Editors' ChoiceMETABOLIC REGULATION

Skinny, Old Mice

STKE  14 Sep 2004:
Vol. 2004, Issue 250, pp. tw329
DOI: 10.1126/stke.2502004tw329

S6 kinase 1 (S6K-1) is known to function in the nutrient-sensing and insulin pathways; in those pathways it is a target of mTOR (mammalian target of rapamycin) and it regulates protein translation. Mice deficient in S6K1 have decreased insulin secretion and are glucose intolerant. Um et al. report that S6K1-deficient mice had reduced fat storage during aging compared with wild-type mice and were resistant to diet-induced obesity. The mice had increased metabolic activity and lipolysis in white adipose tissue because of increased numbers of mitochondria and mRNA for genes involved in energy combustion and oxidative phosphorylation. When fed a high-fat diet, the S6K1-deficient mice had increased circulating free fatty acids compared with wild-type mice on the same diet. Furthermore, despite chronically high levels of circulating free fatty acids and insulin, the S6K1-deficient mice fed a normal or high-fat diet continued to respond to insulin (based on response to an insulin-tolerance test). However, these S6K1-deficient mice had less autophosphorylation of the insulin receptor when fed a high-fat diet, which suggests that receptor desensitization had occurred, as it does in wild-type mice. Thus, in the absence of S6K-1, cells are able to continue to respond to insulin or nutrients despite having desensitized receptors, which suggests that S6K-1 feeds back on the system downstream of the receptor to inhibit the pathway. Indeed, protein kinase B phosphorylation in the S6K1-deficient mice on either a normal or high-fat diet is higher than in wild-type mice, and phosphorylation of insulin receptor substrate 1 is decreased. Thus, loss of negative feedback by S6K-1 on the insulin signaling pathway and increased metabolic activity protect the S6K1-deficient mice from obesity.

S. H. Um, F. Frigerio, M. Watanabe, F. Picard, M. Joaquin, M. Sticker, S. Fumagalli, P. R. Allegrini, S. C. Kozma, J. Auwerx, G. Thomas, Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 9, 200-205 (2004). [Online Journal]