Nuclear receptors reverse McGarry's vicious cycle to insulin resistance

Abstract

Several pathways and pathologies have been suggested as connections between obesity and diabetes, including inflammation of adipose and other tissues, toxic lipids, endoplasmic reticulum stress, and fatty liver. One specific proposal is that insulin resistance induces a vicious cycle in which hyperinsulinemia increases hepatic lipogenesis and exacerbates fatty liver, in turn further increasing insulin resistance. Here I suggest that reversing this cycle via suppression of the lipogenic transcription factor SREBP-1c is a common thread that connects the antidiabetic effects of a surprising number of nuclear hormone receptors, including CAR, LRH-1, TRβ, ERα, and FXR/SHP.

Figure 1. Proposed model for McGarry’s lipogenic vicious cycle, and its reversal

In the red, counterclockwise cycle, insulin resistance generates a self-reinforcing negative regulatory loop in which elevated insulin levels increase SREBP-1c expression and steatosis. This further decreases insulin sensitivity and increases in serum insulin levels to continue the negative cycle. Several NRs, including ERα CAR, LRH-1 TRβ and FXR/SHP act to decrease SREBP-1c expression, lowering steatosis and setting up a positive, anti-lipogenic cycle to improved insulin sensitivity.