Remodeling the Integration of Lipid Metabolism Between Liver and Adipose Tissue by Dietary Methionine Restriction in Rats

Abstract

Dietary methionine restriction (MR) produces an integrated series of biochemical and physiological responses that improve biomarkers of metabolic health, limit fat accretion, and enhance insulin sensitivity. Using transcriptional profiling to guide tissue-specific evaluations of molecular responses to MR, we report that liver and adipose tissue are the primary targets of a transcriptional program that remodeled lipid metabolism in each tissue. The MR diet produced a coordinated downregulation of lipogenic genes in the liver, resulting in a corresponding reduction in the capacity of the liver to synthesize and export lipid. In contrast, the transcriptional response in white adipose tissue (WAT) involved a depot-specific induction of lipogenic and oxidative genes and a commensurate increase in capacity to synthesize and oxidize fatty acids. These responses were accompanied by a significant change in adipocyte morphology, with the MR diet reducing cell size and increasing mitochondrial density across all depots. The coordinated transcriptional remodeling of lipid metabolism between liver and WAT by dietary MR produced an overall reduction in circulating and tissue lipids and provides a potential mechanism for the increase in metabolic flexibility and enhanced insulin sensitivity produced by the diet.

Methionine restriction improves renal insulin signalling in aged kidneys

“…We also observed upregulation of genes involved in lipogenesis and suppressed expression of the gluconeogenic gene, PEPCK in the kidney of MR mice compared to controls inferring improved insulin responsiveness. A similar upregulation in lipogenic genes has been observed in white adipose tissue from MR diet-fed mice with a concomitant decrease in hepatic lipogenic gene expression, and it is believed that this metabolic remodelling may lead to improved insulin sensitivity (7,25).…”

Methionine restriction restores a younger metabolic phenotype in adult mice with alterations in fibroblast growth factor 21

“…Available evidence supports the view that MR increases metabolic flexibility and overall in vivo insulin sensitivity (Hasek et al ., 2010, 2013); however, the effects of dietary MR on tissue-specific insulin sensitivity have not been examined.…”

“…Dietary manipulation in the form of MR has been shown before to dramatically decrease body weight and adiposity and improve insulin sensitivity in young, healthy mice (Hasek et al ., 2010, 2013; Perrone et al ., 2010; Plaisance et al ., 2010). We have shown here for the first time that MR is able to reverse aging-associated alterations in physiology, specifically to decrease body fat, increase physical activity, and improve glucose and lipid homeostasis to the levels measured in young mice (fed a normal diet).…”

“…In 12-month-old mice, MR was able to produce an increase in lipogenic and oxidative gene expression in epididymal WAT and decrease in lipogenic but increase in lipolytic gene expression in the liver, consistent with lipid homeostasis remodeling shown previously by MR in young mice (Perrone et al ., 2010; Hasek et al ., 2013). These changes are likely to account for the decrease in serum and hepatic triglycerides produced by MR, consistent with earlier studies (Ables et al ., 2012; Hasek et al ., 2013).…”

“…As obese adults are the main target for MR intervention in humans (Plaisance et al ., 2011), we aimed to examine the effectiveness of beginning MR at different ages, including adult mice (2 and 12 months old), to investigate whether it can reverse metabolic syndrome, and further identify whether it would make a suitable therapy for adult insulin-resistant humans. In molecular analyses, we focused on altered hepatic and white adipose tissue (WAT) signaling pathways, as MR has been shown, through transcriptional analysis, to exert its main action in these two tissues (Hasek et al ., 2013). …”