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Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1

Author

Listed:
  • Joseph T. Rodgers

    (Johns Hopkins University School of Medicine)

  • Carlos Lerin

    (Johns Hopkins University School of Medicine)

  • Wilhelm Haas

    (Harvard Medical School)

  • Steven P. Gygi

    (Harvard Medical School)

  • Bruce M. Spiegelman

    (Harvard Medical School
    Harvard Medical School)

  • Pere Puigserver

    (Johns Hopkins University School of Medicine)

Abstract

Homeostatic mechanisms in mammals respond to hormones and nutrients to maintain blood glucose levels within a narrow range. Caloric restriction causes many changes in glucose metabolism and extends lifespan; however, how this metabolism is connected to the ageing process is largely unknown. We show here that the Sir2 homologue, SIRT1—which modulates ageing in several species1,2,3 —controls the gluconeogenic/glycolytic pathways in liver in response to fasting signals through the transcriptional coactivator PGC-1α. A nutrient signalling response that is mediated by pyruvate induces SIRT1 protein in liver during fasting. We find that once SIRT1 is induced, it interacts with and deacetylates PGC-1α at specific lysine residues in an NAD+-dependent manner. SIRT1 induces gluconeogenic genes and hepatic glucose output through PGC-1α, but does not regulate the effects of PGC-1α on mitochondrial genes. In addition, SIRT1 modulates the effects of PGC-1α repression of glycolytic genes in response to fasting and pyruvate. Thus, we have identified a molecular mechanism whereby SIRT1 functions in glucose homeostasis as a modulator of PGC-1α. These findings have strong implications for the basic pathways of energy homeostasis, diabetes and lifespan.

Suggested Citation

  • Joseph T. Rodgers & Carlos Lerin & Wilhelm Haas & Steven P. Gygi & Bruce M. Spiegelman & Pere Puigserver, 2005. "Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1," Nature, Nature, vol. 434(7029), pages 113-118, March.
    • Handle: RePEc:nat:nature:v:434:y:2005:i:7029:d:10.1038_nature03354
    DOI: 10.1038/nature03354
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    Cited by:

    1. Jae Woo Park & Eun Roh & Gil Myoung Kang & So Young Gil & Hyun Kyong Kim & Chan Hee Lee & Won Hee Jang & Se Eun Park & Sang Yun Moon & Seong Jun Kim & So Yeon Jeong & Chae Beom Park & Hyo Sun Lim & Yu, 2023. "Circulating blood eNAMPT drives the circadian rhythms in locomotor activity and energy expenditure," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Simeon R. Mihaylov & Lydia M. Castelli & Ya-Hui Lin & Aytac Gül & Nikita Soni & Christopher Hastings & Helen R. Flynn & Oana Păun & Mark J. Dickman & Ambrosius P. Snijders & Robert Goldstone & Oliver, 2023. "The master energy homeostasis regulator PGC-1α exhibits an mRNA nuclear export function," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    3. Yoona Kim & Peter Clifton, 2018. "Curcumin, Cardiometabolic Health and Dementia," IJERPH, MDPI, vol. 15(10), pages 1-34, September.
    4. Guanlan Hu & Catriona Ling & Lijun Chi & Mehakpreet K. Thind & Samuel Furse & Albert Koulman & Jonathan R. Swann & Dorothy Lee & Marjolein M. Calon & Celine Bourdon & Christian J. Versloot & Barbara M, 2022. "The role of the tryptophan-NAD + pathway in a mouse model of severe malnutrition induced liver dysfunction," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    5. Liang Yang & Junfeng Shen & Chunhua Liu & Zhonghua Kuang & Yong Tang & Zhengjiang Qian & Min Guan & Yongfeng Yang & Yang Zhan & Nan Li & Xiang Li, 2023. "Nicotine rebalances NAD+ homeostasis and improves aging-related symptoms in male mice by enhancing NAMPT activity," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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