Hypermetabolism, Hyperphagia, and Reduced Adiposity in Tankyrase-Deficient Mice

Yeh, Tsung-Yin J.; Beiswenger, Kristina K.; Li, Pingping; Bolin, Krista E.; Lee, Ray M.; Tsao, Tsu‐Shuen; Murphy, Anne N.; Hevener, Andrea L.; Chi, Nai‐Wen

doi:10.2337/db08-1781

Cited by 71 publications

(86 citation statements)

References 38 publications

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“…TNKS1 knockout mice develop normally and exhibit only a metabolic disorder (Yeh et al 2009), while TNKS2 deficiency results in reduced body weight (Chiang et al 2006;Hsiao et al 2006). However, TNKS1/2 double-knockout Figure 6.…”

Section: Discussionmentioning

confidence: 99%

Poly-ADP ribosylation of PTEN by tankyrases promotes PTEN degradation and tumor growth

Zhang

Han³

et al. 2014

Genes Dev.

112

126

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PTEN [phosphatidylinositol (3,4,5)-trisphosphate phosphatase and tensin homolog deleted from chromosome 10], a phosphatase and critical tumor suppressor, is regulated by numerous post-translational modifications, including phosphorylation, ubiquitination, acetylation, and SUMOylation, which affect PTEN localization and protein stability. Here we report ADP-ribosylation as a new post-translational modification of PTEN. We identified PTEN as a novel substrate of tankyrases, which are members of the poly(ADP-ribose) polymerases (PARPs). We showed that tankyrases interact with and ribosylate PTEN, which promotes the recognition of PTEN by a PAR-binding E3 ubiquitin ligase, RNF146, leading to PTEN ubiquitination and degradation. Double knockdown of tankyrase1/2 stabilized PTEN, resulting in the subsequent down-regulation of AKT phosphorylation and thus suppressed cell proliferation and glycolysis in vitro and tumor growth in vivo. Furthermore, tankyrases were up-regulated and negatively correlated with PTEN expression in human colon carcinomas. Together, our study revealed a new regulation of PTEN and highlighted a role for tankyrases in the PTEN-AKT pathway that can be explored further for cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Poly-ADP ribosylation of PTEN by tankyrases promotes PTEN degradation and tumor growth

Zhang

Han³

et al. 2014

Genes Dev.

112

126

View full text Add to dashboard Cite

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“…Mitochondria were purified from freshly collected tissues [23], and oxygen consumption was measured in a Mitocell Miniature respirometer (model 782, Strathkelvin Instruments Limited, Motherwell, UK) using pyruvate or palmitoyl- dl -carnitine (Sigma-Aldrich, St Louis, MO, USA) as substrates [24, 25]. …”

Section: Methodsmentioning

confidence: 99%

Adiponectin reduces thermogenesis by inhibiting brown adipose tissue activation in mice

et al. 2014

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Aims/hypothesis Adiponectin is an adipocyte-derived hormone that plays an important role in energy homeostasis. The main objective of this study was to investigate whether or not adiponectin regulates brown adipose tissue (BAT) activation and thermogenesis. Methods Core body temperatures (CBTs) of genetic mouse models were monitored at room temperature and during cold exposure. Cultured brown adipocytes and viral vector-mediated gene transduction were used to study the regulatory effects of adiponectin on Ucp1 gene expression and the underlying mechanisms. Results The CBTs of adiponectin knockout mice (Adipoq−/−) were significantly higher than those of wild type (WT) mice both at room temperature and during the cold (4°C) challenge. Conversely, reconstitution of adiponectin in Adipoq−/− mice significantly blunted β adrenergic receptor agonist-induced thermogenesis of interscapular BAT. After 10 days of intermittent cold exposure, Adipoq−/− mice exhibited higher UCP1 expression and more brown-like structure in inguinal fat than WT mice. Paradoxically, we found that the anti-thermogenic effect of adiponectin requires neither AdipoR1 nor AdipoR2, two well-known adiponectin receptors. In sharp contrast to the anti-thermogenic effects of adiponectin, AdipoR1 and especially AdipoR2 promote BAT activation. Mechanistically, adiponectin was found to inhibit Ucp1 gene expression by suppressing β3-adrenergic receptor expression in brown adipocytes. Conclusions/interpretation This study demonstrates that adiponectin suppresses thermogenesis, which is likely to be a mechanism whereby adiponectin reduces energy expenditure.

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“…Taken together, the current data suggest that PARP-1 influences both central and peripheral sensing of lipids, glucose and amino acids. Little is known about PARPs other than PARP-1, primarily due to the lack of dedicated in vivo studies, however, PARP-2 is known to interplay with beta cell function and certain nuclear receptors [57], while tankyrases impact on beta cell function and feeding [58].…”

Section: Deregulated Nutrient Sensingmentioning

confidence: 99%