Attenuated mTOR signaling and enhanced autophagy in adipocytes from obese patients with type 2 diabetes

The protein kinase mammalian target of rapamycin (mTOR) mediates insulin control ofprotein synthesis, autophagy, mitochondrial function, and, through feedback signaling tophosphorylation of IRS1 at serine residues, mTOR directly controls insulin signaling. Weshow that in adipocytes from patients with type 2 diabetes (T2D) insulin activation of mTORis attenuated and that the resultant phenotype is compatible with, and can be mimicked by,loss of mTOR activation. In T2D adipocytes mitochondrial function is impaired andautophagy strongly upregulated, with concomitant increased autophagic destruction ofmitochondria and lipofuscin particles, and a dependence on autophagy for ATP production.Conversely, mitochondrial dysfunction attenuates insulin activation of mTOR, enhancesautophagy and attenuates feedback to IRS1. Our findings put mTOR in the driver´s seat of aninsulin resistance that in adipocytes can be fuelled by mitochondrial dysfunction,inflammation, ER-stress, or hypoxia.

Svensson, KristofferLinköpings universitet,Cellbiologi,Hälsouniversitetet(Swepub:liu)krisv29 (author)
Ruishalme, IidaLinköpings universitet,Cellbiologi,Hälsouniversitetet,Landstinget i Östergötland (author)
Brännmark, CeciliaLinköpings universitet,Cellbiologi,Hälsouniversitetet(Swepub:liu)cecjo56 (author)
Franck, NiclasLinköpings universitet,Cellbiologi,Hälsouniversitetet(Swepub:liu)nicfr01 (author)
Krook, HansLinköpings universitet,Kirurgi,Hälsouniversitetet,Landstinget i Östergötland (author)
Sandström, PerÖstergötlands Läns Landsting,Linköpings universitet,Kirurgi,Hälsouniversitetet,Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala(Swepub:liu)persa07 (author)
Kjølhede, PrebenÖstergötlands Läns Landsting,Linköpings universitet,Obstetrik och gynekologi,Hälsouniversitetet,Kvinnokliniken US(Swepub:liu)prekj14 (author)
Strålfors, PeterLinköpings universitet,Cellbiologi,Hälsouniversitetet(Swepub:liu)petst48 (author)
Linköpings universitetCellbiologi (creator_code:org_t)

In:Molecular Medicine: Feinstein Institute for Medical Research16:07-Aug, s. 235-2461076-15511528-3658

By the author/editor: Öst, Anita, 1965 ...; Svensson, Kristo ...; Ruishalme, Iida; Brännmark, Cecil ...; Franck, Niclas; Krook, Hans; show more...; Sandström, Per; Kjølhede, Preben; Strålfors, Peter; show less...

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