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Abb. 1 Elucidation of the mechanisms leading to improved metabolic health in mice with disturbed energy efficiency in skeletal muscle

Abb. 1 FGF21 induction in skeletal muscle (SM) of transgenic mice (TG) with mild mitochondrial ... mehr

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Stand: 20.01.2018 21:35:35

Abteilung Physiologie des Energiestoffwechsels (EST)

Projekt 2 : Elucidation of the mechanisms leading to improved metabolic health in mice with disturbed energy efficiency in skeletal muscle

Mario Ost, Verena Coleman, Anja Voigt

In recent years, we have established UCP1-transgenic (TG) mice with ectopic expression of uncoupling protein 1 (UCP1) in skeletal muscle (SM) as a model of improved substrate metabolism and increased longevity. These mice show a delayed development of obesity, improved glucose tolerance and an over 40% increased median lifespan in comparison to their wildtype (WT) littermates when exposed to a high-fat diet. One hallmark of UCP1-TG mice is their increased insulin sensitivity independent of body weight. We then aimed to clarify the underlying physiological, cellular and molecular mechanisms. Surprisingly, we found that increased SM mitochondrial uncoupling in vivo does not reduce the oxidative stress status in the muscle cell but increases it and leads to the induction of the cellular integrated stress response. Moreover, it increases lipid metabolism and reactive lipid-derived carbonyls. This stress induction in turn increases the endogenous antioxidant defense system and redox signaling. Together, our data so far suggest that muscle mitochondrial uncoupling leads to a “healthy” lean phenotype on a high- fat diet by preserving insulin sensitivity through increased substrate metabolism and an induction of reactive oxygen species (ROS) signaling pathways. This argues for the mitochondrial hormesis hypothesis suggesting that ROS are essential signaling molecules for health and longevity.

A further puzzling observation in UCP1-TG mice was an increased metabolic activity in white adipose tissue (WAT), i.e., increased markers of lipogenesis and lipolysis together with an induction of UCP1 expression and various other markers of brown adipose tissue (BAT). This indicated a crosstalk between skeletal muscle and adipose tissue through skeletal muscle uncoupling, leading to a ”browning” of WAT which could possibly contribute to the “healthy aging” phenotype of UCP1-TG mice. Analysis of myokine expression showed an induction of fibroblast growth factor 21 (FGF21) in SM, resulting in over five-fold elevated circulating FGF21 in UCP1-TG mice (Fig. 1). FGF21 is known to be produced by the liver in response to starvation, and FGF21 mimetics are currently under investigation as diabetes therapeutics. Using adipocyte cell cultures, we could further show that the observed effects on WAT are indeed due to the increased FGF21 secretion. We conclude that the induction of FGF21 as a myokine is coupled to disturbance of mitochondrial function and ISR activation in SM. Endocrine-acting FGF21 released from SM has endocrine effects leading to increased browning of WAT, which can possibly explain the healthy metabolic phenotype of UCP1-TG mice. We are currently examining the role of FGF21 and browning for the healthy metabolic phenotype of UCP1-TG mice.

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