title: Fat Mass Reduction With Adipocyte Hypertrophy and Insulin Resistance in Heterozygous PPARγ Mutant Rats.
abstract: Agonist-induced activation of peroxisome proliferator-activated receptor-γ (PPARγ) stimulates adipocyte differentiation and insulin sensitivity. Patients with heterozygous PPARγ dominant-negative mutation develop partial lipodystrophy and insulin resistance. Inconsistent with this evidence in humans, it was reported that heterozygous PPARγ knockout mice have increased insulin sensitivity and that mice with heterozygous PPARγ dominant-negative mutation have normal insulin sensitivity and improved glucose tolerance. In the context of the interspecies intranslatability of PPARγ-related findings, we generated a PPARγ mutant rat with a loss-of-function mutation (Pparg(mkyo)) without dominant-negative activity by using the ENU (N-ethyl-N-nitrosourea) mutagenesis method. Heterozygous Pparg(mkyo/+) rats showed reduced fat mass with adipocyte hypertrophy and insulin resistance, which were highly predictable from known actions of PPARγ agonists and phenotypes of patients with the PPARγ mutation. This report is the first in our knowledge to clearly demonstrate that both alleles of PPARγ are required for normal adipocyte development and insulin sensitivity in vivo. Furthermore, the study indicates that PPARγ regulates mainly adipocyte number rather than adipocyte size in vivo. The choice of appropriate species as experimental models is critical, especially for the study of PPARγ.
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Valentino
authors.initials: V
authors.lastname: Gumbilai
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan Division of Endocrinology and Metabolism, Jichi Medical University, Tochigi, Japan kebihara@jichi.ac.jp.
authors.forename: Ken
authors.initials: K
authors.lastname: Ebihara
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Aizawa-Abe
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan Division of Endocrinology and Metabolism, Jichi Medical University, Tochigi, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Ebihara
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Institute of Laboratory Animals, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Tomoji
authors.initials: T
authors.lastname: Mashimo
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan Department of Health and Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Kiminori
authors.initials: K
authors.lastname: Hosoda
authors.affiliation: Institute of Laboratory Animals, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Tadao
authors.initials: T
authors.lastname: Serikawa
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects*; D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D001786:Blood Glucose / Q000187:drug effects; D001823:Body Composition / Q000187:drug effects / Q000235:genetics; D002452:Cell Count; D048429:Cell Size / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D006579:Heterozygote; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology; D008060:Lipodystrophy / Q000235:genetics / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D000077205:Pioglitazone; D051381:Rats; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077205:Pioglitazone