Bed rest is a useful experimental model of physiological deconditioning which is analogous to accelerated ageing in an increasingly sedentary population. As part of the ELIPS programme, the European Space Agency are planning a long-term bed rest study to determine the impact of a nutritional anti-inflammatory and antioxidant countermeasure (including resveratrol, vitamins E and C, lycopene and epigallocatechin). We hypothesise that bed rest will lead to inflammatory and metabolic disturbances in subcutaneous adipose tissue (fat) which mimic many of the changes in this tissue seen with ageing and physical inactivity - and that the planned countermeasures will offset the changes induced by bed rest. Collectively, our understanding of adipose tissue has changed enormously in recent years and adipose tissue is clearly much more than a simple energy store. Adipose tissue is an active player in diverse physiological systems ranging from bone remodelling through to muscle substrate (fuel) utilisation. Adipose tissue communicates with other tissues via the secretion of archetypal 'adipokines' (e.g., adiponectin) but adipose tissue is also responsible for the secretion of many other proteins and mediators which have implications for other distant tissues including muscle and bone. We hypothesise that increased glucose uptake by adipose tissue in response to bed rest will provoke cellular and oxidative stress - causing adipocytes to secrete/express molecules designed in part to initiate an immune response but which then exacerbates adipose dysfunction. We will take adipose tissue biopsies before and after 60-d bed rest in both control and intervention groups (n=8 to 12 in each group). We will determine changes in whole adipose tissue at both gene expression and protein levels. Since we cannot assume that bed rest and the anti-inflammatory and antioxidant countermeasures will elicit equal effects in the heterogeneous cells that comprise adipose tissue, we will separate adipocytes from non-adipocytes (e.g. immune cells) and examine adipocytes and immune cells separately. We will determine adipocyte glucose uptake in basal and insulin-stimulated conditions. We will examine changes in the number of specific immune cells that are resident within adipose (e.g. macrophages) and also whether these cells have a pro- or anti-inflammatory phenotype. We will culture small pieces of adipose tissue to examine changes in adipokine secretion - and whether the pattern and amount of selected adipokines is impacted upon by bed rest. Finally, we will undertake exploratory work to examine whether altered adipokine secretion with bed rest has the potential to impact upon bone and muscle cell models. Virtually all of the above work will be conducted in the UK using frozen samples. Importantly, the planned countermeasures have the potential to positively impact upon adipose tissue function from the earliest mechanistic step (e.g., resveratrol and epigallocatechin decrease adipose tissue glucose uptake) all the way through to downstream consequences related to secondary oxidative stress and inflammation (e.g., all of the ingredients have been shown to target either oxidative stress and/or inflammation in adipose tissue). To date, most of these mechanisms have only been examined in rodent adipose tissue and thus the planned intervention represents an excellent opportunity to verify whether we can translate these exciting findings into humans. Adipose tissue dysfunction has been implicated in the aetiology of ageing, diabetes, and cardiovascular disease - with physical inactivity being a potential common mediator. In this context, this research will (i) characterise bed rest-induced adipose tissue dysfunction, (ii) demonstrate whether these changes have implications for other tissues (i.e. muscle and bone) and (iii) determine whether the anti-inflammatory and antioxidant countermeasures successfully target adipose tissue dysfunction in humans.
|Effective start/end date||1/07/15 → 30/06/19|