Eleftheria Maratos-Flier, M.D.

Central and Peripheral Factors   Regulating Energy Balance

Over the past two decades there has been a worldwide increase in the prevalence of obesity. In the United States, 60% of the population is either overweight or obese. As a result, rates of obesity-related co-morbities, particularly type II diabetes, are increasing even in adolescent populations. This has created a demand for therapeutic agents, potentially focused on novel pathways. Recently, FGF21 has emerged as a hepatic regulatory factor that acts on remote targets such as white adipose tissue but importantly also mediates effects on the liver itself in an autocrine fashion. We have found that FGF21 is an essential mediator of hepatic fatty acid oxidation during ketosis, both in animals consuming a ketogenic diet and during fasting; others have reported improved glucose homeostasis in obese animals treated with FGF21. However, much remains to be elucidated regarding the biology of FGF21.

The aims of this grant are to investigate the physiology and action of FGF21 to both improve our understanding of this hormone and to better assess the therapeutic potential of FGF21 as a potential future treatment of obesity and diabetes. To achieve this goal, we propose several lines of experimentation. In specific aim 1 we will evaluate the effects of FGF21 on the liver, on both signaling pathways and on gene expression. We will examine the role of PGC1α and PPARα in mediating FGF21 action. We will also examine the role of FGF21 in regulating glucose homeostasis in the liver. In the second aim we will pursue the hypothesis that obesity is an FGF21 resistant state and that the exogenous administration leads to improvements in the metabolic profile of obese mice and also leads to resolution of the hepatic lipid accumulation. In this aim we will also evaluate the role of two dual specificity phosphotases (DUSPs) in modulating FGF21 action. In the third specific aim we will evaluate the phenotype of mice lacking the gene for FGF21; we hypothesize that these mice will have increased sensitivity to diet induced obesity and an abnormal response to consumption of a ketogenic diet. We will also utilize mice lacking FGF21 in order to examine the role of FGF21 in mediating actions of other metabolic factors. Finally, in order to understand the relative contributions of FGF21 from liver and white adipose tissue, we propose to generate a mouse in which the FGF21 gene can be deleted in a tissue specific fashion.

References:

  1. Qu D, Ludwig DS, Gammeltoft S, Piper M, Pelleymounter MA, Cullen MJ, Foulds-Mathes W, Przypek J, Kanarek R and Maratos-Flier E.  A role for melanin concentrating hormone in the central regulation of feeding behavior.  Nature 1996; 380:243-247. PMID: 8637571

  2. Ludwig DS, Mountjoy KG, Tatro JB, Gillette JA, Frederich RC, Flier JS, Maratos-Flier E.  Melanin concentrating hormone: A functional melanocrotin antagonist in the hypothalamus of the rat. 74E:627-633. PMID: 9575823

  3. Shimada M, Tritos N, Lowell BB, Flier JS, Maratos-Flier E. Absence of melanin concentrating hormone produces hypophagia and a lean phenotype.  Nature 396:670-674. PMID: 9872314

  4. Kokkotou EG, Tritos NA, Mastaitis JW, Slieker L, Maratos-Flier E. Melanin Concentrating Hormone receptor is a target of leptin action in the mouse brain. Endocrinology 2001 142:680-686. PMID: 11159839

  5. Ludwig DS, Tritos NA, Mastaitis JW, Kulkarni R, Kokkotou E, Lowell B, Flier JS, Maratos-Flier E. Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance. J. Clin. Invest. 2001 107:379-386. PMCID: PMC199192

  6. Segal-Lieberman G, Trombly DJ, Juthani V, Wang X, Maratos-Flier E. NPY ablation in C57BL/6 mice leads to mild obesity and to an impaired refeeding response to fasting, e-published ahead of print, Am J Physiol Endocrinol Metab. 2003; 284(6):E1131-9. PMID: 12582011

  7. Pissios P, Trombly DJ, Tzameli I, Maratos-Flier E. Melanin-concentrating hormone receptor 1 activate ERK and synergizes with Gs coupled pathways. Endocrinology. 2003; 144(8):3514-23. PMID: 12865333

  8. Segal-Lieberman G, Bradley RL, Kokkotou E, Carlson M, Trobmly DJ, Wang X, Bates S, Myers MG Jr., Flier JS, Maratos-Flier E. Melanin-concentrating hormone is a critical mediator of the leptin deficient phenotype. Proc Natl Acad Sci U S A. 2003;100(17):10085-90. PMCID: PMC187774

  9. Kokkotou E, Jeon JY, Wang X, Marino FE, Carlson M, Trombly DJ, Maratos-Flier E. Mice with MCH ablation resist diet induced obesity through strain specific mechanisms. AJP Regulatory, Integrative and Comparative Physiology. 2005 289:R117-124. PMID: 15731402

  10. Jeon J, Bradley RL, Kokkotou E, Marino FE, Wang X, Pissios P, Maratos-Flier E. MCH-/- Mice are Resistant to Aging Associated Increases in Body Weight and Insulin Diabetes. 2006. 55:428-34. PMID: 16443777

  11. Kennedy AR, Pissios P, Out H, Xue B, Asakura K, Furukawa N, Marino FE, Liu FF, Kahn BB, Liberman TA, Maratos-Flier E. A high-fat, ketogenic diet induces a unique metabolic state in mice. Am J Physiol Endocrinol Metab 2007. 292:E1724-39. PMID: 17299079

  12. Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARa and is a  mediator of hepatic lipid metabolism in ketotic states. Cell Metab 2007 6:426-437. PMID: 17550778

  13. Pissios P, Frank L, Kennedy AR, Porter DR, Marino FE, Pothos EN, Maratos-Flier. Regulation of Mesolimbic Dopamine by Melanin Concentrating Hormone. Biol. Psych. 2008 64:184-91. PMID: 18281019

  14. Bradley RL and Maratos-Flier E. Dietary Fatty Acids Differentially Regulate Production of TNF-a and IL-10 by 3T3-L1  Adipocytes. Obesity. 2008 16:938-44. PMID: 18356844

 
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