title: Distinct functions of Ulk1 and Ulk2 in the regulation of lipid metabolism in adipocytes.
abstract: ULK1 (unc-51 like kinase 1) is a serine/threonine protein kinase that plays a key role in regulating the induction of autophagy. Recent studies using autophagy-defective mouse models, such as atg5- or atg7-deficient mice, revealed an important function of autophagy in adipocyte differentiation. Suppression of adipogenesis in autophagy-defective conditions has made it difficult to study the roles of autophagy in metabolism of differentiated adipocytes. In this study, we established autophagy defective-differentiated 3T3-L1 adipocytes, and investigated the roles of Ulk1 and its close homolog Ulk2 in lipid and glucose metabolism using the established adipocytes. Through knockdown approaches, we determined that Ulk1 and Ulk2 are important for basal and MTORC1 inhibition-induced autophagy, basal lipolysis, and mitochondrial respiration. However, unlike other autophagy genes (Atg5, Atg13, Rb1cc1/Fip200, and Becn1) Ulk1 was dispensable for adipogenesis without affecting the expression of CCAAT/enhancer binding protein ? (CEBPA) and peroxisome proliferation-activated receptor gamma (PPARG). Ulk1 knockdown reduced fatty acid oxidation and enhanced fatty acid uptake, the metabolic changes that could contribute to adipogenesis, whereas Ulk2 knockdown had opposing effects. We also found that the expression levels of insulin receptor (INSR), insulin receptor substrate 1 (IRS1), and glucose transporter 4 (SLC2A4/GLUT4) were increased in Ulk1-silenced adipocytes, which was accompanied by upregulation of insulin-stimulated glucose uptake. These results suggest that ULK1, albeit its important autophagic role, regulates lipid metabolism and glucose uptake in adipocytes distinctly from other autophagy proteins.
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics; University of Minnesota; Minneapolis, MN USA.
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Ro
authors.forename: Chang Hwa
authors.initials: CH
authors.lastname: Jung
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Hahn
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.forename: Young-Mi
authors.initials: YM
authors.lastname: Kim
authors.forename: Young Sung
authors.initials: YS
authors.lastname: Yun
authors.forename: Ji-Man
authors.initials: JM
authors.lastname: Park
authors.forename: Kwan Hyun
authors.initials: KH
authors.lastname: Kim
authors.forename: Minchul
authors.initials: M
authors.lastname: Seo
authors.forename: Tae-Youl
authors.initials: TY
authors.lastname: Ha
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Arriaga
authors.forename: David A
authors.initials: DA
authors.lastname: Bernlohr
authors.forename: Do-Hyung
authors.initials: DH
authors.lastname: Kim
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism* / Q000502:physiology; D050156:Adipogenesis / Q000235:genetics; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D000071189:Autophagy-Related Protein-1 Homolog; D002454:Cell Differentiation / Q000235:genetics; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; C401061:Ulk2 protein, mouse; D000071189:Autophagy-Related Protein-1 Homolog; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C112444:Ulk1 protein, mouse; D005947:Glucose
keywords: ULK1; ULK2; adipocytes; adipogenesis; lipid metabolism; mTORC1