Forskning ved Københavns Universitet - Københavns Universitet


mTORC2 Regulation of Muscle Metabolism and Insulin Sensitivity

Publikation: Bog/antologi/afhandling/rapportPh.d.-afhandlingForskning

Type 2 diabetes (T2D) is a pandemic that continues to grow at alarming rates. In healthy individuals, blood glucose levels are tightly controlled. After eating a meal blood glucose levels rise. This triggers insulin release from the pancreas, which in turn signals organs like the liver, fat and skeletal muscle to take up blood glucose, ultimately lowering blood glucose levels. A hallmark of T2D is decreased organ sensitivity to the effects of the insulin. Therefore, an early event in the pathogenesis of T2D is an increase in insulin secretion in response to eating a meal, as more insulin is required to lower blood glucose levels. If insulin sensitivity is chronically decreased, this can stress the pancreas to the point of organ failure in genetically susceptible individuals, who therefore are unable to produce sufficient amounts of insulin. This highlights a) the importance of understanding why organs can become insulin insensitive and b) the need to identify and study insulin sensitizing effects.

Blood glucose entry into skeletal muscle is largely regulated by the glucose transporter (GLUT) 4. GLUT4 acts as a channel in the impenetrable plasma membrane through which glucose can enter. In the absence of insulin, the
majority of GLUT4 resides within the muscle. Conversely, insulin stimulation increases the muscle’s permeability to glucose, by triggering GLUT4 translocation to the plasma membrane. The effect of insulin on GLUT4 translocation is
mediated by a chain of molecular signaling events that are initiated by insulin binding to its receptor on the muscle’s plasma membrane. The recently discovered mammalian target of rapamycin complex 2 (mTORC2) has been
implicated as an integral member of this signaling chain and therefore might be necessary for insulin stimulated GLUT4 translocation and therefore glucose uptake. However, this has not been rigorously investigated in skeletal muscle, especially in vivo.

Therefore the aim of this PhD thesis was to investigate the physiological relevance of mTORC2 in skeletal muscle metabolism, particular glucose metabolism. Pharmacological mTOR inhibition decreased insulin sensitivity in mouse skeletal muscle, as insulin stimulated glucose uptake into muscle was reduced. These effects were likely due to the loss of mTORC2 activity, because specific pharmacological mTORC1 inhibition did not impair insulin stimulated
glucose uptake. Furthermore, the reduction in insulin stimulated glucose uptake with mTORC2 inhibition occurred despite normal GLUT4 translocation in muscle cells. Genetic abrogation of mTORC2 activity due to muscle specific knockout of Rictor (Ric mKO) in mice impaired in vivo skeletal muscle glucose uptake, but this could not be explained by defects in the insulin signaling chain necessary for glucose uptake. To better understand the underlying molecular mechanisms of how mTORC2 regulates metabolism in skeletal muscle, we performed unbiased, global quantitative phospho- and total proteomic analyses of mouse Ric mKO muscles. This revealed that mTORC2 controls skeletal muscle glycolysis and lipid storage. In agreement, Ric mKO mice exhibited reduced muscle glycolytic flux,
greater reliance on fat as an energy substrate, re-partitioning of lean to fat mass and higher intramyocellular triacylglycerol (IMTG) levels compared to Ric WT mice. Increased IMTG was accompanied by elevated protein expression of the lipid droplet coating protein, Perilipin 3 (PLIN3) due to increased AMPK activity and nuclear FoxO1 protein content in Ric mKO muscle.

Overall, this thesis demonstrates that mTORC2 regulates skeletal muscle insulin sensitivity by controlling muscle glycolytic flux and lipid storage via an AMPK-FoxO1-PLIN3 signaling axis.
Udgivelses stedCopenhagen
ForlagDepartment of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen
Antal sider74
ISBN (Trykt)978-87-7611-867-9
StatusUdgivet - 2014

Bibliografisk note

CURIS 2015 NEXS 153

ID: 136855916