Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

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Nina Höller

Nariae Baik-Schneditz

Bernhard Schwaberger

Lukas Peter Mileder

Niels Hammer

Gerhard Pichler

Roland Malli

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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Hartig, SM; Bader, DA; Abadie, KV; Motamed, M; Hamilton, MP; Long, W; York, B; Mueller, M; Wagner, M; Trauner, M; Chan, L; Bajaj, M; Moore, DD; Mancini, MA; McGuire, SE.
Ubc9 Impairs Activation of the Brown Fat Energy Metabolism Program in Human White Adipocytes.
Mol Endocrinol. 2015; 29(9):1320-1333 Doi: 10.1210/me.2015-1084 [OPEN ACCESS]
Web of Science PubMed FullText FullText_MUG

Co-Autor*innen der Med Uni Graz: Trauner Michael; Wagner Martin
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Abstract:: Insulin resistance and type 2 diabetes mellitus (T2DM) result from an inability to efficiently store and catabolize surplus energy in adipose tissue. Subcutaneous adipocytes protect against insulin resistance and T2DM by coupling differentiation with the induction of brown fat gene programs for efficient energy metabolism. Mechanisms that disrupt these programs in adipocytes are currently poorly defined, but represent therapeutic targets for the treatment of T2DM. To gain insight into these mechanisms, we performed a high-throughput microscopy screen that identified ubiquitin carrier protein 9 (Ubc9) as a negative regulator of energy storage in human sc adipocytes. Ubc9 depletion enhanced energy storage and induced the brown fat gene program in human sc adipocytes. Induction of adipocyte differentiation resulted in decreased Ubc9 expression commensurate with increased brown fat gene expression. Thiazolidinedione treatment reduced the interaction between Ubc9 and peroxisome proliferator-activated receptor (PPAR)γ, suggesting a mechanism by which Ubc9 represses PPARγ activity. In support of this hypothesis, Ubc9 overexpression remodeled energy metabolism in human sc adipocytes by selectively inhibiting brown adipocyte-specific function. Further, Ubc9 overexpression decreased uncoupling protein 1 expression by disrupting PPARγ binding at a critical uncoupling protein 1 enhancer region. Last, Ubc9 is significantly elevated in sc adipose tissue isolated from mouse models of insulin resistance as well as diabetic and insulin-resistant humans. Taken together, our findings demonstrate a critical role for Ubc9 in the regulation of sc adipocyte energy homeostasis.
Find related publications in this database (using NLM MeSH Indexing): Adipocytes, White - metabolism; Adipose Tissue, Brown - metabolism; Animals -; Diabetes Mellitus, Type 2 - physiopathology; Disease Models, Animal -; Energy Metabolism - physiology; High-Throughput Screening Assays -; Humans -; Hypoglycemic Agents - pharmacology; Insulin Resistance - physiology; Male -; Mice -; Mice, Inbred C57BL -; PPAR gamma - antagonists & inhibitors; RNA Interference -; RNA, Small Interfering -; Rosiglitazone -; Thiazolidinediones - pharmacology; Ubiquitin-Conjugating Enzymes - genetics; Ubiquitin-Conjugating Enzymes - metabolism