Immune cells drive chronic inflammation underlying obesity-related T2DM. We previously reported a cholesterol metabolism pathway as the top coordinated transcriptional module in human monocytes associated with both obesity and T2DM (FDR <0.05) . To investigate whether this pathway is a modifiable link between obesity and T2DM, we randomly assigned 112 adults with obesity and prediabetes aged 40-70 years, 71% woman, 29% African American, to a weight loss intervention using Medifast meal replacement (N=63) or a weight stable control group (N=49) for 4 months. The outcome was a composite measure as the average of standard scores of cholesterol metabolism gene transcripts in monocytes. The intervention achieved 10% weight loss. The control group remained weight stable. Compared with the weight stable group, the weight loss group experienced reductions in both the composite measure and HbA1c (Table) . Changes in the composite measure and HbA1c were correlated (r=0.24, p=0.01) . For individual gene transcripts of this pathway, weight loss reversed obesity-associated upregulation in cholesterol synthesis (FDFT1 and SQLE) , fatty acid synthesis (SCD and FADS1) , and cholesterol uptake (LDLR and MYLIP) (p values <0.05) .
In conclusion, weight loss induces beneficial changes in the cholesterol metabolism pathway in monocytes, a potential therapeutic target for obesity-related T2DM.
J.Ding: Research Support; Medifast, Inc. K.Lohman: None. S.B.Kritchevsky: None. J.S.Parks: None. I.Hoeschele: None. B.J.Nicklas: None. J.Demons: None. Y.Liu: None.
National Institutes of Health (R01DK103531)