Tissue-specific insulin signaling in the regulation of metabolism and aging

Abstract

In mammals, insulin signaling regulates glucose homeostasis and plays an essential role in metabolism, organ growth, development, fertility, and lifespan. The defects in this signaling pathway contribute to various metabolic diseases such as type 2 diabetes, polycystic ovarian disease, hypertension, hyperlipidemia, and atherosclerosis. However, reducing the insulin signaling pathway has been found to increase longevity and delay the aging-associated diseases in various animals, ranging from nematodes to mice. These seemly paradoxical findings raise an interesting question as to how modulation of the insulin signaling pathway could be an effective approach to improve metabolism and aging. In this review, we summarize current understanding on tissue-specific functions of insulin signaling in the regulation of metabolism and lifespan. We also discuss the potential benefits and limitations in modulating tissue-specific insulin signaling pathway to improve metabolism and healthspan.

Keywords: aging; insulin signaling; metabolism; tissue-specific.

Figure 1. Insulin signaling and function

The binding of insulin to its receptor on cell membrane results in insulin receptor (IR) tyrosine kinase activation and IR tyrosine phosphorylation. APPL1 functions as a piggyback protein that promotes IRS binding to the tyrosine phosphorylated IR, leading to IRS tyrosine phosphorylation and subsequent activation of the PI3K/PDK1/Akt signaling pathway. Activation of Akt promotes the phosphorylation and inhibition of TSC1/2, a negative regulator of the mTORC1 signaling pathway. Akt also phosphorylates many other cellular proteins and plays key roles in various cellular events. Tyrosine phosphorylation of IR promotes the association of the adaptor proteins Shc and Grb2 to the IR, leading to the activation of the RAS-RAF-MEK-ERK1/2 cascade, which is essential for cell growth, differentiation and protein synthesis.

Figure 2. Conserved insulin/IGF-1 regulation in longevity

The insulin/IGF-1-like pathway is conserved among various species and suppressing this pathway extends lifespan in species such as worm, fly, and mouse.

Figure 3. mTORC1 signaling and regulation

mTORC1, which regulates various cellular events such as cell growth, autophagy, and mRNA translation, is activated by insulin-stimulated and Akt-mediated phosphorylation and inhibition of TSC1/2, a negative regulator of mTOR. Inhibition of TSC1/2 leads to the activation of small G protein Rheb and thus enhanced mTORC1 signaling. mTORC1-mediated phosphorylation of Grb10 at Ser^501/503 switches the binding preference of Grb10 from the insulin receptor to Raptor, leading to the dissociation of Raptor from mTOR and thus down-regulation of mTORC1 signaling.