title: Adipocyte Dynamics and Reversible Metabolic Syndrome in Mice with an Inducible Adipocyte-Specific Deletion of the Insulin Receptor.
abstract: Insulin and IGF1 signaling are important for adipose tissue development and function; however, their role in mature adipocytes is unclear. Mice with a tamoxifen-inducible knockout of insulin and/or IGF1 receptors (IR/IGF1R) demonstrate a rapid loss of white and brown fat due to increased lipolysis and adipocyte apoptosis. This results in insulin resistance, glucose intolerance, hepatosteatosis, islet hyperplasia with hyperinsulinemia, and cold intolerance. This phenotype, however, resolves over 10-30 days due to a proliferation of preadipocytes and rapid regeneration of both brown and white adipocytes as identified by mTmG lineage tracing. This cycle can be repeated with a second round of receptor inactivation. Leptin administration prior to tamoxifen treatment blocks development of the metabolic syndrome without affecting adipocyte loss or regeneration. Thus, IR is critical in adipocyte maintenance, and this loss of adipose tissue stimulates regeneration of brown/white fat and reversal of metabolic syndrome associated with fat loss.
authors.affiliation: Section of Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Masaji
authors.initials: M
authors.lastname: Sakaguchi
authors.affiliation: Section of Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Shiho
authors.initials: S
authors.lastname: Fujisaka
authors.affiliation: Section of Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Weikang
authors.initials: W
authors.lastname: Cai
authors.affiliation: Section of Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Jonathon N
authors.initials: JN
authors.lastname: Winnay
authors.affiliation: Section of Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Konishi
authors.affiliation: Section of Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA; Division of Endocrinology and Metabolism, Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Brian T
authors.initials: BT
authors.lastname: O'Neill
authors.affiliation: Section of Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Mengyao
authors.initials: M
authors.lastname: Li
authors.affiliation: Section of Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Rubén
authors.initials: R
authors.lastname: García-Martín
authors.affiliation: Section of Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Section of Islet Cell & Regenerative Biology, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Hu
authors.affiliation: Section of Islet Cell & Regenerative Biology, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Rohit N
authors.initials: RN
authors.lastname: Kulkarni
authors.affiliation: Section of Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA. Electronic address: c.ronald.kahn@joslin.harvard.edu.
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005234:Fatty Liver / Q000150:complications / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D018149:Glucose Intolerance / Q000150:complications / Q000378:metabolism / Q000473:pathology; D006943:Hyperglycemia / Q000150:complications / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020738:Leptin / Q000494:pharmacology; D008060:Lipodystrophy / Q000150:complications / Q000378:metabolism / Q000473:pathology; D024821:Metabolic Syndrome / Q000150:complications / Q000378:metabolism*; D051379:Mice; D009928:Organ Specificity / Q000187:drug effects; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*; D012038:Regeneration / Q000187:drug effects; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D007328:Insulin; D020738:Leptin; D013629:Tamoxifen; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin
keywords: adipocyte regeneration; adipogenesis; brown adipocyte; fatty liver; insulin action; insulin receptor knockout; insulin resistance; leptin; lineage tracing; β cell proliferation