Rajat Singh, M.B.,B.S., M.D.

Autophagy and Integrative Metabolism

Autophagy is a lysosomal recycling program that degrades unwanted cytoplasmic contents to maintain cellular quality control. Autophagy occurs at basal levels in all cells and is induced during starvation and stress. Autophagy requires the de novo formation of a double-walled limiting membrane that sequesters cargo destined for degradation and seals upon itself to form an autophagosome. The delivery of the engulfed cargo to lysosomes by autophagosome-lysosome fusion results in cargo degradation. We demonstrated a role for autophagy in mobilization and degradation of intracellular lipid stores by a process we termed lipophagy, thus mapping autophagy to metabolic regulation.  We have recently shown that lipophagy in  hypothalamic neurons generates neuron-intrinsic free fatty acids that 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, immunohistochemical, and image-based approaches in vitro and in conditional knockout mouse models. More specifically, our interests lie in understanding how autophagy in the CNS and peripheral tissues controls energy, glucose, and lipid metabolism in a time-, diet-, and age-dependent manner. The second focus of the lab is to understand how age-related autophagy failure causes metabolic disturbances. We are also interested in understanding in a novel - twice a day feeding intervention - will prevent metabolic aging in mice and humans. Our long -term goals are to develop approaches to stimulate autophagy and prevent the onset of metabolic aging. 

Reciprocal regulation of chaperone-mediated autophagy and the circadian clock. Juste YR, Kaushik S, Bourdenx M, Aflakpui R, Bandyopadhyay S, Garcia F, Diaz A, Lindenau K, Tu V, Krause GJ, Jafari M, Singh R, Muñoz J, Macian F, Cuervo AM. Nature Cell Biology. 2021. doi: 10.1038/s41556-021-00800-z.

Shear stress turns on the primary cilium and lipophagy. Martinez-Lopez N, Singh R. Nature Cell Biology. 2020;22(9):1029-1030.

Dysregulation of TFEB contributes to manganese-induced autophagic failure and mitochondrial dysfunction in astrocytes. Zhang Z, Yan J, Bowman AB, Bryan MR, Singh R, Aschner M. Autophagy. 2020;16(8):1506-1523.

Complement C3 and Autophagy Keep the β Cell Alive. Toledo M, Singh R. Cell Metabolism. 2019;29(1):4-6.

Autophagy regulates the liver clock and glucose metabolism by degrading CRY1. Toledo M, Batista-Gonzalez A, Merheb E, Aoun ML, Tarabra E, Feng D, Sarparanta J, Merlo P, Botre F, Schwartz GJ, Pessin JE, Singh R.  Cell Metabolism. Cell Metabolism. 2018;28(2):268-281. Recommended by F1000 Prime

Blocking p62/SQSTM1-dependent SMN degradation ameliorates Spinal Muscular Atrophy disease phenotypes. Rodriguez-Muela N, Parkhitko A, Grass T, Gibbs RM, Norabuena EM, Perrimon N, Singh R, Rubin LL. Journal of Clinical Investigation. 2018 Jul 2;128(7):3008-3023.

System-wide benefits of intermeal fasting by autophagy. Martinez-Lopez N, Tarabra E, Toledo E, Garcia-Macia M, Sahu S, Coletto L, Batista-Gonzalez A, Barzilai N, Pessin JE, Schwartz GJ, Kersten S, Singh R. Cell Metabolism. 2017; 26: 856-871. Highlighted: Nature Reviews in Endocrinology  

Self-renewal of a purified Tie2+ hematopoietic stem cell population relies on mitochondrial clearance. Ito K, Turcotte R, Cui J, Zimmerman SE, Pinho S, Mizoguchi T, Arai F, Runnels JM, Alt C, Teruya-Feldstein J, Mar JC, Singh R, Suda T, Lin CP, Frenette PS, Ito K. Science. 2016; 354: 1156-1160.

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Klionsky DJ, … Singh R, … Zughaier SM. Autophagy. 2016; 12: 1-222.

Autophagy in the CNS and periphery coordinate lipophagy and lipolysis in the brown adipose tissue and liver. Martinez-Lopez N, Garcia-Macia M, Sahu S, Athonvarangkul D, Liebling E, Merlo P, Cecconi F, Schwartz GJ, Singh R. Cell Metabolism. 2016; 23: 113-127.

Autophagy and lipid droplets in the liver. Martinez-Lopez N, Singh R. Annual Review of Nutrition. 2015; 35: 215-237.

Loss of the RNA polymerase III repressor MAF1 confers obesity resistance. Bonhoure N, Byrnes A, Moir RD, Hodroj W, Preitner F, Praz V, Marcelin G, Chua SC Jr, Martinez-Lopez N, Singh R, Moullan N, Auwerx J, Willemin G, Shah H, Hartil K, Vaitheesvaran B, Kurland I, Hernandez N, Willis IM. Genes & Development. 2015; 29: 934-947.

Autophagy proteins regulate ERK phosphorylation. Martinez-Lopez N, Athonvarangkul D, Mishall P, Sahu S, Singh R. Nature Communications. 2013; 4: 2799.

Autophagy in Myf5+ progenitors regulates energy and glucose homeostasis through control of brown fat and skeletal muscle development. Martinez-Lopez N, Athonvarangkul D, Sahu S, Coletto L, Zong H, Bastie CC, Pessin JE, Schwartz GJ, Singh R. EMBO Reports. 2013; 14(9): 795-803.

Mapping autophagy onto your metabolic radar. Yamada E, Singh R. Diabetes. 2012; 61: 272-280.

Loss of autophagy in hypothalamic POMC neurons impairs lipolysis. Kaushik S, Arias E, Kwon H, Martinez-Lopez N, Sahu S, Schwartz GJ, Pessin JE, Singh R. EMBO Reports. 2012; 13(3): 258-265.  
Comment: Rubinsztein DC. Autophagy-alias self-eating-appetite and ageing. EMBO Reports 2012;13(3):173-174. Issue Cover

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Autophagy in the cellular energetic balance. Singh R, Cuervo AM. Cell Metabolism. 2011;13:495-504.    
Cell Metabolism: Top 10 Reviews, 2005-2014, as chosen by the readers  

Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance. Kaushik S, Rodriguez-Navarro, JA, Arias E, Kiffin R, Sahu S, Schwartz GJ, Cuervo AM, Singh R. Cell Metabolism. 2011; 14: 173-183.  
Featured: The Scientist magazine, The Los Angeles Times, Fox News, EurekAlert.com, Jay Leno, National Public Radio  
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Nuclear factor κB up-regulation of CCAAT/enhancer-binding protein β mediates hepatocyte resistance to tumor necrosis factor α toxicity. Wang Y, Singh R, Xiang Y, Greenbaum LE, Czaja MJ. Hepatology. 2010; 52: 2118-2126

Macroautophagy and chaperone-mediated autophagy are required for hepatocyte resistance to oxidant stress. Wang Y, Singh R, Xiang Y, Czaja MJ. Hepatology. 2010; 52: 266-277

Autophagy regulates adipose mass and differentiation. Singh R, Xiang Y, Wang Y, Baikati Y, Cuervo AM, Luu YK, Tang Y, Pessin JE, Schwartz GJ, Czaja MJ. Journal of Clinical Investigation. 2009: 119(11): 3329-3339. 
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Autophagy regulates lipid metabolism. Singh R,* Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, Cuervo AM, Czaja MJ. Nature. 2009;458:1131-1135. *co-first.
Nature News and Views: Zechner R, Madeo F. Cell biology: Another way to get rid of fat. Nature 2009; 458: 1118-1119.   
Preview: Weidberg H, Shvets E, Elazar Z. Lipophagy: Selective catabolism designed for lipids. Dev Cell 2009; 16: 628-30. 
Hepatology Elsewhere: Kersten S, Müller M. Dropping liver fat droplets. Hepatology 2009; 50: 645-647. 
Featured in communication media: ABC, BBC, Discover Magazine, Science Central, Science Daily, Washington Post
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Differential effects of JNK1 and JNK2 inhibition on insulin resistance and steatohepatitis. Singh R, Wang Y, Xiang Y, Tanaka KE, Gaarde WA, Czaja MJ. Hepatology. 2009;49:87-96.

Comment: c-Jun N-terminal kinase signaling in the pathogenesis of nonalcoholic fatty liver disease: Multiple roles in multiple steps. Kodama Y, Brenner DA. Hepatology 2009; 49: 6-8.