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Increased apoptosis and browning of TAK1-deficient adipocytes protects against obesity
Antonia Sassmann-Schweda, … , Nina Wettschureck, Stefan Offermanns
Antonia Sassmann-Schweda, … , Nina Wettschureck, Stefan Offermanns
Published May 19, 2016
Citation Information: JCI Insight. 2016;1(7):e81175. https://doi.org/10.1172/jci.insight.81175.
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Research Article Endocrinology Metabolism

Increased apoptosis and browning of TAK1-deficient adipocytes protects against obesity

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Abstract

Obesity is an increasing health problem worldwide, and nonsurgical strategies to treat obesity have remained rather inefficient. We here show that acute loss of TGF-β–activated kinase 1 (TAK1) in adipocytes results in an increased rate of apoptotic adipocyte death and increased numbers of M2 macrophages in white adipose tissue. Mice with adipocyte-specific TAK1 deficiency have reduced adipocyte numbers and are resistant to obesity induced by a high-fat diet or leptin deficiency. In addition, adipocyte-specific TAK1-deficient mice under a high-fat diet showed increased energy expenditure, which was accompanied by enhanced expression of the uncoupling protein UCP1. Interestingly, acute induction of adipocyte-specific TAK1 deficiency in mice already under a high-fat diet was able to stop further weight gain and improved glucose tolerance. Thus, loss of TAK1 in adipocytes reduces the total number of adipocytes, increases browning of white adipose tissue, and may be an attractive strategy to treat obesity, obesity-dependent diabetes, and other associated complications.

Authors

Antonia Sassmann-Schweda, Pratibha Singh, Cong Tang, Astrid Wietelmann, Nina Wettschureck, Stefan Offermanns

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Figure 1

Consequences of TAK1 deficiency in white adipocytes.

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Consequences of TAK1 deficiency in white adipocytes.
(A) Quantitative PC...
(A) Quantitative PCR (left) and Western blot (right) showing levels of TAK1 RNA or protein, respectively, in adipocytes and the stromal vascular fraction (SVF) of epididymal WAT and in BAT after tamoxifen induction (n = 5–7/group). (B and C) Effect of TNF-α on phosphorylation of JNK (B) as well as IκBα phosphorylation and degradation (C) in epididymal WAT explants from wild-type (control) and AdTAK1-KO mice. (D) Images of isolated epididymal adipocytes from AdTAK1-KO and wild-type (control) mice at day of isolation and after 72 hours of ex vivo culture (left panels). Right panel: statistical evaluation of caspase-3 activity in the absence or presence of 20 μM Z-VAD-FMK (ZVAD) after 48 hours of adipocyte culture (n = 3/group). Scale bars: 1 mm. (E) Effect of 4-OH-tamoxifen treatment of isolated epididymal adipocytes from Adipoq-CreERT2;TAK1fl/fl mice on caspase activity (n = 7–8/group). (F) Analysis of TUNEL staining of epididymal adipose tissue from wild-type (control) and AdTAK1-KO mice (n = 15/group). (G) Caspase-3 activity in freshly isolated epididymal adipocytes from AdTAK1-KO and wild-type (control) mice 2 days after tamoxifen induction, 16 weeks after tamoxifen induction, 16 weeks after tamoxifen induction and HFD feeding, and 16 weeks after tamoxifen induction in ob/ob background animals (n = 3–7/group). (H) Effect of TNF-α and etanercept (ETN) on caspase-3 activity in epididymal adipocytes prepared from wild-type (control) and AdTAK1-KO mice (n = 3/group). Right panel: AdTAK1-KO and control mice were treated with etanercept (100 mg/kg) in vivo on days 1, 3, and 5 after tamoxifen induction, and caspase-3 activity was determined in freshly isolated adipocytes from these animals (n = 3–4). Shown are mean values ± SEM; *P ≤ 0.05,**P ≤ 0.01, ***P ≤ 0.001 (ANOVA [D, G, and H] or t test [A, E, and F]).
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