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Widenmaier, Scott

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Widenmaier

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Scott

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Widenmaier, Scott

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2014 - 20182

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Author's Publications: search.filters.isAuthorOfPublication.8585310a-71d6-492f-838b-3fc181d26891

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    Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity
    (Springer Nature, 2018) Bartelt, Alexander; Widenmaier, Scott; Schlein, Christian; Johann, Kornelia; Goncalves, Renata; Eguchi, Kosei; Fischer, Alexander W; Parlakgul, Gunes; Snyder, Nicole; Nguyen, Truc B; Bruns, Oliver T; Franke, Daniel; Bawendi, Moungi G; Lynes, Matthew; Leiria, Luiz O; Tseng, Yu-Hua; Inouye, Karen; Arruda, Ana; Hotamisligil, Gokhan
    Objective Brown adipose tissue (BAT) generates heat in response to cold, and low BAT activity has been linked to obesity. However, recent studies were inconclusive as to whether BAT is involved in diet‐induced thermogenesis and mitigates weight gain from prolonged overeating. Therefore, this study investigated whether BAT activity is related to metabolic adaptation arising from 8 weeks of overfeeding in humans. Methods Fourteen men (aged 24 ± 3 years, BMI 24.5 ± 1.6 kg/m2) were overfed by 40% for 8 weeks. Before and after, energy expenditure and metabolic adaptation were measured by whole‐room respiratory calorimetry. A marker of BAT activity was measured using infrared imaging of the supraclavicular BAT depot. Results At the end of 8 weeks of overfeeding, metabolic adaptation—defined as the percent increase in sleeping energy expenditure beyond that expected from weight gain—rose from −0.9 ± 3.9% to 4.7 ± 5.6% (P = 0.001). However, BAT thermal activity was unchanged (P = 0.81). Moreover, BAT thermal activity did not correlate with the degree of metabolic adaptation (P = 0.32) or with the change in body weight (P = 0.51). Conclusions BAT thermal activity does not change in response to overfeeding, nor does it correlate with adaptive thermogenesis. Our data suggest that BAT does not mediate metabolic adaptation to overeating in humans.
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    Coordinated regulation of protein synthesis and degradation by mTORC1
    (Springer Science and Business Media LLC, 2014-07-13) Zhang, Yinan; Nicholatos, Justin William; Dreier, John; Ricoult, Stephane Jean Hermann; Widenmaier, Scott; Hotamisligil, Gokhan; Kwiatkowski, David; Manning, Brendan
    Eukaryotic cells coordinately control anabolic and catabolic processes to maintain cell and tissue homeostasis. Mechanistic target of rapamycin complex 1 (mTORC1) promotes nutrient-consuming anabolic processes, such as protein synthesis1. Here we show that as well as increasing protein synthesis, mTORC1 activation in mouse and human cells also promotes an increased capacity for protein degradation. Cells with activated mTORC1 exhibited elevated levels of intact and active proteasomes through a global increase in the expression of genes encoding proteasome subunits. The increase in proteasome gene expression, cellular proteasome content, and rates of protein turnover downstream of mTORC1 were all dependent on induction of the transcription factor nuclear factor erythroid-derived 2-related factor 1 (NRF1; also known as NFE2L1). Genetic activation of mTORC1 through loss of the tuberous sclerosis complex tumour suppressors, TSC1 or TSC2, or physiological activation of mTORC1 in response to growth factors or feeding resulted in increased NRF1 expression in cells and tissues. We find that this NRF1-dependent elevation in proteasome levels serves to increase the intracellular pool of amino acids, which thereby influences rates of new protein synthesis. Therefore, mTORC1 signalling increases the efficiency of proteasome-mediated protein degradation for both quality control and as a mechanism to supply substrate for sustained protein synthesis.