First Thesis Advisor
David Guertin, PhD
mTOR, mTORC1, Raptor, Adipose, Adipocytes, Metabolism, Diabetes, Obesity, Lipodystrophy, Metabolic Syndrome
Metabolic disorders are commonly associated with obesity, a condition where excess caloric intake leads to massive adipose tissue (AT) expansion and eventual dysfunction. When adipose tissue loses its ability to store excess energy properly, lipids accumulate in non-adipose tissues such as liver, and muscle. This ectopic lipid deposition is a significant risk factor in the development of a collection of disorders described as metabolic syndrome. While metabolic syndrome is typically linked with obesity, patients who have an inability to develop adipose tissue depots (lipodystrophy) develop similar clinical outcomes. There is evidence that aberrant mTORC1 signaling may occur in both settings, and may be a factor that contributes to adipose dysfunction.
I find that adipocyte specific loss of Raptor, a key mTORC1 subunit, leads to progressive lipoatrophy, and associated metabolic dysfunction including AT inflammation, hepatosteatosis, and insulin resistance. Interestingly, inhibition of autophagy, a pathway upregulated during Raptordeletion, prevents lipoatrophy but does not protect from ectopic lipid deposition and AT inflammation. These results suggest that outputs of mTORC1 in adipocytes individually regulate adipocyte storage capacity, and AT health. Furthermore, ablation of the amino acid sensing RagGTPases, thought to be necessary for mTORC1 activity, does not phenocopy Raptor KO, suggesting RagGTPase independent functions of mTORC1 in adipocytes. RagA/B deletion, however, did consistently increase Ucp1 expression in WAT, indicating a possible noncanonical role of the Rags in regulating Ucp1.
Overall, these studies advance our understanding of regulation of adipose tissue metabolism, and shed light on previously unstudied nutrient specific signaling pathways in adipocytes.
Lee PL. (2018). Adipocyte mTORC1 Signaling Separately Regulates Metabolic Homeostasis and Adipose Tissue Mass, Independent of RagGTPase Activity. GSBS Dissertations and Theses. https://doi.org/10.13028/qdp4-sv98. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/988
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