Education:
1998-2003 Summa Cum Laude, B.S. in Zoology/Biology, University of Oklahoma
2003-2007 Ph.D. in Genetics and Development, Department of Molecular Biology, UT Southwestern Medical Center, Dissertation: MEF2 and HDAC Proteins Regulate Striated Muscle Development and Remodeling, Mentor: Dr. Eric Olson
2007-2012 Post-Doctoral Research Fellow, Howard Hughes Medical Institute, Department of Pharmacology, UT Southwestern Medical Center, Research focus: Endocrine Control of Metabolic Flux, Mentors: Drs. David Mangesldorf, Steven Kliewer, and Shawn Burgess
Clinical/Research Interests:
The Potthoff lab 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
The regulation of metabolic homeostasis is a complex process coordinated by numerous growth factors and hormones signaling the availability of energy and nutrients. While it is well known that the liver functions to maintain energy homeostasis by producing energy sources for other cells during nutrient deprivation, the liver is also becoming recognized as a major regulator of systemic energy metabolism through production of hepatokines. These liver derived hormones signal nutrient availability to other tissues and control substrate utilization to maintain energy balance. My lab is interested in unraveling these hepatic pathways that govern systemic energy balance by focusing on known and novel hepatokines. 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. To identify and examine hepatokine function, my lab integrates biochemistry, proteomics, cell biology, metabolomics, and mouse genetics. By unraveling these liver-derived networks, we hope to identify a new therapeutic to treat obesity and metabolic disease.
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 [1, 2]. In addition, these SNPs associate with increased sugar sensitivity and an increase in hip to waist ratio [3]. 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 [4]. 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 [4]. 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 (reviewed in [5]). Recently, we and others found that FGF21 increases energy expenditure by signaling to the CNS [6-8]. Our lab seeks to identify the central circuit 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 [9]. This largely occurs due to metabolic adaptations by the CNS to defend a new body weight through changes in metabolic rate [9-11]. 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 [12, 13]. 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.
References
1. Tanaka, T., et al., Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake. Am J Clin Nutr, 2013. 97(6): p. 1395-402.
2. Chu, A.Y., et al., Novel locus including FGF21 is associated with dietary macronutrient intake. Hum Mol Genet, 2013. 22(9): p. 1895-902.
3. Frayling, T.M., et al., A Common Allele in FGF21 Associated with Sugar Intake Is Associated with Body Shape, Lower Total Body-Fat Percentage, and Higher Blood Pressure. Cell Rep, 2018. 23(2): p. 327-336.
4. von Holstein-Rathlou, S., et al., FGF21 Mediates Endocrine Control of Simple Sugar Intake and Sweet Taste Preference by the Liver. Cell Metab, 2016. 23(2): p. 335-43.
5. BonDurant, L.D. and M.J. Potthoff, Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis. Annu Rev Nutr, 2018. 38: p. 173-196.
6. BonDurant, L.D., et al., FGF21 Regulates Metabolism Through Adipose-Dependent and -Independent Mechanisms. Cell Metab, 2017. 25(4): p. 935-944 e4.
7. Ameka, M., et al., Liver Derived FGF21 Maintains Core Body Temperature During Acute Cold Exposure. Sci Rep, 2019. 9(1): p. 630.
8. Lan, T., et al., FGF19, FGF21, and an FGFR1/beta-Klotho-Activating Antibody Act on the Nervous System to Regulate Body Weight and Glycemia. Cell Metab, 2017. 26(5): p. 709-718 e3.
9. MacLean, P.S., et al., NIH working group report: Innovative research to improve maintenance of weight loss. Obesity (Silver Spring), 2015. 23(1): p. 7-15.
10. Fothergill, E., et al., Persistent metabolic adaptation 6 years after "The Biggest Loser" competition. Obesity (Silver Spring), 2016. 24(8): p. 1612-9.
11. MacLean, P.S., et al., The Accumulating Data to Optimally Predict Obesity Treatment (ADOPT) Core Measures Project: Rationale and Approach. Obesity (Silver Spring), 2018. 26 Suppl 2: p. S6-S15.
12. Frayling, T.M., et al., A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science, 2007. 316(5826): p. 889-94.
13. Dina, C., et al., Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet, 2007. 39(6): p. 724-6.
Funding:
9/01/19 - 4/1/29, VA Merit I01BX004634, “Central Mechanisms Regulating Macronutrient Intake”, Role: PI (Potthoff)
7/15/2023 – 8/1/2028, NIH/NIA R01 AG083950, “Therapeutic Potential of FGF21 for Alzheimer’s Disease”, Role: PI (Potthoff)
Select Honors and Accomplishments:
2025 Harold Hamm Endowed Chair in Clinical Diabetes Research
2020 Roy J. Carver Professorship in Neuroscience and Pharmacology
2020 University of Iowa Distinguished Scholar Award
2016 University of Iowa Early Career Scholar Award
2013 American Diabetes Association (ADA) Junior Faculty Award
2011 University of Texas Southwestern Medical Center Travel Award
2007-2012 Howard Hughes Medical Institute Research Fellowship
2004-2007 National Institute of Health (NIH) Cardiology Training Grant
2003 University of Texas Southwestern Academic Scholarship
2003 Honors College Phi Beta Kappa Distinguished Undergraduate Research Award
2000-01; 03 Corrine Price Scholarship
2000-2002 Jon Winthrop Scholarship
2000 Adams Summer Research Grant
2000-2003 Blanche Adams Scholarship
1999-2003 University of Oklahoma Alumni Scholar
Select Publications:
- Sullivan AI, Flippo KH, Aklan I, Claflin KE, Morgan DA, Naber MC, Rahmouni K, Potthoff MJ. Mice harboring the obesity-associated SNP rs1421085 exhibit increased body weight and reveal an IRX3 neuronal circuit regulating body weight. Molecular Metabolism. 2025 Aug 18:100:102234. Link
- Rose JP, Morgan DA, Sullivan AI, Fu X, Inigo-Vollmer M, Burgess SC, Meyerholz DK, Rahmouni K, Potthoff MJ. FGF21 reverses MASH through coordinated actions on the CNS and liver. Cell Metabolism. 2025 Jul 1;37(7):1515-1529.e6. Link
- Flippo KH, Trammell S.A.J., Gillum MP, Aklam I, Perez MB, Yavuz Y, Smith NK, Jensen-Cody SO, Zhou B, Claflin KE, Beierschmitt A, Fink-Jensen A, Knop FK, Palmour RM, Grueter BA, Atasoy D, and Potthoff MJ. FGF21 Suppresses Alcohol Consumption Through an Amygdalo-striatal Circuit. Cell Metabolism. 2022 Feb 1;34(2):317-328.e6. doi: 10.1016/j.cmet.2021.12.024. Link
- Jensen-Cody, SO, Flippo, KH, Claflin, KE, Yavuz, Y Walters, GC, Usachev, YM, Atasoy, D, Gillum, MP, Potthoff, MJ: FGF21 Signals to Glutamatergic Neurons in the Ventromedial Hypothalamus to Suppress Carbohydrate Intake. Cell Metabolism. 2020 Aug. 4; 32:1-14. Link
- BonDurant LD, Ameka M, Naber MC, Markan KR, Idiga S, Ornitz DM, Potthoff MJ. FGF21 Regulates Metabolism through Adipose-Dependent and -Independent Mechanisms. Cell Metabolism. Apr 4;25(4):935-944.e4, 2017. Link
Link to full publication list