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bioRxiv · 10.1101/2022.12.21.521172

Hepatic mTORC2 compensates for loss of adipose mTORC2 in mediating energy storage and glucose homeostasis

Frei, I. C.·Weissenberger, D.·Muller, C.·Hall, M. N.·Shimobayashi, M.
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Abstract

Mammalian target of rapamycin complex 2 (mTORC2) is a protein kinase complex that plays an important role in energy homeostasis. Loss of adipose mTORC2 reduces lipogenic enzyme expression and de novo lipogenesis in adipose tissue. Adipose-specific mTORC2 knockout mice also displays triglyceride accumulation in the liver. However, the mechanism and physiological role of hepatic triglyceride accumulation upon loss of adipose mTORC2 are unknown. Here, we show that loss of adipose mTORC2 increases expression of de novo lipogenic enzymes in the liver, thereby causing accumulation of hepatic triglyceride and hypertriglyceridemia. Simultaneous inhibition of lipogenic enzymes in adipose tissue and liver by ablating mTORC2 in both tissues prevented accumulation of hepatic triglycerides and hypertriglyceridemia. However, loss of adipose and hepatic mTORC2 caused severe insulin resistance and glucose intolerance. Thus, our findings suggest that increased hepatic lipogenesis is a compensatory mechanism to cope with loss of lipogenesis in adipose tissue, and further suggest that mTORC2 in adipose tissue and liver plays a crucial role in maintaining whole-body energy homeostasis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/521172v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@904812org.highwire.dtl.DTLVardef@6b9f43org.highwire.dtl.DTLVardef@1a507b9org.highwire.dtl.DTLVardef@19e08a7_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Frei, I. C., Weissenberger, D., Muller, C., Hall, M. N., Shimobayashi, M.. 2022-12-21. Hepatic mTORC2 compensates for loss of adipose mTORC2 in mediating energy storage and glucose homeostasis. https://doi.org/10.1101/2022.12.21.521172

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