Diet-Induced Obesity in the Selenocysteine Lyase Knockout Mouse

Abstract

Aims: Selenocysteine lyase (Scly) mediates selenocysteine decomposition. It was previously demonstrated that, upon adequate caloric intake (12% kcal fat) and selenium deficiency, disruption of Scly in mice leads to development of metabolic syndrome. In this study, we investigate the effect of a high-fat (45% kcal) seleniumadequate diet in Scly knockout (KO) mice on development of metabolic syndrome. Involvement of selenoproteins in energy metabolism after Scly disruption was also examined in vitro in the murine hepatoma cell line, Hepa1-6, following palmitate treatment. Results: Scly KO mice were more susceptible to diet-induced obesity than their wild-type counterparts after feeding a high-fat selenium-adequate diet. Scly KO mice had aggravated hyperinsulinemia, hypercholesterolemia, glucose, and insulin intolerance, but unchanged inflammatory cytokines and expression of most selenoproteins, except increased serum selenoprotein P (Sepp1). Scly KO mice also exhibited enhanced hepatic levels of pyruvate and enzymes involved in the regulation of pyruvate cycling, such as pyruvate carboxylase (Pcx) and pyruvate dehydrogenase (Pdh). However, in vitro silencing of Scly in Hepa1-6 cells led to diminished Sepp1 expression, and concomitant palmitate treatment decreased Pdh expression. Innovation: The role of selenium in lipid metabolism is recognized, but specific selenium-dependent mechanisms leading to obesity are unclear. This study uncovers that Scly has a remarkable effect on obesity and metabolic syndrome development triggered by high-fat exposure, independent of the expression of most selenoproteins. Conclusion: Diet-induced obesity in Scly KO mice is aggravated, with effects on pyruvate levels and consequent activation of energy metabolism independent of selenoprotein levels. Antioxid. Redox Signal. 23, 761-774.

The Effect of Selenium Supplementation on Glucose Homeostasis and the Expression of Genes Related to Glucose Metabolism

“…Pigs fed with a supranutritional dose of Se exhibited decreased expression of mRNA for pyruvate kinase (enzyme responsible for pyruvate synthesis in the last step of glycolysis) [33]. Interestingly, increased pyruvate levels in the liver and increased expression of pyruvate metabolizing enzymes (pyruvate carboxylase (Pcx) and pyruvate dehydrogenase (Pdh)) were shown in mice with a knocked out gene for selenocysteine lyase (SCLY, the enzyme catalyzing conversion of selenocysteine into alanine and selenide, an important step in Se metabolism, as selenide is a substrate for selenoprotein biosynthesis) [45]. Recently it has been also shown that Se affects glycolysis in cancer cells, suggesting that down-regulation of glycolytic enzymes is a novel mechanism of Se toxicity in cancer and that this mechanism targets the well-known metabolic hallmark of cancer cells associated with enhanced glycolysis, which is called the Warburg effect [46].…”

The Evolving Versatility of Selenium in Biology

“…In addition, mice developed obesity, fatty liver, and hypercholesterolemia. In their present article, Berry and colleagues raise the question whether the obvious role of Scly in lipid metabolism could be independent of its function in selenoprotein biosynthesis and, indeed, report on numerous findings that point to a link between selenium and energy metabolism (9). The results of the two studies with Scly KO mice are quite unexpected and, in part, provocative and might pave the way for a completely new field in the biology of selenium and selenoproteins.…”

“…However, the Se recycling pathway remained neglected until the knockdown of Scly in HeLa cells revealed its involvement in selenoprotein biosynthesis. Disruption of Scly in mice led to even more surprising results (9). Selenoproteins in livers of the selenium-adequately fed mice were not strikingly affected with the exception of SelS, which was decreased.…”

“…An important player in selenoprotein biosynthesis appears to also be the Scly, an enzyme, which specifically breaks down Sec into alanine and selenide (9). This way, selenium derived from Sec of selenoproteins can be recycled.…”

N‐ϒ‐(l‐Glutamyl)‐l‐Selenomethionine Inhibits Fat Storage via the Stearoyl‐CoA Desaturases FAT‐6 and FAT‐7 and the Selenoprotein TRXR‐1 in Caenorhabditis elegans

“…Dietary fat has been implicated to play a significant role in the rise of obesity . The role of specific selenium‐dependent mechanisms leading to obesity remains largely unknown . Lipid plays three major functions in organisms, including participating in signaling cascades, being structure elements in cell membranes, and playing a key molecule in energy metabolism .…”