Loss of hepatic DEPTOR alters the metabolic transition to fasting

Abstract

ObjectiveThe mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that functions into distinct protein complexes (mTORC1 and mTORC2) that regulates growth and metabolism. DEP-domain containing mTOR-interacting protein (DEPTOR) is part of these complexes and is known to reduce their activity. Whether DEPTOR loss affects metabolism and organismal growth in vivo has never been tested.MethodsWe have generated a conditional transgenic mouse allowing the tissue-specific deletion of DEPTOR. This model was crossed with CMV-cre mice or Albumin-cre mice to generate either whole-body or liver-specific DEPTOR knockout (KO) mice.ResultsWhole-body DEPTOR KO mice are viable, fertile, normal in size, and do not display any gross physical and metabolic abnormalities. To circumvent possible compensatory mechanisms linked to the early and systemic loss of DEPTOR, we have deleted DEPTOR specifically in the liver, a tissue in which DEPTOR protein is expressed and affected in response to mTOR activation. Liver-specific DEPTOR null mice showed a reduction in circulating glucose upon fasting versus control mice. This effect was not associated with change in hepatic gluconeogenesis potential but was linked to a sustained reduction in circulating glucose during insulin tolerance tests. In addition to the reduction in glycemia, liver-specific DEPTOR KO mice had reduced hepatic glycogen content when fasted. We showed that loss of DEPTOR cell-autonomously increased oxidative metabolism in hepatocytes, an effect associated with increased cytochrome c expression but independent of changes in mitochondrial content or in the expression of genes controlling oxidative metabolism. We found that liver-specific DEPTOR KO mice showed sustained mTORC1 activation upon fasting, and that acute treatment with rapamycin was sufficient to normalize glycemia in these mice.ConclusionWe propose a model in which hepatic DEPTOR accelerates the inhibition of mTORC1 during the transition to fasting to adjust metabolism to the nutritional status.

DEPTOR is an in vivo tumor suppressor that inhibits prostate tumorigenesis via the inactivation of mTORC1/2 signals

“…6E) and the body weight ( Supplementary Fig. 6F) of the mice at the age of 3 weeks among the three genotypes showed no significant difference, which is consistent with the findings using whole-body Deptor-KO mice with the deletion at the exon 2 [36]. These results indicate that Deptor disruption does not cause embryonic and postnatal death.…”

Tanc2-dependent direct and regulated mTOR inhibition balances mTORC1/2 signaling in developing mouse and human neurons

“…Indeed, our results indicate that Tanc2 and Tanc1/Deptor inhibit mTOR more strongly at around postnatal weeks 2 and 4, respectively. These results are in line with the differential impacts of homozygous Tanc2 and Tanc1/Deptor deletions in mice, where the deletion of Tanc2, but not Tanc1 or Deptor, leads to embryonic lethality 14,16 .…”

“…5a-f). These results suggest that Tanc2 and Deptor/Tanc1 distinctly inhibit mTORC1/2 signaling at early and late stages of mouse brain development, respectively, in line with the embryonic lethality of Tanc2, but not Deptor or Tanc1, KO mice 14,16 .…”

Altered Lipid Metabolism Impairs Skeletal Muscle Force in Young Rats Submitted to a Short-Term High-Fat Diet

“…After a 6 h fast (from 6 to 12 h), rats were anesthetised and administered with 38 μl/kg insulin (Humulin, Lilly, Canada). After 5 min, SOL and EDL muscles were quickly collected and weighed as previously described ( Caron et al, 2017 ). Briefly, muscle tissues were homogenized in a buffer (50 mM HEPES, pH 7.4, 2 mM EDTA, 10 mM sodium pyrophosphate, 10 mM sodium glycerophosphate, 40 mM NaCl, 50 mM NaF, 2 mM sodium orthovanadate, 1% Triton-X 100, with one tablet of Roche EDTA-free protease inhibitor per 25 ml solution) supplemented with 1% sodium deoxycholate and 0.1% sodium lauryl sulfate.…”