Abstract
Targeted deletion of S6 kinase (S6K) 1 in mice leads to higher energy expenditure and improved glucose metabolism. However, the molecular mechanisms controlling these effects remain to be fully elucidated. Here, we analyze the potential role of dietary lipids in regulating the mTORC1/S6K system. Analysis of S6K phosphorylation in vivo and in vitro showed that dietary lipids activate S6K, and this effect is not dependent upon amino acids. Comparison of male mice lacking S6K1 and 2 (S6K-dko) with wt controls showed that S6K-dko mice are protected against obesity and glucose intolerance induced by a high-fat diet. S6K-dko mice fed a high-fat diet had increased energy expenditure, improved glucose tolerance, lower fat mass gain, and changes in markers of lipid metabolism. Importantly, however, these metabolic phenotypes were dependent upon dietary lipids, with no such effects observed in S6K-dko mice fed a fat-free diet. These changes appear to be mediated via modulation of cellular metabolism in skeletal muscle, as shown by the expression of genes involved in energy metabolism. Taken together, our results suggest that the metabolic functions of S6K in vivo play a key role as a molecular interface connecting dietary lipids to the endogenous control of energy metabolism.
Highlights
Control of energy balance plays a central role in diseases such as obesity and metabolic syndrome, where pharmacological suppression of appetite alone appears to be insufficient to prevent or reverse weight gain and adiposity
Since S6K1 has been reported to function in vivo as a nutrient sensor that responds to branched-chain amino acids such as leucine [3], we further assessed whether S6K1 activation by fatty acids was dependent on amino acids
The results of this study show that S6 kinases (S6K) are directly activated by fatty acids in vitro and in vivo, a finding that appears to expand the role of S6K as a nutrient sensor
Summary
Control of energy balance plays a central role in diseases such as obesity and metabolic syndrome, where pharmacological suppression of appetite alone appears to be insufficient to prevent or reverse weight gain and adiposity. The mechanism through which S6K controls energy homeostasis could involve regulation of lipid metabolism, since ex vivo studies in muscle, primary hepatocytes and epididymal white adipose tissue have shown that the combined absence of S6K1 and 2 leads to changes in AMPK activity, mitochondrial biogenesis and beta oxidation [7]. It remains unclear whether these effects are retained in vivo or whether the control of systemic energy metabolism by S6K is regulated by dietary lipids
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