S. Ehrlicher1, S. Dasari2, S. Newsom1, M. Robinson1

1Oregon State University, Corvallis, OR;2Mayo Clinic, Rochester, MN

PURPOSE: Changes to the mitochondrial proteome are implicated in insulin resistance and are regulated in part by autophagy, which is activated by exercise and suppressed by nutrients. We investigated the remodeling of the mitochondrial proteome in response to high fat feeding including sensitivity of autophagy to nutrients and requirement of exercise induced autophagy for metabolic flexibility. METHODS: Insulin resistance was induced in C57BL/6J mice (WT) using 12 weeks of high-fat (HF) compared to low-fat (LF) diet. Proteomic identification by mass spectrometry was performed on mitochondria isolated from the gastrocnemius in HF versus LF fed mice. The ability for nutrients to suppress accumulation of the autophagy marker LC3II was determined during intravenous infusion of saline, hyperinsulinemia with euglycemia or hyperglycemia with hyperinsulinemia (n=7-10). The requirement of autophagy for metabolic adaptations to exercise was assessed using a mouse model that cannot induce autophagy with exercise (BCL) versus WT control. LF and HF diet mice performed eight weeks of treadmill training then respiratory exchange ratio (RER) was measured during 24 hours of feeding or fasting (n=3-5). RESULTS: The abundance of 40 mitochondrial proteins was greater (fold change > 0.5 and p<0.05) in HF mice compared to LF mice, primarily in pathways of β-oxidation. Despite insulin resistance to glucose metabolism, autophagy activation was similar between diet groups during hyperglycemic-hyperinsulinemic conditions (HF, LC3II = 0.04 ±0.02; LF, LC3II = 0.03 ±0.01) but was lower (p<0.05) than saline (HF, LC3II = 0.08 ±0.04; LF, LC3II = 0.06 ±0.03). BCL and WT mice had similar RER values following exercise training that reflected the LF diet (WT, RER = 0.94 ±0.01; BCL, RER = 0.93 ±0.03) and HF diet (WT, RER = 0.76 ±0.004; BCL, RER = 0.76 ±0.01). Additionally, all mice were able to shift to lipid oxidation during fasting (LF WT, RER = 0.71 ±0.01; LF BCL, RER = 0.72 ±0.01; HF WT, RER = 0.72 ±0.004; HF BCL, RER = 0.72 ±0.003). CONCLUSION: Insulin resistance shifted the mitochondrial proteome to greater β-oxidation capacity and did not change suppression of autophagy to insulin and glucose, but may impair the sensitivity of autophagy to insulin. The lack of autophagy activation during exercise did not impede whole body metabolic flexibility.

Funding: K01DK103829 to MMR

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