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

Namiki Fujii,Naoyuki Okita,Kanae Takeda,Atsushi Yamada,Takumi Narita,Yoshikazu Chujo,Tomokazu Konishi,Yoshikazu Higami,Masahiro Sakai,Masaki Kobayashi,Isao Shimokawa,Yuka Sudo,Yurika Furuta

doi:10.1111/acel.12576

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.

Highlights

Caloric restriction (CR) is the most robust, reproducible, and simple experimental manipulation known to extend lifespan and delay onset of many age-associated pathophysiological changes in various laboratory rodents
Srebp-1c was required for CR-associated activation of fatty acid biosynthesis in white adipose tissue (WAT)
At 8–10 months of age, body weight was higher in KO than in WT and the effects of CR on body weight were slightly attenuated in KO

Summary

Introduction

Caloric restriction (CR) is the most robust, reproducible, and simple experimental manipulation known to extend lifespan and delay onset of many age-associated pathophysiological changes in various laboratory rodents. Suppression of growth hormone/insulin-like growth factor (GH/ IGF-1) signaling, reduction of mTOR signaling, activation of sirtuin, enhanced mitochondrial biogenesis, reduced oxidative stress, and suppressed inflammation mediate many of the beneficial effects of CR. Fat-specific insulin receptor knockout (FIRKO) mice lived longer than their controls (Blu€her et al, 2003). Transcription factors, including CCAAT/enhancer-binding protein (C/EBP)-a, C/EBPb, and peroxisome proliferator-activated receptor-c (PPARc), are master regulators of adipocyte differentiation (Farmer, 2006). Hetero-deficient PPARc knockout (KO) mice exhibited a shortened lifespan (Argmann et al, 2009). The characteristics of WAT seem to influence age-associated pathophysiology and the lifespan of rodents

Results

Discussion

Conclusion