm whether insulin suppresses cellular autophagy in astrocytes through insulin receptors, we assessed the expression of autophagic genes following insulin stimulation in both wild‐type (WT) and insulin receptor knockout (IRKO) astrocytes. Compared with WT astrocytes, insulin partially suppresses the expression of autophagic genes in IRKO astrocytes, indicating insulin also can signal through the IGF‐1 receptor in astrocytes. In summary, insulin signaling potently suppresses the autophagic process in astrocytes. This connection between autophagy gene transcription and insulin levels may be an important mechanism for the CNS‐related complications in diabetic patients.