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Matthew J. Potthoff, PhD

Portrait
Associate Professor of Neuroscience and Pharmacology
Director of Molecular Medicine PhD Program

Contact Information

Primary Office
3322 Pappajohn Biomedical Discovery Building (PBDB)
Iowa City, IA 52242
319-384-4438

Lab
3310C Pappajohn Biomedical Discovery Building (PBDB)
Iowa City, IA 52242
319-335-7660

Education

BS, Suma Cum Laude, Biology / Zoology, University of Oklahoma
PhD, Genetics and Development, Department of Molecular Biology, UT Southwestern Medical Center
Postdoctoral Research Fellow, Endocrine Control of Metabolic Flux, Howard Hughes Medical Institute, Department of Pharmacology, UT Southwestern Medical Center

Education/Training Program Affiliations

Interdisciplinary Graduate Program in Genetics, Interdisciplinary Graduate Program in Molecular Medicine, Medical Scientist Training Program

Center, Program and Institute Affiliations

Fraternal Order of Eagles Diabetes Research Center, Iowa Neuroscience Institute, UI Obesity Research and Education Initiative

Research Summary

My research program is focused on two strategically developed areas of research. The first is exploring how energy and glucose homeostasis is regulated by novel endocrine pathways. More specifically, we examine how endocrine signals in the periphery communicate with the central nervous system. Second, my lab is exploring the role of epigenetics in regulating neuronal activity and its impacts on metabolism, neurodegeneration, and aging.

Endocrine Regulation of Metabolism
My lab is interested in known and novel hepatokines, or liver-derived factors, and how these endocrine pathways govern systemic energy balance. The purpose is two-fold: 1) secreted factors are a rich source of new therapeutics because they are designed to circulate and signal, and 2) nutrient signaling is dysregulated in several diseases including diabetes and cancer. My lab has been particularly interested in the hepatokine, fibroblast growth factor 21 (FGF21) which regulates energy homeostasis and macronutrient preference. Single-nucleotide polymorphisms (SNPs) in the human FGF21 gene have been associated with changes in macronutrient intake, namely increased carbohydrate intake. In addition, these SNPs associate with increased sugar sensitivity and an increase in hip to waist ratio. Consistent with the human studies, we found that FGF21 functions in a negative feedback loop to suppress carbohydrate intake, but not the intake of lipid or protein. Consumption of simple sugars induces hepatic and circulating FGF21 levels, and FGF21 then functions to reduce carbohydrate intake and meal size via direct actions in the central nervous system (CNS) to affect taste processing not taste sensing. In addition, pharmacological administration of FGF21 to obese animal models increases energy expenditure and causes weight loss, and extended administration of FGF21 analogs to obese humans reduces fasting glucose and insulin levels, and body weight. Recently, we and others found that FGF21 increases energy expenditure by signaling to the CNS. Our lab seeks to identify the central circuits responsible for these unique metabolic, and potentially therapeutically targetable, effects of FGF21.

Genetic Variation and Lifestyle-induced Epigenetic Changes that Regulate Metabolism, Neurodegeneration, and Aging

Obesity is a major health and economic burden with two in three adults being overweight and one in three adults being obese in the United States. Critically, obesity can account for 80-90% of the risk for type II diabetes. While there have been advances in weight loss treatments/approaches, “weight regain after weight loss remains the most substantial problem in obesity therapeutics” according to the NIH Working Group Report on Obesity. This largely occurs due to metabolic adaptations by the CNS to defend a new body weight through changes in metabolic rate. Numerous genome wide association studies (GWAS) over the last decade have identified single nucleotide polymorphisms (SNPs) in an intronic region of the Fto gene as a major contributor to childhood and adult obesity. However, the gene or genes affected by these SNPs and how they contribute to obesity remains an unanswered question. Thus, we developed novel mouse models allowing for specific genetic access to neural circuits the control systemic metabolism and body weight regulation. In addition, we are exploring how epigenetic changes in response to diet and environmental cues contribute to CNS-mediated control of body weight regain, obesity, and metabolic disease.


Publications

Nayak, M. K., Ghatge, M., Flora, G. D., Dhanesha, N., Jain, M., Markan, K. R., Potthoff, M. J., Lentz, S. R. & Chauhan, A. K. (2021). The metabolic enzyme pyruvate kinase M2 regulates platelet function and arterial thrombosis. Blood, 137(12), 1658-1668. PMID: 33027814.

Flippo, K. H., Potthoff, M. J. (2021). Metabolic Messengers: FGF21. Nature metabolism, 3(3), 309-317. PMID: 33758421.

Jensen-Cody, S. O., Potthoff, M. J. (2021). Hepatokines and metabolism: Deciphering communication from the liver. Molecular metabolism, 44, 101138. PMID: 33285302.

Flippo, K. H., Jensen-Cody, S. O., Claflin, K. E. & Potthoff, M. J. (2020). FGF21 signaling in glutamatergic neurons is required for weight loss associated with dietary protein dilution. Scientific reports, 10(1), 19521. PMID: 33177640.

Jensen-Cody, S. O., Flippo, K. H., Claflin, K. E., Yavuz, Y., Sapouckey, S. A., Walters, G. C., Usachev, Y. M., Atasoy, D., Gillum, M. P. & Potthoff, M. J. (2020). FGF21 Signals to Glutamatergic Neurons in the Ventromedial Hypothalamus to Suppress Carbohydrate Intake. Cell metabolism, 32(2), 273-286.e6. PMID: 32640184.

Markan, K. R., Boland, L. K., King-McAlpin, A. Q., Claflin, K. E., Leaman, M. P., Kemerling, M. K., Stonewall, M. M., Amendt, B. A., Ankrum, J. A. & Potthoff, M. J. (2020). Adipose TBX1 regulates ß-adrenergic sensitivity in subcutaneous adipose tissue and thermogenic capacity in vivo. Molecular metabolism, 36, 100965. PMID: 32240964.

Gansemer, E. R., McCommis, K. S., Martino, M., King-McAlpin, A. Q., Potthoff, M. J., Finck, B. N., Taylor, E. B. & Rutkowski, D. T. (2020). NADPH and Glutathione Redox Link TCA Cycle Activity to Endoplasmic Reticulum Homeostasis. iScience, 23(5), 101116. PMID: 32417402.

Sapouckey, S. A., Morselli, L. L., Deng, G., Patil, C. N., Balapattabi, K., Oliveira, V., Claflin, K. E., Gomez, J., Pearson, N. A., Potthoff, M. J., Gibson-Corley, K. N., Sigmund, C. D. & Grobe, J. L. (2020). Exploration of cardiometabolic and developmental significance of angiotensinogen expression by cells expressing the leptin receptor or agouti-related peptide. American journal of physiology. Regulatory, integrative and comparative physiology, 318(5), R855-R869. PMID: 32186897.

Flippo, K. H., Potthoff, M. J. (2019). Chronicles of an FGF chimera: The odyssey continues. (Vols. 49). pp. 15-16. EBioMedicine. PMID: 31672336.

Ameka, M., Markan, K. R., Morgan, D. A., BonDurant, L. D., Idiga, S. O., Naber, M. C., Zhu, Z., Zingman, L. V., Grobe, J. L., Rahmouni, K. & Potthoff, M. J. (2019). Liver Derived FGF21 Maintains Core Body Temperature During Acute Cold Exposure. Scientific reports, 9(1), 630. PMID: 30679672.

Sandgren, J. A., Deng, G., Linggonegoro, D. W., Scroggins, S. M., Perschbacher, K. J., Nair, A. R., Nishimura, T. E., Zhang, S. Y., Agbor, L. N., Wu, J., Keen, H. L., Naber, M. C., Pearson, N. A., Zimmerman, K. A., Weiss, R. M., Bowdler, N. C., Usachev, Y. M., Santillan, D. A., Potthoff, M. J., Pierce, G. L., Gibson-Corley, K. N., Sigmund, C. D., Santillan, M. K. & Grobe, J. L. (2018). Arginine vasopressin infusion is sufficient to model clinical features of preeclampsia in mice. JCI insight, 3(19). PMID: 30282823.

BonDurant, L. D., Potthoff, M. J. (2018). Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis. Annual review of nutrition, 38, 173-196. PMID: 29727594.

Zhang, P., Kuang, H., He, Y., Idiga, S. O., Li, S., Chen, Z., Yang, Z., Cai, X., Zhang, K., Potthoff, M. J., Xu, Y. & Lin, J. D. (2018). NRG1-Fc improves metabolic health via dual hepatic and central action. JCI insight, 3(5). PMID: 29515030.

Klingelhutz, A. J., Gourronc, F. A., Chaly, A., Wadkins, D. A., Burand, A. J., Markan, K. R., Idiga, S. O., Wu, M., Potthoff, M. J. & Ankrum, J. A. (2018). Scaffold-free generation of uniform adipose spheroids for metabolism research and drug discovery. Scientific reports, 8(1), 523. PMID: 29323267.

Cushing, E. M., Chi, X., Sylvers, K. L., Shetty, S. K., Potthoff, M. J. & Davies BSJ, (2017). Angiopoietin-like 4 directs uptake of dietary fat away from adipose during fasting. Molecular metabolism, 6(8), 809-818. PMID: 28752045.

Potthoff, M. J. (2017). FGF21 and metabolic disease in 2016: A new frontier in FGF21 biology. (Vols. 13). (2), pp. 74-76. Nat Rev Endocrinology. PMID: 27983736.

Pereira, R. O., Tadinada, S. M., Zasadny, F. M., Oliveira, K. J., Pires, K., Olvera, A., Jeffers, J., Souvenir, R., Mcglauflin, R., Seei, A., Funari, T., Sesaki, H., Potthoff, M. J., Adams, C. M., Anderson, E. J. & Abel, E. D. (2017). OPA1 deficiency promotes secretion of FGF21 from muscle that prevents obesity and insulin resistance. EMBO J, 36(14), 2126-2145. PMID: 28607005.

BonDurant, L. D., Ameka, M., Naber, M. C., Markan, K. R., Idiga, S. O., Acevedo, M. R., Walsh, S. A., orntiz, D. M. & Potthoff, M. J. (2017). FGF21 Regulates Metabolism Through Adipose-Dependent and -Independent Mechanisms. Cell Metab, 25(4), 935-944. PMID: 28380381.

Markan, K. R., Naber, M. C., Small, S. M., Peltekian, L., Kessler, R. L. & Potthoff, M. J. (2017). FGF21 resistance is not mediated by downregulation of beta-klotho expression in white adipose tissue. Mol Metab, 6(6), 602-610. PMID: 28580290.

Soberg, S., Sandholt, C. H., Jespersen, N. Z., Toft, U., Madsen, A. L., von Holstein-Rathlou, S., Grevengoed, T. J., Christensen, K. B., Bredie, W., Potthoff, M. J., Solomon, T., Scheele, C., Linneberg, A., Jorgensen, T., Pedersen, O., Hansen, T., Gillum, M. P. & Grarup, N. (2017). FGF21 Is a Sugar-Induced Hormone Associated with Sweet Intake and Preference in Humans. Cell Metab, 25(5), 1045-1053. PMID: 28467924.

von Holstein-Rathlou, S., BonDurant, L., Peltekian, L., Naber, M. C., Yin, T. C., Claflin, K. E., Ibarra Urizar, A., Madsen, A. N., Ratner, C., Holst, B., Karstoft, K., Vandenbeuch, A., Anderson, C. B., Cassell, M. D., Thompson, A. P., Solomon, T. P., Rahmouni, K., Kinnamon, S. C., Pieper, A. A., Gillum, M. P. & Potthoff, M. J. (2016). FGF21 Mediates Endocrine Control of Simple Sugar Intake and Sweet Taste Preference by the Liver. Cell Metabolism, 23(2), 335-43. PMID: 26724858.

Gillum, M. P., Potthoff, M. J. (2016). FAP finds FGF21 easy to digest. (Vols. 473). (9), pp. 1125-7. Biochem J. PMID: 27118870.

Littlejohn, N. K., keen, H. L., Weidemann, B. J., Claflin, K. E., Tobin, K. V., Markin, K. R., Park, S., Naber, M. C., Gourronc, F. A., Pearson, N. A., Liu, X., Morgan, D. A., Klingelhutz, A. J., Potthoff, M. J., Rahmouni, K., Sigmund, C. D. & Grobe, J. L. (2016). Suppression of Resting Metabolism by the Angiotensin AT2 Receptor. Cell Rep, 16(6), 1548-60. PMID: 27477281.

Kolb, R., Phan, L., Borcherding, N., Liu, Y., Yuan, F., Janowski, A. M., Xie, Q., Markan, K. R., Li, W., Potthoff, M. J., Fuentes-Mattei, E., Ellies, L. G., Knudson, C. M., Lee, M. H., Yeung, S. J., Cassel, S. L., Sutterwala, F. S. & Zhang, W. (2016). Obesity-associated NLRC4 inflammasome activation drives breast cancer progression. Nat Commun, 7, 13007. PMID: 27708283.

Markan, K. R., Potthoff, M. J. (2016). Metabolic fibroblast growth factors (FGFs): Mediators of energy homeostasis. Semin Cell Dev Biol, 53(85-93). PMID: 26428296.

McGlashon, J. M., Gorecki, M. C., Kozlowski, A. E., Thimbeck, C. K., Markan, K. R., Leslie, K. L., Kotas, M. E., Potthoff, M. J., Richerson, G. B. & Gillum, M. P. (2015). Central serotonergic neurons activate and recruit thermogenic brown and beige fat and regulate glucose and lipid homeostasis. Cell Metabolism, 21(5), 692-705. PMID: 25955206.

Gray, L. R., Sultana, M. R., Rauckhorst, A. J., Oonthonpan, L., Tompkins, S. C., Sharma, A., Fu, X., Miao, R., Pewa, A. D., Brown, K. S., Lane, E. E., Dohlman, A., Zepeda-Orozco, D., Xie, J., Rutter, J., Norris, A. W., Cox, J. E., Burgess, S. C., Potthoff, M. J. & Taylor, E. B. (2015). Hepatic Mitochondrial Pyruvate Carrier 1 is Required for Efficient Regulation of Gluconeogenesis and Whole-body Glucose Homeostasis. Cell Metabolism, 22(4), 669-81. PMID: 26344103.

Markan, K. R., Naber, M. c., Ameka, M. K., Anderegg, M. D., Mangelsdorf, D. J., Kliewer, S. A., Mohammadi, M. & Potthoff, M. J. (2014). Circulating FGF21 is Liver Derived and Enhances Glucose Uptake During Refeeding and Overfeeding. Diabetes, 63(12), 4057-4063. PMID: 25008183.

Potthoff, M. J., Kliewer, S. A. & Mangelsdorf, D. J. (2014). Endocrine fibroblast growth factors 15/19 and 21: From feast to famine. Genes Dev, 26(4), 312-324. PMID: 22302876.

Potthoff, M. J., Finck, B. N. (2014). Head Over Hepatocytes for FGF21. (Vols. 63). (12), pp. 4013. Diabetes. PMID: 25414019.

Potthoff, M. J., Potts, A., He, T., Duarte, J. A., Taussig, R., Mangelsdorf, D. J., Kliewer, S. A. & Burgess, S. C. (2013). Colesevelam Suppresses Hepatic Glycogenolysis by TGR5-mediated Induction of GLP-1 Action in DIO Mice. Am J Physiol: Gastrointestinal and Liver Physiol, 304(4), G371-G380. PMID: 23257920.

Zhang, Y., Xie, Y., Berglund, E. D., Coate, K. C., He, T. T., Katafuchi, T., Xiao, G., Potthoff, M. J., Wei, W., Wan, Y., Yu, R. T., Evans, R. M., Kliewer, S. A. & Mangelsdorf, D. J. (2012). The Starvation Hormone, Fibroblast Growth Factor-21, Extends Lifespan in Mice. elife, 1, e00065. DOI: 10.7554/3Life.00065.

Potthoff, M. J., Boney-Montoya, J., Choi, M., Satapati, S., He, T., Suino-Powell, K., Xu, H. E., Gerard, R. D., Finck, B. N., Burgess, S. C., Mangelsdorf, D. J. & Kliewer, S. A. (2011). FGF15/19 Regulates Hepatic Glucose Metabolism By Inhibiting the CREB-PGC-1a Pathway. Cell Metabolism, 13(6), 729-738.

Moresi, V., Williams, A. H., Meadows, E., Flynn, J. M., Potthoff, M. J., McAnally, J., Shelton, J. M., Backs, J., Klein, W. H., Richardson, J. A., Bassel-Duby, R. & Olson, E. N. (2010). Myogenin and Class II HDACs Control Neurogenic Muscle Atrophy by Inducing E3 Ubiquitin Ligases. Cell, 143(1), 35-45. PMID: 20887891.

Sunny, N. E., Satapati, S., Fu, X., He, T., Mehdibeigi, R., Spring-Robinson, C., Duarte, J., Potthoff, M. J., Browning, J. D. & Burgess, S. C. (2010). Progressive adaptation of hepatic ketogenesis in mice fed a high-fat diet. Am J Physiol Endocrinol Metab, 298(6), E1226-E1235. PMID: 20233938.

Potthoff, M. J., Inagaki, T., Satapati, S., Ding, X., He, T., Goetz, R., Mohammadi, M., Finck, B. N., Mangelsdorf, D. J., Kliewer, S. A. & Burgess, S. C. (2009). FGF21 Induces PGC-1alpha and Regulates Carbohydrate and Fatty Acid Metabolism During the Adaptive Starvation Response. Proc Natl Acad Sci U S A, 106(26), 10853-10858. PMID: 19541642.

Satapati, S., He, T., Inagaki, T., Potthoff, M. J., Merritt, M. E., Esser, V., Mangelsdorf, D. J., Kliewer, S. A., Browning, J. D. & Burgess, S. C. (2008). Partial resistance to peroxisome proliferator-activated receptor-alpha agonists in ZDF rats is associated with defective hepatic mitochondrial metabolism. Diabetes, 57(8), 2012-2021. PMID: 18469201.

Potthoff, M. J., Wu, H., Arnold, M. A., Shelton, J. M., Backs, J., McAnally, J., Richardson, J. A., Bassel-Duby, R. & Olson, E. N. (2007). Histone deacetylase degradation and MEF2 activation promote the formation of slow-twitch myofibers. J Clin Invest, 117(9), 2459-2467. PMID: 17786239.

Montgomery, R. L., Davis, C. A., Potthoff, M. J., Haberland, M., Fielitz, J., Qi, X., Hill, J. A., Richardson, J. A. & Olson, E. N. (2007). Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility. Genes Dev, 21(14), 1790-1802. PMID: 17639084.

Potthoff, M. J., Olson, E. N. & Bassel-Duby, R. (2007). Skeletal muscle remodeling. Curr Opin Rheumatol, 19(6), 542. PMID: 17917533.

Biography

My research program is focused on two strategically developed areas of research. The first is exploring how energy and glucose homeostasis is regulated by novel endocrine pathways. More specifically, we examine how endocrine signals in the periphery communicate with the central nervous system. Second, my lab is exploring the role of epigenetics in regulating neuronal activity and its impacts on metabolism, neurodegeneration, and aging.

Endocrine Regulation of Metabolism
My lab is interested in known and novel hepatokines, or liver-derived factors, and how these endocrine pathways govern systemic energy balance. The purpose is two-fold: 1) secreted factors are a rich source of new therapeutics because they are designed to circulate and signal, and 2) nutrient signaling is dysregulated in several diseases including diabetes and cancer. My lab has been particularly interested in the hepatokine, fibroblast growth factor 21 (FGF21) which regulates energy homeostasis and macronutrient preference. Single-nucleotide polymorphisms (SNPs) in the human FGF21 gene have been associated with changes in macronutrient intake, namely increased carbohydrate intake. In addition, these SNPs associate with increased sugar sensitivity and an increase in hip to waist ratio. Consistent with the human studies, we found that FGF21 functions in a negative feedback loop to suppress carbohydrate intake, but not the intake of lipid or protein. Consumption of simple sugars induces hepatic and circulating FGF21 levels, and FGF21 then functions to reduce carbohydrate intake and meal size via direct actions in the central nervous system (CNS) to affect taste processing not taste sensing. In addition, pharmacological administration of FGF21 to obese animal models increases energy expenditure and causes weight loss, and extended administration of FGF21 analogs to obese humans reduces fasting glucose and insulin levels, and body weight. Recently, we and others found that FGF21 increases energy expenditure by signaling to the CNS. Our lab seeks to identify the central circuits responsible for these unique metabolic, and potentially therapeutically targetable, effects of FGF21.

Genetic Variation and Lifestyle-induced Epigenetic Changes that Regulate Metabolism, Neurodegeneration, and Aging

Obesity is a major health and economic burden with two in three adults being overweight and one in three adults being obese in the United States. Critically, obesity can account for 80-90% of the risk for type II diabetes. While there have been advances in weight loss treatments/approaches, "weight regain after weight loss remains the most substantial problem in obesity therapeutics" according to the NIH Working Group Report on Obesity. This largely occurs due to metabolic adaptations by the CNS to defend a new body weight through changes in metabolic rate. Numerous genome wide association studies (GWAS) over the last decade have identified single nucleotide polymorphisms (SNPs) in an intronic region of the Fto gene as a major contributor to childhood and adult obesity. However, the gene or genes affected by these SNPs and how they contribute to obesity remains an unanswered question. Thus, we developed novel mouse models allowing for specific genetic access to neural circuits the control systemic metabolism and body weight regulation. In addition, we are exploring how epigenetic changes in response to diet and environmental cues contribute to CNS-mediated control of body weight regain, obesity, and metabolic disease.