Regulation of Lipid and Glycogen Synthesis

Project Summary

The mechanisms by which nutrient and hormonal signals regulate the storage and breakdown triglycerides and glycogen are still not completely understood. We are interested in the molecular mechanisms which control lipid and glycogen levels in muscle, liver and adipose tissue. We are particularly interested in the mechanisms by which insulin and amino acids modulate glycogen and lipid synthesis.

One of the pathways that lie at the intersection between nutrient levels and metabolic responses is the mTORC1 pathway. This protein kinase complex is regulated by a variety of anabolic signals including energy status (via AMPK), amino acids and growth factors such as insulin. mTORC1 can integrate these signals and alters metabolism to either store or use those nutrients. Some examples of mTORC1-dependent changes include:

Promoting triglyceride and glycogen synthesis.
mTORC1 can promote lipid synthesis by several mechanisms. These include regulating the transcription factors Lipin and SREBP1c. We have shown that SREBP is important for mTORC1 regulation of glycogen in the liver (see Lu et al.) and are investigating the role of the mTORC1/SREBP1c axis in adipose and muscle tissues as well)
Altering energy utilization
Another way by which mTORC1 can alter nutrient homeostasis is to promote nutrient utilization in energy consuming tissues. The up-regulation of metabolism is a normal response to energy excess, a process known as diet-induced thermogenesis. Several recent papers have shown that mTORC1 in muscle can increase energy expenditure, and we are investigating the mechanisms by which this happens as a way to promote negative energy balance.
Generate new muscle and adipose tissue
mTORC1 also plays an essential role in the formation of new muscle tissue (myogenesis) and adipocytes (adipogenesis). A recent paper from our group showed that this mechanism is conserved even in fruit flies (see Hatfield et al.)

To study this we are using a variety of mouse and cell culture models where we can test the effects of manipulating nutrient sensing pathways to determine the effects of these on glycogen and triglyceride storage.

Who is Working on This?

Dave Bridges
Assistant Professor, Department of Nutritional Sciences, University of Michigan since 2016-06-01
Molly Carter
Graduate Lab Assistant, Department of Nutritional Sciences, University of Michigan since 2016-09-01
Cody Cousineau
Graduate Lab Assistant, Department of Nutritional Sciences, University of Michigan since 2016-08-29
Innocence Harvey
Doctoral Candidate, Department of Nutritional Sciences, University of Michigan since 2016-09-01
Liliana Pfeifer
Undergraduate Research Assistant, Department of Nutritional Sciences, University of Michigan since 2017-05-01
JeAnna Redd
Senior Research Assistant, Department of Nutritional Sciences, University of Michigan since 2016-08-01

What sources of funding support this project?

Obesity is a public health epidemic wordwide and affects nearly a third of adult Americans. Several devastating co-morbidities are associated with obesity, including insulin resistance/type II diabetes and non-alcoholic steatohepatitis/non-alcoholic fatty liver disease. Paradoxically, in obese states, lipid storage is not suppressed, in spite of resistance to insulin action. This finding that has important consequences for the management of obesity and its complications. An emerging molecular mechanism linking obesity to excessive lipid storage is the mTORC1/SREBP1c pathway, which our group and others have identified as both activated with obesity, and as a key regulator of lipogenesis and new adipocyte formation. This study will test the hypothesis that mTORC1 activation in the obese state elevates lipid levels, due to activation of both adipogenesis and lipogenesis. To accomplish this, we have developed several new innovative models to test specific aspects of this hypothesis. First, we have generated adipose-specificTsc1 knockout mice as a model of chronic adipose mTORC1 activation. The chronic elevations in mTORC1 signaling in these mice are associated with elevated fat mass and increased hepatic steatosis, likely due to enhanced de novo lipogenesis in adipose tissue. We will determine the molecular changes resulting from chronic mTORC1 elevation, and identify the molecular mechanisms underlying these mTORC1-dependent increases in lipid storage. Elevated adiposity may is caused by increased adipogenesis, so we will determine the molecular mechanisms by which mTORC1 positively regulates adipogenesis. We will specifically evaluate the hypothesis that mTORC1 regulates PPARγ mRNA stability via a miRNA-dependent mechanism. To test the role of mTORC1 in the liver, we will study both activation and inhibition this kinase via ablation of the essential mTORC1 component Rptor, and Tsc1 respectively in adult mouse livers. This approach will allow us to evaluate whether mTORC1 is necessary and sufficient for the development and maintenance of hepatic steatosis in adult liver tissues for the first time. This is an important gap in our knowledge, since in obesity-associated liver disease, mTORC1 is not activated during development, but co-incident with elevations in adiposity. We will explore the physiological significance of a positive feedback loop in SREBP1c using genome-edited rats. This key mTORC1 target plays an important role in de novo lipogenesis and the amplification of SREBP1c action by a transcriptional feed-forward circuit has been proposed to be an important component of both diet-induced hepatic steatosis and obesity. By deleting only the relevant SRE at the endogenous Srebf1 locus, we can test the importance of this circuit in a controlled and direct manner. Importantly, these rats will also allow us to separate the direct activation of SREBP1c by mTORC1 and other signals, from the confounding effects of positive feedback. Together these studies will answer fundamental mechanistic questions regarding how mTORC1 and SREBP1c regulate adipogenesis and lipogenesis, providing insights into potential routes of therapeutic intervention for obesity and liver disease.

Publications

What have we published on this topic?

Michael Keufner, Kevin Pham, JeAnna Redd, Erin Stephenson, Innocence Harvey, Xiong Deng, Dave Bridges, Eric Boilard, Marshal Elam and Edwards Park. Secretory phospholipase A2 group IIA (PLA2G2A) modulates insulin sensitivity and metabolism. 2017. Journal of Lipid Research Full Text Details.
Suriyan Ponnusamy, Quynh Tran, Thirumagal Thiyagarajan, Duane Miller, Dave Bridges and Ramesh Narayanan. An Estrogen Receptor b-Selective Agonist Inhibits Non-Alcoholic Steatohepatitis (NASH) in Preclinical Models by Regulating Bile Acid and Xenobiotic Receptors 2017. Experimental Biology and Medicine 242(6):606-616 Full Text Details.
Suriyan Ponnusamy, Quynh Tran, Innocence Harvey, Heather Smallwood, Thirumagal Thiyagarajan, Souvik Banerjee, Daniel Johnson, James Dalton, Ryan Sullivan, Duane Miller, Dave Bridges and Ramesh Narayanan. Pharmacologic activation of estrogen receptor-beta; increases mitochondrial function, energy expenditure, and brown adipose tissue. 2017. FASEB Journal 31(1):266-281 Full Text Details.
Alysse Charrier, Li Wang, Erin Stephenson, Siddharth Gantha, Chih-wei Ko, Colleen Croninger, Dave Bridges and David Buchner. Zinc finger protein 407 overexpression upregulates PPAR-target gene expression and improves glucose homeostasis in mice. 2016. American Journal of Physiology - Endocrinology and Metabolism 311(5):E869-E880 Full Text Details.
Erin Stephenson, Sridhar Jaligama, Alyse Ragauskas, JeAnna Redd, Jyothi Parvathareddy, Matthew Peloquin, Jordy Saravia, Joan Han, Stephania Cormier and Dave Bridges. Exposure to environmentally persistent free radicals during gestation lowers energy expenditure and impairs skeletal muscle mitochondrial function in 2016. American Journal of Physiology - Endocrinology And Metabolism 310(11):E1003-E1015 Full Text Details.
Qingming Dong, Francesco Giorgianni, Sarka Beranova-Giorgianni, Xiong Deng, Robert O'Meally, Dave Bridges, Edwards Park, Marshal Elam and Rajendra Raghow. Glycogen synthase kinase-3 mediated phosphorylation of serine 73 targets sterol response element binding protein-1c (SREBP-1c) for proteasomal degrada 2015. Bioscience Reports 36(1):e00284 Full Text Details.
C. Song, K. Ghafoor, H. Ghafoor, N. Kahn, S. Thirunavukkarasu, B. Jennings, A. Estes, S. Zaidi, Dave Bridges, Patrick Tso, F. Gonzalez and K. Malik. Cytochrome P450 1B1 Contributes to the Development of Atherosclerosis and Hypertension in Apolipoprotein E-Deficient Mice. 2016. Hypertension 67(1):206-13 Full Text Details.
Xiong Deng, Qingming Dong, Dave Bridges, Rajendra Raghow, Edwards Park and Marshal Elam. Docosahexaenoic Acid Inhibits Proteolytic Processing of Sterol Regulatory Element-binding Protein-1c (SREBP-1c) via Activation of AMP-activated Kinase 2015. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 185(12):1521-9 Full Text Details.
Irit Hochberg, Innocence Harvey, Quynh Tran, Erin Stephenson, Ariel Barkan, Alan Saltiel, William Chandler and Dave Bridges. Gene expression changes in subcutaneous adipose tissue due to Cushing's disease. 2015. Journal of Molecular Endocrinology 55(2):81-94 Full Text Details.
Irit Hochberg, Quynh Tran, Ariel Barkan, Alan Saltiel, William Chandler and Dave Bridges. Gene Expression Signature in Adipose Tissue of Acromegaly Patients. 2015. PLOS One 10(6):e0129359 Full Text Details.
David Buchner, Alysse Charrier, Ethan Srinivasan, Li Wang, Michelle Paulsen, Mats Ljungman, Alan Saltiel and Dave Bridges. Zinc Finger Protein 407 (ZFP407) Regulates Insulin-Stimulated Glucose Uptake and Glucose Transporter 4 (Glut4) mRNA. 2015. The Journal of biological chemistry 290(10):6376-86 Full Text Details.
Dave Bridges and Alan Saltiel. Phosphoinositides: Key Modulators of Energy Metabolism 2014. Biochimica and Biophysica Acta - Molecular and Cell Biology of Lipids 1851(6):857-866 Full Text Details.
Qingming Dong, Francesco Giorgianni, Xiong Deng, Sarka Beranova-Giorgianni, Dave Bridges, Edwards Park, Marshal Elam and Rajendra Raghow. Phosphorylation of Sterol Regulatory Element Binding Protein-1a by Protein Kinase A (PKA) Regulates Transcriptional Activity 2014. Biochemical and Biophysical Research Communications 449(4):449-54 Full Text Details.
Binbin Lu, Dave Bridges, Yemen Yang, Kaleigh Fisher, Alan Cheng, Louise Chang, Zhuoxian Meng, Jiande Lin, Michael Downes, Ruth Yu, Christopher Liddle, Ronald Evans and Alan Saltiel. Metabolic Crosstalk: molecular links between glycogen and lipid metabolism in obesity. 2014. Diabetes 63(9):2935-48 Full Text Details.
Tsukasa Suzuki, Dave Bridges, Daisuke Nakada, Georgios Skiniotis, Sean Morrison, Jiande Lin, Alan Saltiel and Ken Inoki. Inhibition of AMPK catabolic action by GSK3. 2013. Molecular cell 50(3):407-19 Full Text Details.
Bernat Baeza-Raja, Pingping Li, Natacha Le Moan, Benjamin Sachs, Christian Schachtrup, Dimitrios Davalos, Eirini Vagena, Dave Bridges, Choel Kim, Alan Saltiel, Jerrold Olefsky and Katerina Akassoglou. p75 neurotrophin receptor regulates glucose homeostasis and insulin sensitivity. 2012. Proceedings of the National Academy of Sciences of the United States of America 109(15):5838-43 Full Text Details.

What are some key papers on this topic?

Andrew Shin, Martin Fasshauer, Nika Filatova, Linus Grundell, Elizabeth Zielinski, Jian-Ying Zhou, Thomas Scherer, Claudia Lindtner, Amanda Lapworth, Olga Ilkayeva, Uwe Knippschild, Anna Wolf, Ludger Shedja, Kevin Grove, Richard Smith, Wei-Jun Qian, Chrisopher Lynch, Christopher Newgard and Christophe Buettner. Brain Insulin Lowers Circulating BCAA Levels by Inducing Hepatic BCAA Catabolism. 2014. Cell metabolism S1550-4131(14):00400-8 Full Text Our Thoughts Details.
Jingxiang Huang, O. Nelson, Heiko Jansen, Elizabeth Galbreath, Kurt Morgenstern, Jamie Gehring, Kimberly Rigano, Jae Lee, Jianhua Gong, Adam Shaywitz, Chantal Vella, Charles Robbins and Kevin Corbit. Grizzly Bears Exhibit Augmented Insulin Sensitivity while Obese Prior to a Reversible Insulin Resistance during Hibernation 2014. Cell Metabolism 20(2):376-82 Full Text Our Thoughts Details.
Xiaoyuan Xu, Ambar Grijalva, Alicja Skowronski, Marco van Eijk, Mireille J Serlie and Anthony Ferrante. Obesity activates a program of lysosomal-dependent lipid metabolism in adipose tissue macrophages independently of classic activation. 2014. Cell metabolism 18(6):816-30 Full Text Our Thoughts Details.
Naresh Bal, Santosh Maurya, Danesh Sopariwala, Sanjaya Sahoo, Subash Gupta, Sana Shaikh, Meghna Pant, Leslie Rowland, Eric Bombardier, Sanjeewa Goonasekera, Russel Tupling, Jeffery Molkentin and Muthu Periasamy. Sarcolipin is a newly identified regulator of muscle-based thermogenesis in mammals. 2012. Nature Medicine 18(19):1575-9 Full Text Our Thoughts Details.
Hui Zhang, Jingxiang Huang, Katrin Düvel, Bernard Boback, Shulin Wu, Rachel Squillace, Chin-Lee Wu and Brendan Manning. Insulin stimulates adipogenesis through the Akt-TSC2-mTORC1 pathway. 2009. PLOS One 4(7):e6189 Full Text Our Thoughts Details.

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