Work package 5: Molecular Physiology – University of Copenhagen

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Work package 5

Molecular Physiology

Work package-leader: Jørgen Wojtaszewski

Work package 5 will work to improve our mechanistic understanding of integrated human physiology in health and disease. WP5 researchers will develop and provide tools and analytic knowhow for the explorations of the central hypotheses brought forward in WP 1-4, providing insights to possible mechanistic links.

The central research idea is that if we can understand cellular signaling or other cellular adaptations evoked by physical activity or dietary interventions, we may be able to formulate counteractive measures that will improve cellular integrity and function and thereby whole organism health.

Til toppenBackground

Many, but likely not all, adverse effects of an unhealthy life style, aging and hormonal disturbances/changes are associated with whole-body impaired metabolic function including insulin resistance. Although the cause of insulin resistance is multi-factorial, the organs affected are likely to be skeletal muscle, liver and fat tissues as the function and integrity of these tissues have major influence on the whole-body insulin sensitivity and health.

Til toppenOverall aim

The aim is to increase our mechanistic understanding of integrated human physiology, in health and disease. The central research idea is that if we can understand cellular signaling or other cellular adaptations evoked by physical activity or dietary interventions, we may be able to formulate counteractive measures that will improve cellular integrity and function and thereby whole organism health. Thus, we work to mechanistically explain whole-body insulin resistance; i.e. 1) to provide metabolomic, epigenomic and molecular finger prints of insulin resistance, 2) to describe potential alterations in these in response to physical activity and dietary interventions, and 3) to provide evidence for cause-effect relationships. WP5 researchers will develop and provide tools and analytic knowhow for the explorations of the central hypotheses brought forward in WP1-4, providing insights to possible mechanistic links.

The direct synergy between WP1-4 and WP 5 caTil toppenn be viewed upon at 3 levels:

  1. Prior work performed by WP5 researchers has developed analytical tools to investigate insulin signaling and has identified defects in insulin signaling in PCOS, obese and elderly subjects. This knowledge and knowhow will enable WP5 to provide explanations as to how physical activity or dietary interventions may circumvent these defects.
  2. When appropriate via metabolomic, epigenomic or metagenomic analyses of the cohorts (WP1-4) WP 5 will identify new molecules/pathways and raise new hypotheses to explain the metabolic phenotypic changes seen in the WPs. Specific changes in the metabolome, epigenome or microbiome upon interventions like physical activity and dietary changes may bring forward new specific hypotheses for the mechanistic explanation of phenotypic alterations, e.g. improved insulin sensitivity. Saving samples from the interventions in a common biobank (www.cube.ku.dk) will allow for future analyses.
  3. Inspired by observations in 1 and 2, WP5 will provide evidence for causal links between primary endpoints (e.g. insulin sensitivity) and cellular or molecular changes by investigating rodent models, including “post-menopause” (Oophorectomized rats), “PCOS” (various), obesity (high-fat feeding). In addition, the use of specific transgenic models, cell systems and/or pharmacology may be used to bring further evidence for causality between specific proteins/pathways and phenotype.

Til toppenThe WP5 proposal is a scientific journey towards unraveling basic, molecular mechanisms of cellular adaptations to physical activity and dietary interventions. The samples obtained from WP1- 4 or models produced in WP5 are indeed unique and highly valid also for future explorations.

Researchers

Researchers, work package 5