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Aims/Introduction  Previous studies have shown that an organism's nutritional status changes the protein levels of insulin receptor substrate 1 ( IRS ‐1) in a tissue‐specific manner. Although the mechanisms underlying the regulation of  IRS ‐1 in the nutrient‐rich conditions associated with diabetes and insulin resistance have been well studied, those under nutrient‐poor conditions remain unknown. The aim of the present study was to investigate how  IRS ‐1 protein levels change depending on the nutritional status of 3T3‐L1 preadipocytes.    Materials and Methods  3T3‐L1 preadipocytes were treated with glucose‐, amino acid‐ and serum‐free medium for starvation.  IRS ‐1 protein levels were detected by western blot. Autophagy activity was observed by western blot and fluorescence microscopy. The effect of autophagy and p62, an adaptor for selective autophagy, on  IRS ‐1 protein levels under starvation conditions was examined by western blot and immunocytochemistry.    Results  We showed that the levels of  IRS ‐1, but not those of insulin receptor and protein kinase B, decreased when starvation activated autophagy. The inhibition of autophagy by chloroquine or autophagy‐related 7 ( Atg7 ) ribonucleic acid interference counteracted the starvation‐induced decrease of  IRS ‐1. Additionally,  Atg7  knockdown increased insulin‐stimulated phosphorylation of protein kinase B under starvation conditions. Furthermore, p62 colocalized with  IRS ‐1 under starvation conditions, and  p62  knockdown counteracted the starvation‐induced degradation of  IRS ‐1.    Conclusions  Autophagy through p62 plays an important role in regulating  IRS ‐1 protein levels in response to nutritional deficiency. The present findings suggest that autophagy might function as energy depletion‐sensing machinery that finely tunes insulin signal transduction.

p62‐mediated autophagy affects nutrition‐dependent insulin receptor substrate 1 dynamics in 3T3‐L1 preadipocytes