New Publication by Postdoctoral Fellow Krystle Kalafut, PhD
In a study published in Nature Communications, Krystle Kalafut, now a fellow in the Hotamışlıgil Lab, and colleagues found that a molecular mechanism involving AKT-mediated phosphorylation of TSC2 is the predominant pathway by which insulin activates mTORC1 in mouse liver tissue. The same mechanism was required for full mTORC1 activation in response to glucose, which stimulates endogenous insulin secretion. However, AKT-mediated phosphorylation of TSC2 was dispensable for mTORC1 activation when mice were fed a protein-rich diet.
In the C26 model of cancer cachexia, reduced food intake is the primary driver for body weight loss and tissue wasting, as well as changes in circulating levels of key nutrients. The symptom of weakness however is independent of food intake.
Instead, dietary protein emerged as the dominant signal responsible for postprandial hepatic mTORC1 activation. Protein was required for robust mTORC1 activation in the mouse liver after feeding, while amino acids, the building blocks of protein, were sufficient to produce near-maximal activation in primary mouse liver cells. The studies also showed that dietary protein content determines how strongly mTORC1 activation depends on insulin, with insulin playing a greater role when dietary protein content was low.
The researchers also examined the proposed relationship between liver mTORC1 activity and obesity-associated metabolic disease. Markers of mTORC1 signaling were not hyperactivated in the livers of obese mice fed a high-fat diet, despite high insulin levels and impaired glucose regulation. Moreover, blocking mTORC1 activation through the insulin-responsive AKT–TSC2 pathway did not protect the mice from obesity-associated metabolic impairments.
Together, these findings reveal a mode of mTORC1 regulation in which dietary protein is dominant over the insulin-mediated signal after feeding. The findings clarify how the mouse liver integrates nutritional and hormonal cues and challenge the idea that liver mTORC1 is broadly and persistently hyperactivated in obesity.
Congratulations to the collective research from Krystle Kalafut, Yann Cormerais, Madi Cissé, Samuel Lapp, Karen Inouye, Gökhan Hotamışlıgil and Brendan Manning for this important work.
READ THE FULL PUBLICATION HERE
