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Experimental and human studies on aging of adipose tissues: Role for Parkin

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Universitat de Barcelona. Departament de Bioquímica i Biomedicina Molecular

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[eng] Brown and beige adipose tissues are mediators of adaptive energy expenditure in mammals, in contrast with the energy storage role of white fat. Mitochondrial activity, including uncoupled respiration, and the release of the so-called “batokines” in brown and beige adipocytes account for the majority of local and systemic adaptations to energy expenditure requirements mediated by these cells. One of these batokines is fibroblast growth factor 21 (FGF21), which has been recently proposed to be an antiaging hormone. Aging is associated with a decline in brown adipose tissue (BAT) activity and in browning of white adipose tissue (WAT). It has been proposed that the extent of BAT decline in aging may play a causative role in the enhanced propensity to age-associated metabolic conditions, and it has even been speculated that BAT reactivation may reverse them. On the other hand, aging is associated with increased amount of WAT. A loss of mitochondrial homeostasis by defective mitochondrial quality control as a result of decreased biogenesis but also to decreased degradation through mitophagy has been proposed as an underlying cause of aging in multiple tissues. Recently, Parkin has been identified as a key component of adipose tissue plasticity in response to thermogenic requirements, associated with the adaptive control of mitophagy. In the present study we investigated the impact of aging on adipose tissues in mice and humans with special focus on the status of the FGF21 system. We also tried to establish the role of Parkin in our mice model at distinct stages of aging. Parkin transcript and protein levels were up-regulated in relation to aging in mice adipose tissues, which may point to a compensatory homeostasis against diminished Parkin- independent mitophagy. Middle-aged wild-type mice presented an age-associated phenotype reminiscent of obesity and signs of BAT malfunction in middle-aged mice, which did not affect thermogenic response at this specific aging stage. Thus, our data would not support a massive effect of BAT in systemic derangements associated with aging. Parkin-KO mice were protected against age-associated obesity found in control animals. BAT activity does not seem to conduct the protection of Parkin-KO mice against aging-associated adiposity, as Parkin-KO mice do not present enhanced BAT- or browning-mediated energy expenditure. This phenomenon might rather be attributable to diminished food intake and risen energy expenditure-related processes in Parkin-KO mice. Our data denote that Parkin is possibly involved in the in the metabolic flexibility of lipid versus carbohydrate metabolism. FGF21 expression and its secretion in mice may be induced as stress hormone by mitochondrial dysfunctions in aged tissues. However, the chronic metabolic and stress-related disorders might elicit an FGF21 resistance, menacing healthy aging. Middle-aged mice lacking Parkin abolish increased levels of FGF21, which might be associated to the prevention of obesity occurring in those animals. In humans, serum FGF21 levels were increased in parallel with indicators of mildly deteriorated glucose homeostasis. FGF21- responsiveness machinery was not disrupted in subcutaneous adipose tissue from elderly individuals relative to those from young controls. Therefore, in contrast to what is observed in chronic metabolic pathologies or mice aging, high levels of FGF21 in healthy aging are not associated with repressed FGF21-responsiveness machinery in adipose tissue.

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cc by-nc-sa (c) Delgado Anglés, Alejandro, 2022

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Tesis Doctorals - Departament - Bioquímica i Biomedicina Molecular

# metadata.dc.title[].value
Experimental and human studies on aging of adipose tissues: Role for Parkin