Sterol regulatory element-binding protein-1c orchestrates metabolic remodeling of white adipose tissue by caloric restriction

Abstract

SummaryCaloric restriction (CR) can delay onset of several age‐related pathophysiologies and extend lifespan in various species, including rodents. CR also induces metabolic remodeling involved in activation of lipid metabolism, enhancement of mitochondrial biogenesis, and reduction of oxidative stress in white adipose tissue (WAT). In studies using genetically modified mice with extended lifespans, WAT characteristics influenced mammalian lifespans. However, molecular mechanisms underlying CR‐associated metabolic remodeling of WAT remain unclear. Sterol regulatory element‐binding protein‐1c (Srebp‐1c), a master transcription factor of fatty acid (FA) biosynthesis, is responsible for the pathogenesis of fatty liver (steatosis). Our study showed that, under CR conditions, Srebp‐1c enhanced mitochondrial biogenesis via increased expression of peroxisome proliferator‐activated receptor gamma coactivator‐1α (Pgc‐1α) and upregulated expression of proteins involved in FA biosynthesis within WAT. However, via Srebp‐1c, most of these CR‐associated metabolic alterations were not observed in other tissues, including the liver. Moreover, our data indicated that Srebp‐1c may be an important factor both for CR‐associated suppression of oxidative stress, through increased synthesis of glutathione in WAT, and for the prolongevity action of CR. Our results strongly suggested that Srebp‐1c, the primary FA biosynthesis‐promoting transcriptional factor implicated in fatty liver disease, is also the food shortage‐responsive factor in WAT. This indicated that Srebp‐1c is a key regulator of metabolic remodeling leading to the beneficial effects of CR.

A nutritional memory effect counteracts the benefits of dietary restriction in old mice

“…Considering that lipogenesis is strongly downregulated in the liver of DR-fed mice 22 , and that TGs in the WAT contain FAs with shorter chain length and fewer double bonds-an indicator of rapidly de novo synthesized FAs-the switch-resistant lipid dynamics are likely a result of tissueautonomous changes. Consistent with our findings, DR is known to promote lipogenesis in the WAT 23,58 and to increase mitochondrial biogenesis 3 . Although mitochondrial biogenesis after 4 weeks of DR was shown to promote non-shivering thermogenesis in WAT 3 , we found no evidence for UCP1-mediated thermogenic activity in mice treated for 2 or 22 months with DR, suggesting this to be a transient phenotype or one that is dependent on environmental and/or husbandry conditions.…”

A nutritional memory impairs survival, transcriptional and metabolic response to dietary restriction in old mice

“…Taking advantage of our extensive lipidomics data set and published pathway databases, we successfully applied a novel reaction dynamics analysis 32 , yielding ex-vivo-validated predictions based on measurements of steady-state levels at just a single time point. Consistent with our findings, DR is known to promote lipogenesis in the WAT 23,47 and to increase mitochondrial biogenesis 3 . Whilst mitochondrial biogenesis after four weeks of DR was shown to promote non-shivering thermogenesis in WAT 3 , we found no evidence for thermogenic activity in 2-or 22-months treated DR mice, suggesting this to be a transient phenotype.…”

“…Moreover, synthesis of CL is essential for mitochondrial biogenesis during cold-exposure 50 . Finally, wholebody deletion of the lipogenic transcription factor Srebf1c abrogates lipogenesis and mitochondrial biogenesis in the WAT of DR fed mice, thus strongly implicating Srebf1-driven lipid synthesis in adipose tissue as a limiting element for mitochondrial dynamics and potentially, essential for improved survival under DR 47 . In line with this hypothesis, fat body-specific induction of mitochondrial biogenesis by the Pgc1α homologue spargel is sufficient to extend lifespan in Drosophila 51 .…”

Mitochondrial intermediate peptidase is a novel regulator of sirtuin‐3 activation by caloric restriction

“…A retroviral vector expressing FLAG-Sirt3 was constructed by excising cDNA encoding FLAG-mouse Sirt3 from mSIRT3-L (Addgene plasmid 33309) and cloning this fragment into EcoRI-and ApaI-digested pMXs-AMNN-puro, the details of which were published in our previous study [1]. The pMXs-puro-mU6 vector was constructed as previously reported [5].…”