PMID- 36535626 OWN - NLM STAT- MEDLINE DCOM- 20230130 LR - 20230224 IS - 2212-8778 (Electronic) IS - 2212-8778 (Linking) VI - 67 DP - 2023 Jan TI - DEPTOR loss impairs brown adipocyte development in vitro but has limited impacts in mice. PG - 101660 LID - S2212-8778(22)00229-0 [pii] LID - 10.1016/j.molmet.2022.101660 [doi] LID - 101660 AB - OBJECTIVES: The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth and metabolism. In mice, activation of mTOR controls cold adaptation by promoting the recruitment and the activation of brown adipose tissue (BAT). DEP-domain containing mTOR-interacting protein (DEPTOR) interacts with mTOR to modulate its activity. Whether DEPTOR levels are modulated by cold in BAT and whether this protein regulates brown adipocyte development and thermogenic activation has never been tested. METHODS: DEPTOR levels were measured in mouse tissues upon cold exposure and in brown preadipocytes following the induction of adipogenesis. Lentiviruses expressing short-hairpin RNA were used to repress DEPTOR expression in brown preadipocytes in vitro. Conditional deletion of DEPTOR in brown preadipocytes and in mature brown fat cells was achieved by crossing DEPTOR floxed mice with either Myf5-Cre or Ucp1-Cre(ERT2) mice. These animals were exposed to cold and extensively phenotyped. RESULTS: DEPTOR is highly expressed in BAT and its levels are induced by chronic cold exposure, a condition that triggers BAT expansion and activation. Supporting a role for DEPTOR in brown fat cell recruitment, we found that DEPTOR is induced during brown adipocyte development and that its depletion impairs adipogenesis in vitro. This adipogenic lesion was associated with defects in both Akt activation and the expression of key adipogenic regulators. Conditional deletion of DEPTOR in brown preadipocytes or mature brown fat cells did not impact BAT recruitment and thermogenesis in mice but slightly reduced the expression of adipogenic and lipogenic genes. CONCLUSIONS: DEPTOR is highly expressed in BAT and its levels are dynamically regulated during brown fat cell development and upon cold exposure. Although DEPTOR depletion severely represses brown fat adipogenesis in vitro, its deletion is dispensable for BAT development, recruitment, and thermogenic activation in mice. CI - Copyright (c) 2022 The Author(s). Published by Elsevier GmbH.. All rights reserved. FAU - Colas, Charles AU - Colas C AD - Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Quebec - Universite Laval (CRIUCPQ), 2725 Chemin Ste-Foy, Quebec, QC, Canada, G1V 4G5; Centre de recherche sur le cancer de l'Universite Laval, Universite Laval, 9 rue McMahon, Quebec, QC, Canada, G1R 3S3. FAU - Mouchiroud, Mathilde AU - Mouchiroud M AD - Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Quebec - Universite Laval (CRIUCPQ), 2725 Chemin Ste-Foy, Quebec, QC, Canada, G1V 4G5; Centre de recherche sur le cancer de l'Universite Laval, Universite Laval, 9 rue McMahon, Quebec, QC, Canada, G1R 3S3. FAU - Al Dow, Manal AU - Al Dow M AD - Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Quebec - Universite Laval (CRIUCPQ), 2725 Chemin Ste-Foy, Quebec, QC, Canada, G1V 4G5; Centre de recherche sur le cancer de l'Universite Laval, Universite Laval, 9 rue McMahon, Quebec, QC, Canada, G1R 3S3. FAU - Kolnohuz, Alona AU - Kolnohuz A AD - Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Quebec - Universite Laval (CRIUCPQ), 2725 Chemin Ste-Foy, Quebec, QC, Canada, G1V 4G5; Centre de recherche sur le cancer de l'Universite Laval, Universite Laval, 9 rue McMahon, Quebec, QC, Canada, G1R 3S3. FAU - Gelinas, Yves AU - Gelinas Y AD - Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Quebec - Universite Laval (CRIUCPQ), 2725 Chemin Ste-Foy, Quebec, QC, Canada, G1V 4G5; Centre de recherche sur le cancer de l'Universite Laval, Universite Laval, 9 rue McMahon, Quebec, QC, Canada, G1R 3S3. FAU - Caron, Alexandre AU - Caron A AD - Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Quebec - Universite Laval (CRIUCPQ), 2725 Chemin Ste-Foy, Quebec, QC, Canada, G1V 4G5; Faculte de Pharmacie, Universite Laval, 1050 avenue de la Medecine, Quebec, QC, Canada, G1V0A6. FAU - Laplante, Mathieu AU - Laplante M AD - Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Quebec - Universite Laval (CRIUCPQ), 2725 Chemin Ste-Foy, Quebec, QC, Canada, G1V 4G5; Centre de recherche sur le cancer de l'Universite Laval, Universite Laval, 9 rue McMahon, Quebec, QC, Canada, G1R 3S3; Departement de Medecine, Universite Laval, 1050 avenue de la Medecine, Quebec, QC, Canada, G1V0A6. Electronic address: mathieu.laplante@criucpq.ulaval.ca. LA - eng GR - 374552/CIHR/Canada GR - 419593/CIHR/Canada PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20221216 PL - Germany TA - Mol Metab JT - Molecular metabolism JID - 101605730 RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - 0 (deptor protein, mouse) SB - IM MH - Animals MH - Mice MH - *Adipocytes, Brown/metabolism MH - Adipogenesis/genetics MH - *Adipose Tissue, Brown/metabolism MH - Cell Differentiation/genetics MH - TOR Serine-Threonine Kinases/metabolism PMC - PMC9827061 OTO - NOTNLM OT - Adipogenesis OT - Cold exposure OT - DEPTOR OT - Thermogenesis OT - brown adipocyte OT - brown adipose tissue OT - mTOR EDAT- 2022/12/20 06:00 MHDA- 2023/01/24 06:00 PMCR- 2022/12/16 CRDT- 2022/12/19 19:27 PHST- 2022/10/01 00:00 [received] PHST- 2022/12/09 00:00 [revised] PHST- 2022/12/11 00:00 [accepted] PHST- 2022/12/20 06:00 [pubmed] PHST- 2023/01/24 06:00 [medline] PHST- 2022/12/19 19:27 [entrez] PHST- 2022/12/16 00:00 [pmc-release] AID - S2212-8778(22)00229-0 [pii] AID - 101660 [pii] AID - 10.1016/j.molmet.2022.101660 [doi] PST - ppublish SO - Mol Metab. 2023 Jan;67:101660. doi: 10.1016/j.molmet.2022.101660. Epub 2022 Dec 16.