Scripps Research Joint Appointments

Faculty, Kellogg School of Science and Technology

Research Focus

The United States is experiencing an epidemic of metabolic diseases that have obesity and/or insulin resistance as defining features. Abundant calorie-rich foods and reduced physical activity leads to weight gain and increased risk of developing insulin resistance and diseases of the metabolic syndrome. Determining the mechanisms involved in the homeostatic regulation of appetite and expenditure of energy is an important step in the development of new therapies against obesity and diabetes.

The Butler lab currently has two areas of interest. We have identified a novel peptide hormone which we have called adropin. Adropin is a peptide hormone released by the liver in response to signals of metabolic state. Studies in the laboratory suggest that obesity is a state of adropin deficiency. Deletion of the gene encoding adropin results in a "pre-diabetic" condition: insulin resistance and impaired glucose tolerance. Moreover, adropin therapy has shown promise in preclinical studies with improvements in the metabolic conditions associated with obesity. We recently reported that it is possible to measure adropin in humans. In humans, obesity is associated with low levels of this hormone in the circulation, and low levels correlate with risk factors for metabolic disease. With support from Novo Nordisk's Diabetes Innovation Award Research Program, we are now examining the mechanisms involved in the regulation of metabolic homeostasis by this novel hormone.

We are also investigating how the 24 rhythms of wakefulness and metabolism are regulated by nutrients. Specifically, during periods of nutrient scarcity organisms rapidly synchronize their circadian rhythm with nutrient intake. Our data suggests that the melanocortin-3 receptor (MC3R), a g-protein-coupled receptor, is involved in this process. MC3R are regulated by neuropeptides released from neurons which respond to local and systemic signals of metabolic state and nutrient intake. Loss of MC3R function results in an impaired ability to anticipate nutrient intake and the development of a metabolic condition similar to diabetes. Supported by the National Institute of Diabetes, Digestive and Kidney Disease, we are currently investigating which MC3R-expressing neurons in the central nervous system have a critical role in synchronizing rhythms with food intake.

Education

B.Sc., (Zoology), University of Canterbury, Christchurch, New Zealand, 1990
Ph.D., University of Auckland, Auckland, New Zealand, 1995

Professional Experience

Postdoctoral training:
Fogarty International Fellow at the National Institute of Diabetes, Digestive and Kidney Diseases, NIH (1996-1997)
The Vollum Institute, Oregon Health & Science University (1998-2001).

Previous Faculty Appointments:
Assistant Professor (2001-2005); Associate Professor (2005-2009), The Pennington Biomedical Research Center, Louisiana State University System.

Awards & Professional Activities

Editorial boards
Endocrinology
Journal of Clinical Investigation (Consulting Editor)
Scientific Reports

Awards
Lilly Scientific Achievement Award from The Obesity Society (2008)
Junior Faculty Award from the American Diabetes Association (2004-2007)

Selected References

Adropin:

Kumar KG, Trevaskis JL, Lam DD, Sutton GM, Koza RA, Chouljenko VN, Kousoulas KG, Rogers PM, Kesterson RA, Thearle M, Ferrante AW Jr, Mynatt RL, Burris TP, Dong JZ, Halem HA, Culler MD, Heisler LK, Stephens JM and Butler AA. Identification of adropin as a secreted factor linking dietary macronutrient intake with energy homeostasis and lipid metabolism. Cell Metab. 2008 Dec;8(6):468-81.

Faculty of 1000 selection - recommended.

Kumar KG, Zhang J, Gao S, Rossi J, McGuinness OP, Halem HH, Culler MD, Mynatt RL and Butler AA. Adropin deficiency is associated with increased adiposity and insulin resistance. Obesity 2012 Jul;20(7):1394-402.

Butler AA, Tam CS, Stanhope KL, Wolfe BM, Ali MR, O'Keeffe M, St-Onge MP, Ravussin E and Havel PJ. Low circulating adropin concentrations with obesity and aging correlate with risk factors for metabolic disease and increase after gastric bypass surgery in humans. J Clin Endocrinol Metab. 2012 Oct; 97(10):3783-3791.

Melanocortins:

Begriche K, Lavasseur PR, Zhang J, Rossi J, Solt LA, Marks DL, Young B, Burris TP, Mynatt RL and Butler AA. Genetic dissection of the functions of the melanocortin-3 receptor, a seven-transmembrane G-protein coupled receptor, indicates roles for central and peripheral receptors in energy homeostasis. Journal of Biological Chemistry 2011 Nov 25, 286(47):40771-40781.

Sutton GM, Begriche K, Kumar KG, Gimble JM, Perez-Tilve D, Nogueiras R, McMillan RP, Hulver MW, Tschöp MH and Butler AA. Central nervous system melanocortin-3 receptors are required for synchronizing metabolism during entrainment to restricted feeding during the light cycle. FASEB J. 2010 Mar;24(3):862-72.

Sutton GM, Perez-Tilve D, Nogueiras R, Fang J, Kim JK, Cone RD, Gimble JM, Tschöp MH, Butler AA. The melanocortin-3 receptor is required for entrainment to meal intake.  J Neurosci. 2008 Nov 26;28(48):12946-55

Zhou L, Sutton GM, Rochford JJ, Semple RK, Lam DD, Oksanen LJ, Thornton-Jones ZD, Clifton PG, Yueh CY, Evans ML, McCrimmon RJ, Elmquist JK*, Butler AA* and Heisler LK*. Serotonin 2C receptor agonists improve type 2 diabetes via melanocortin-4 receptor signaling pathways. Cell Metab. 2007 Nov;6(5):398-405. * corresponding authors.

Discussed by Pissios P and Maratos-Flier E - More Then Satiety: Central Serotonin Signaling And Glucose Homeostasis (News and Views). Cell Metabolism 2007 Nov; 6(5):345-347, and in Miller KJ and Azzara AV - An Old Dog Leans A New Trick: Regulation Of Peripheral Glucose Homeostasis By The Serotonin (5-HT)2C receptor. Molecular Interventions 2008 8:73-77, and in Crunkhorn S - Metabolic Disease: New Opportunity for Serotonin Receptor Agonists. Nature Reviews Drug Discovery
Faculty of 1000 - must read.

Invited commentaries:

Butler AA. More news about NUCB2/Nesfatin-1: a new factor in the hypothalamic control of glucose homeostasis? Diabetes 2012 Aug; 61(8):1920-22

Butler AA and Kozak LP. A recurring problem with the analysis of energy expenditure in genetic models expressing lean and obese phenotypes. Diabetes 2010 Feb;59(2):323-9.

Butler AA and O'Rourke RW. Bariatric surgery in the era of personalized medicine. Gastroenterology 2013 Mar; 144(3):497-500

Links

Scripps Research Appoints Two New Faculty Members to the Department of Metabolism and Aging in Florida

Scripps researcher gets $1M from Novo Nordisk

Scripps Florida Scientist Awarded $1.9 Million to Study Food Intake and Metabolism

Team Uncovers Link Between Hormone Levels and Risk for Metabolic Disease