Mitochondrial Hormesis links nutrient restriction to improved metabolism in fat cell

Abstract

Fasting promotes longevity by reprogramming metabolic and stress resistance pathways. However, although the impact on adipose tissue physiology through hormonal inputs is well established, the direct role of fasting on adipose cells is poorly understood. Herein we show that white and beige adipocytes, as well as mouse epididymal and subcutaneous adipose depots, respond to nutrient scarcity by acquiring a brown-like phenotype. Indeed, they improve oxidative metabolism through modulating the expression of mitochondrial-and nuclear-encoded oxidative phosphorylation genes as well as mitochondrial stress defensive proteins (UCP1, SOD2). Such adaptation is placed in a canonical mitohormetic response that proceeds via mitochondrial reactive oxygen species (mtROS) production and redistribution of FoxO1 transcription factor into nucleus. Nuclear FoxO1 (nFoxO1) mediates retrograde communication by inducing the expression of mitochondrial oxidative and stress defensive genes. Collectively, our findings describe an unusual white/beige fat cell response to nutrient availability highlighting another health-promoting mechanism of fasting.

Immortalized Parkinson's Disease lymphocytes have enhanced mitochondrial respiratory activity

“…Two mitochondrial dyes, MitoTracker Green FM and MitoTracker Red CMXRos (Thermo Fisher Scientific), were used to estimate mitochondrial mass and membrane potential (Pendergrass et al, 2004; Cottet-Rousselle et al, 2011; Martins et al, 2015; Henzi and Schwaller, 2015; Barbato et al, 2015). Fluorescence microscopy confirmed that both dyes stained the mitochondria with very little background staining of the cytosol (data not shown).…”

Molecular mechanisms underlying metabolic syndrome: the expanding role of the adipocyte

“…CR determines metabolic changes of adipose tissue that may explain its beneficial effects on whole-body homeostasis (22,24,184). Among these effects, CR promotes mitochondrial adaptations and the activation of thermogenesis in adipose tissue (185). At a molecular level, food withdrawal reduces plasma insulin and IGF-1 (186), with subsequent improvement of insulin sensitivity.…”

Feast and famine: Adipose tissue adaptations for healthy aging

“…Specifically cold exposure directly activates a thermogenic gene program in white and beige adipocytes independently of the canonical cAMP/Protein Kinase A/cAMP response element-binding protein pathway that is downstream of β-adrenergic receptors (Ye et al, 2013). Similarly, nutrient shortage as well as the nutrient restriction mimetic rapamycin, boost mitochondrial metabolism in white and beige adipocytes independently of cAMP/PKA signalling and are equally able to reduce adipocyte size (Barbato et al, 2015;Chakrabarti et al, 2010). Stimulation of β-adrenergic receptors is accompanied by a prominent change in intracellular redox homeostasis that shifts towards a prooxidant status (Lettieri Barbato et al, 2015a).…”

“…The best practice to recapitulate mitohormesis is nutrient shortage, which promotes a transient mt ROS flux crucial to signal stress defensive program by an evolutionary conserved mechanism (Barbato et al, 2015;Ristow and Schmeisser, 2014). It has been shown that fat cells have the ability to improve oxidative/antioxidant metabolism during fasting and mt ROS are upstream mediator of 14 such response (Barbato et al, 2015;Lettieri Barbato et al, 2014a).…”

“…It has been shown that fat cells have the ability to improve oxidative/antioxidant metabolism during fasting and mt ROS are upstream mediator of 14 such response (Barbato et al, 2015;Lettieri Barbato et al, 2014a). In particular, it can be hypothesized that, during the initial phase of time-controlled fasting (Early Phase), cells build up a stress defensive response by means of a weak mt ROS wave production.…”