Caloric restriction-associated remodeling of rat white adipose tissue: effects on the growth hormone/insulin-like growth factor-1 axis, sterol regulatory element binding protein-1, and macrophage infiltration

Abstract

The role of the growth hormone (GH)-insulin-like growth factor (IGF)-1 axis in the lifelong caloric restriction (CR)-associated remodeling of white adipose tissue (WAT), adipocyte size, and gene expression profiles was explored in this study. We analyzed the WAT morphology of 6-7-month-old wild-type Wistar rats fed ad libitum (WdAL) or subjected to CR (WdCR), and of heterozygous transgenic dwarf rats bearing an anti-sense GH transgene fed ad libitum (TgAL) or subjected to CR (TgCR). Although less effective in TgAL, the adipocyte size was significantly reduced in WdCR compared with WdAL. This CR effect was blunted in Tg rats. We also used high-density oligonucleotide microarrays to examine the gene expression profile of WAT of WdAL, WdCR, and TgAL rats. The gene expression profile of WdCR, but not TgAL, differed greatly from that of WdAL. The gene clusters with the largest changes induced by CR but not by Tg were genes involved in lipid biosynthesis and inflammation, particularly sterol regulatory element binding proteins (SREBPs)-regulated and macrophage-related genes, respectively. Real-time reverse-transcription polymerase chain reaction analysis confirmed that the expression of SREBP-1 and its downstream targets was upregulated, whereas the macrophage-related genes were downregulated in WdCR, but not in TgAL. In addition, CR affected the gene expression profile of Tg rats similarly to wild-type rats. Our findings suggest that CR-associated remodeling of WAT, which involves SREBP-1-mediated transcriptional activation and suppression of macrophage infiltration, is regulated in a GH-IGF-1-independent manner. AGE (2013) 35:1143-1156 DOI 10.1007 Yoshikazu Chujo, Namiki Fujii, Naoyuki Okita, and Tomokazu Konishi contributed equally to this work. Electronic supplementary materialThe online version of this article

Epigenetic Mechanisms of Colon Cancer Prevention: What Can Nutrition Do?

“…Studies in adults have demonstrated a positive correlation between protein intake and serum IGF-I levels (Castaneda et al 2000 ), and a 50 % reduction in calorie intake or a 30 % reduction in protein intake results in a decline in serum IGF-I and IGFBP-3 levels and an increase in IGFBP-2 level (Smith et al 1995 ). The fi nding is consistent with animal experiments (Chujo et al 2013 ) showing that restriction of nutrients has diverse effects on IGF-I gene transcription (Nogueira et al 2012 ). Although all of these studies show a signifi cant infl uence of food intake on the IGF family, the precise nature of the relationships between energy and protein intake and levels of IGFs in circulation and colon cancer remains to be determined (Qu et al 1997 ).…”

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

“…These observations suggested that WAT derived from long‐lived strains of mice, that is, good‐quality WAT, can increase whole‐body lipid utilization. Recently, we proposed that Srebp‐1c‐induced activation of FA biosynthesis is one of the major mechanisms by which CR can remodel metabolism in WAT (Okita et al ., 2012; Chujo et al ., 2013). Previous studies clearly demonstrated that CR significantly enhanced whole‐body lipid utilization and increased endogenously synthesized FAs in WAT, but not in the liver (Bruss et al ., 2010).…”

“…Total RNA was extracted from frozen WAT and liver tissue and quantitative real‐time PCR (qRT–PCR) was performed as described previously (Chujo et al ., 2013). The methods are briefly described as additional experimental procedures in Data S2 (Supporting information).…”

“…Our findings suggested that CR‐associated alterations of gene expression were highly regulated, in a GH/IGF‐1‐independent manner. In particular, CR downregulated inflammatory gene expression in a GH/IGF‐1‐independent manner (Chujo et al ., 2013). In contrast, CR upregulated expression of Srebp‐1c (the mouse homolog of human SREBP‐1c) and its downstream target genes, especially those involved in FA biosynthesis, also in a GH/IGF‐1‐independent manner (Okita et al ., 2012; Chujo et al ., 2013).…”

“…In particular, CR downregulated inflammatory gene expression in a GH/IGF‐1‐independent manner (Chujo et al ., 2013). In contrast, CR upregulated expression of Srebp‐1c (the mouse homolog of human SREBP‐1c) and its downstream target genes, especially those involved in FA biosynthesis, also in a GH/IGF‐1‐independent manner (Okita et al ., 2012; Chujo et al ., 2013). Moreover, CR significantly increased de novo FA biosynthesis in WAT but not in the liver (Bruss et al ., 2010).…”