Rajat Singh, M.D., M.B.,B.S.
Autophagy or “self-eating” is an in-bulk lysosomal degradative pathway that plays a crucial role in cellular homeostasis through protein and organelle turnover. Autophagy occurs at basal levels in all cells and is induced following conditions such as stress or nutrient-deprivation. Briefly, the process of autophagy requires the de novo formation of a double-walled limiting membrane that engulfs cellular cargo destined for degradation and then seals upon itself to form an autophagosome. The delivery of the engulfed cargo to the lysosome occurs by fusion of the autophagosome with the lysosome leading to degradation of the cargo. We have recently demonstrated a novel role of autophagy in the mobilization and degradation of intracellular lipid stores in the liver, thus pointing to a possible function of autophagy in energy homeostasis. We have also recently shown that this lipophagic role of autophagy functions in hypothalamic neurons to generate neuron-intrinsic free acids that, in turn, drive neuronal feeding mechanisms.
The primary focus of the lab is to examine the organ-specific roles of autophagy in the regulation of lipid metabolism and energy homeostasis using biochemical, immunochemical, and image-based approaches in vitro and in conditional knockout mouse models.
We are interested in:
1. Roles for autophagy in discrete hypothalamic neurons in food intake and energy balance
2. Signaling mechanisms modulating autophagy in hypothalamic neurons
3. Metabolic and regulatory functions of autophagy in adipose biology
Aging is considered to reduce autophagic activity. The second focus of the laboratory is to examine the effect of aging-induced reduction of hypothalamic and adipose autophagy on the development of the metabolic syndrome of aging.
- Kaushik, S., Arias, E., Kwon, H., Martinez-Lopez, N., Athonvarangkul, D., Sahu, S., Schwartz, G.J., Pessin, J.E., Singh, R. Loss of autophagy in hypothalamic POMC neurons impairs lipolysis. EMBO Reports 2012 Jan 17. doi: 10.1038/embor.2011.260.
- Singh, R. Hypothalamic lipophagy and energetic balance. Aging (Albany NY) 2011 Oct;3(10):934-42.
- Kaushik, S., Rodriguez-Navarro, J.A., Arias, E., Kiffin, R., Sahu, S., Schwartz, G.J., Cuervo, A.M., Singh, R. Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance. Cell Metabolism 2011 Aug 3;14(2):173-83.
- Singh, R., Cuervo, A.M. Autophagy in the cellular energetic balance. Cell Metabolism 2011;13(5):495-504.
- Hubbard, V.M., Valdor, R., Patel, B., Singh, R., Cuervo, A.M., Macian, F. Macroautophagy regulates energy metabolism during effector T cell activation. J. Immunology 2010;185(12):7349-57.
- Kaushik, S., Singh, R., Cuervo, A.M. Autophagic pathways and metabolic stress. Diabetes Obes Metab 2010 Oct;12 Suppl 2:4-14.
- Wang, Y., Singh, R., Xiang, Y., Greenbaum, L.E., Czaja, M.J. Nuclear factor κB up-regulation of CCAAT/enhancer-binding protein β mediates hepatocyte resistance to tumor necrosis factor α toxicity. Hepatology 2010;52(6):2118-26.
- Singh, R. Autophagy and regulation of lipid metabolism. Results Probl. Cell Differentiation. 2010;52:35-46.
- Wang, Y., Singh, R., Xiang, Y., Czaja, M.J. Macroautophagy and chaperone-mediated autophagy are required for hepatocyte resistant to oxidative stress. Hepatology 2010;52(1):266-77.
- Singh, R., Xiang Y, Wang, Y., Baikati, K., Cuervo, A.M., Luu, Y.K., Tang, Y., Pessin, J.E., Schwartz, G.J., Czaja, M.J. Autophagy regulates adipose mass and differentiation in mice. J. Clin. Investigation 2009; 119(11):3329-39.
- Singh, R.,* Kaushik, S.,* Wang, Y., Xiang, Y., Novak, I., Komatsu, M., Tanaka, K., Cuervo, A.M., Czaja, M.J. Autophagy regulates lipid metabolism. Nature 2009; 458:1131-1135.
- Singh, R., Wang, Y., Xiang, Y., Tanaka, K.E., Gaarde, W.A., Czaja, M.J. Differential effects of JNK1 and JNK2 inhibition on murine steatohepatitis and insulin resistance. Hepatology 2009; 49:87-96.
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