Understanding the mechanism by which healthy diet or exercise training improves metabolic outcomes is crucial to developing therapeutic targets for obesity-associated diseases. In this study, female mice were fed a high-fat diet (HFD) for 12 weeks and divided into 4 groups of lifestyle interventions that followed for 6 weeks: a. HFD; b. diet-change to chow; c. HFD+exercise; d. diet-change+exercise. Age-matched mice continuously fed a chow diet served as controls. An oral glucose tolerance test was performed 48 hours after the final exercise session. HFD induced obesity, dyslipidemia, fatty liver, and impaired glucose tolerance, which were completely reversed by diet-change. Exercise alone did not change obesity but partially improved glucose tolerance and fatty liver. The increased daily energy intake caused by HFD feeding was corrected by diet-change while exercise alone increased the energy expenditure and decreased RQ. Western blotting showed that HFD decreased pAKT, pAMPKβ, Glut4, and proteins involved in β-oxidation pathways in skeletal muscles compared to controls, which was reversed by diet-change alone. Exercise training alone partially reversed pAKT and Glut4 but significantly increased proteins in β-oxidation pathways compared to controls and the diet-change group. Exercise and diet-change in combination improved metabolic outcomes similarly to diet-change alone. RNAseq of visceral adipose tissue showed that HFD modified multiple canonical pathways. Among those pathways, 1) Ca+, G-protein coupled receptor, and hepatic fibrosis signaling were reversed by diet-change and exercise training alone; 2) cAMP-mediated and ILK signaling were reversed by diet-change alone; and 3) PKA signaling was reversed by exercise training alone. Further analysis of those pathways showed several genes that were modified by HFD and reversed by all three lifestyle interventions, which could be potentially targeted for improving metabolic diseases.

Disclosure

L.Zhu: None. J.An: None. B.Litts: None. C.L.Atzrodt: None. J.M.Stafford: None.

Funding

National Institutes of Health (DK109102, HL144846, AG077038); U.S. Department of Veterans Affairs (BX005459-01)

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