|Moore, David -|
Submitted to: Cell Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: March 8, 2012
Publication Date: May 2, 2012
Citation: Moore, D.D. 2012. Nuclear receptors reverse McGarry's vicious cycle to insulin resistance. Cell Metabolism. 15:615-622. Interpretive Summary: Accumulation of fat in the liver is linked to diabetes. This is due to a self-reinforcing negative cycle in which liver fat causes more liver fat and increased resistance to insulin. In this perspective on mechanisms of insulin resistance, this is termed McGarry’s vicious cycle. Research from our laboratory and others have identified several hormonal signals that can decrease liver fat, thereby reversing this cycle. These signals share a mechanism of inhibiting a primary driver of fat accumulation, which provides insight into both causes of metabolic disease and therapeutic approaches to treat it.
Technical 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. In this perspective, I suggest that reversing this vicious 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, TRbeta, ERalpha, and FXR/SHP.