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    • Another critical alteration in Pgam deficient BAT under fast

    2018-11-05

    Another critical alteration in Pgam5-deficient BAT under fasting and cold stress is the enhancement of FGF21 (Fig. 4a and d). Because the pre-treatment of ISRIB almost completely blocked the enhancement of Fgf21 potassium channel in Pgam5-deficient BAT (Fig. 4e), phospho-eif2α-ATF4 pathway may be involved in the enhanced FGF21 induction. From the previous analysis of Fgf21 KO mice, it is known that FGF21 contributes to cold resistance (Fisher et al., 2012). In addition, FGF21 has been shown to promote lipid metabolism (Owen et al., 2015). Unexpectedly, however, the pre-treatment of ISRIB did not suppress the enhanced lipid metabolism observed in Pgam5 KO mice (Figure S4a and b). Therefore, FGF21 induction may not be causal for the enhancement of lipid metabolism at least in Pgam5 KO mice (Fig. 6). Several recent reports suggested that dysfunctional mitochondria activate the phospho-eif2α-ATF4 pathway, which eventually leads to FGF21 induction (Dogan et al., 2014; Keipert et al., 2014; Kim et al., 2013a,b). Enhanced eif2α phosphorylation (Fig. 4d) and electron-dense abnormal mitochondria (Fig. 3b-e) were observed in Pgam5-deficient BAT after fasting and cold stress. From these observations, we now hypothesize that the appearance of dysfunctional mitochondria in Pgam5-deficient BAT under fasting and cold stress might activate the phospho-eif2α-ATF4 pathway, which triggers the FGF21 induction (Fig. 6). Uncovering the precise molecular mechanisms by which PGAM5 protects proper mitochondrial integrity under fasting and cold stress is one of the most tempting future directions. It would be possible that PGAM5 in BAT itself protects proper mitochondrial integrity from metabolic perturbations. Alternatively, it could be speculated that exhausted mitochondria intolerable to metabolic challenges caused by the enhanced lipid metabolism may give rise to dysfunctional mitochondria in Pgam5-deficient BAT. The resistance to HFD-induced obesity was another drastic phenotype of Pgam5 KO mice (Fig. 5a–j). It has been reported that the administration of FGF21 or its analogs induces weight loss through increased energy expenditure (Coskun et al., 2008; Gaich et al., 2013; Kharitonenkov et al., 2005). Because FGF21 induction was enhanced in Pgam5-deficient BAT under fasting and cold stress (Fig. 4a, c and d), we examined the possibility that its enhancement also contributes to the lean phenotype of Pgam5 KO mice under HFD-fed conditions. However, serum FGF21 concentration was even reduced in Pgam5 KO mice under HFD-fed conditions (Figure S5). Several previous studies also reported that the serum FGF21 level is rather increased in obese animals compared with lean animals (Zhang et al., 2008), raising the possibility that obesity is an FGF21-resistance condition (Fisher et al., 2010). Thus, the above results in Pgam5 KO mice might reflect these previous observations. The identification of the factors that are responsible for the resistance of Pgam5 KO mice to HFD-induced obesity is expected in future studies. Several clinical studies suggest the inverse correlation between the BAT activity and body fatness (Lee et al., 2014). In this aspect, it is noteworthy that the lipid utilization might be activated in Pgam5-deficient BAT under stressed conditions or even from basal state (Fig. 2f and e). Moreover, very recently, it has been reported that PGAM5 KO mice show slight decrease of body weight from basal state (Moriwaki et al., 2016). The elucidation of the mechanisms of enhanced lipid metabolism in Pgam5-deficient BAT may not only uncover the reasons why Pgam5 KO mice show such a drastic lean phenotype but also provide some clinical clues to the therapeutic targets for human obesity and related metabolic disorders. In this report, we found that mitochondria-resident stress responsive protein PGAM5 acts as a metabolic regulator in vivo. We hope that our study will provide a key to uncover more detailed functions of PGAM5 as a metabolic regulator and will shed new light on mitochondrial stress-responsive molecules as potential therapeutic targets for metabolic disorders.