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The AMPK-PP2A axis in insect fat body is activated by 20-hydroxyecdysone to antagonize insulin/IGF signaling and restrict growth rate

Significance Final body size determination in animals remains a long-standing puzzle in the field of developmental biology. In insects, insulin/insulin-like growth factor signaling (IIS) and the steroid hormone 20-hydroxyecdysone (20E) are mainly responsible for the growth rate and growth period, respectively, and consequently the final body size. Here, we report that 20E activates AMPK by up-regulating its gene expression and inducing sugar starvation. In turn, AMPK activates protein phosphatase 2A, which further dephosphorylates and inactivates key components in IIS in the fat body, and eventually suppresses the larval growth rate. These data answer the question of how 20E antagonizes IIS and modulates growth rate. In insects, 20-hydroxyecdysone (20E) limits the growth period by triggering developmental transitions; 20E also modulates the growth rate by antagonizing insulin/insulin-like growth factor signaling (IIS). Previous work has shown that 20E cross-talks with IIS, but the underlying molecular mechanisms are not fully understood. Here we found that, in both the silkworm Bombyx mori and the fruit fly Drosophila melanogaster, 20E antagonized IIS through the AMP-activated protein kinase (AMPK)-protein phosphatase 2A (PP2A) axis in the fat body and suppressed the growth rate. During Bombyx larval molt or Drosophila pupariation, high levels of 20E activate AMPK, a molecular sensor that maintains energy homeostasis in the insect fat body. In turn, AMPK activates PP2A, which further dephosphorylates insulin receptor and protein kinase B (AKT), thus inhibiting IIS. Activation of the AMPK-PP2A axis and inhibition of IIS in the Drosophila fat body reduced food consumption, resulting in the restriction of growth rate and body weight. Overall, our study revealed an important mechanism by which 20E antagonizes IIS in the insect fat body to restrict the larval growth rate, thereby expanding our understanding of the comprehensive regulatory mechanisms of final body size in animals.