Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity.
Elucidating the signalling mechanisms by which obesity leads to impaired insulin action is critical in the development of therapeutic strategies for the treatment of diabetes. Recently, mice deficient for S6 Kinase 1 (S6K1), an effector of the mammalian target of rapamycin (mTOR) that acts to integrate nutrient and insulin signals, were shown to be hypoinsulinaemic, glucose intolerant and have reduced beta-cell mass. However, S6K1-deficient mice maintain normal glucose levels during fasting, suggesting hypersensitivity to insulin, raising the question of their metabolic fate as a function of age and diet. Here, we report that S6K1-deficient mice are protected against obesity owing to enhanced beta-oxidation. However on a high fat diet, levels of glucose and free fatty acids still rise in S6K1-deficient mice, resulting in insulin receptor desensitization. Nevertheless, S6K1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from S6K1 to insulin receptor substrate 1 (IRS1), which blunts S307 and S636/S639 phosphorylation; sites involved in insulin resistance. Moreover, wild-type mice on a high fat diet as well as K/K A(y) and ob/ob (also known as Lep/Lep) mice-two genetic models of obesity-have markedly elevated S6K1 activity and, unlike S6K1-deficient mice, increased phosphorylation of IRS1 S307 and S636/S639. Thus under conditions of nutrient satiation S6K1 negatively regulates insulin signalling.
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.
Sung Hee
SH
Um
Francesca
F
Frigerio
Mitsuhiro
M
Watanabe
Frédéric
F
Picard
Manel
M
Joaquin
Melanie
M
Sticker
Stefano
S
Fumagalli
Peter R
PR
Allegrini
Sara C
SC
Kozma
Johan
J
Auwerx
George
G
Thomas
D017667:Adipocytes / Q000378:metabolism; D000375:Aging / Q000502:physiology*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D004041:Dietary Fats / Q000494:pharmacology*; D004789:Enzyme Activation; D005215:Fasting / Q000097:blood / Q000502:physiology; D005230:Fatty Acids, Nonesterified / Q000097:blood; D017353:Gene Deletion; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008066:Lipolysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000097:blood / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism*; D010084:Oxidation-Reduction; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D001786:Blood Glucose; D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D012333:RNA, Messenger; D011972:Receptor, Insulin; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1