My main research interests revolve around the peptide hormone ghrelin. Ghrelin is produced primarily by endocrine cells lining the stomach and intestine. Since its initial discovery as the endogenous ligand for the growth hormone secretagogue receptor (ghrelin receptor), ghrelin has been shown to play important roles in body weight homeostasis and blood glucose homeostasis. My major contributions to the ghrelin literature have included a detailed study of the distribution of ghrelin receptors throughout the rat and mouse brains, a study with a novel ghrelin receptor-null mouse line in which we demonstrated the requirement of intact ghrelin signaling pathways for the development of diet-induced obesity, and a study describing new antidepressant and anxiety-lowering roles for ghrelin, especially following chronic stress. My current research focuses on gaining a better understanding of ghrelin’s roles in the regulation of body weight, the regulation of motivated behaviors aimed at obtaining food and drugs of abuse (food reward and drug reward), the regulation of mood and anxiety, and the maintenance of glucose homeostasis. These studies involve the use of various neuroanatomical approaches as well as unique transgenic mouse models in which we can selectively restrict or selectively disable ghrelin receptor expression from specific brain sites, specific neuronal subtypes or specific peripheral cell types. Sites of interest include various hypothalamic nuclei, midbrain dopaminergic reward circuits, the caudal brainstem and the pancreatic islets of Langerhans. Another main interest of my lab involves investigations of ghrelin cell physiology. In particular, I am interested in learning the molecular basis for ghrelin biosynthesis and ghrelin release. These studies largely make use of a novel transgenic mouse model in which green fluorescent protein is expressed under the control of the ghrelin promoter. A third major interest involves further elucidation of the longitudinal changes in various aspects of physiology induced by different types of bariatric (weight loss) surgery. This latter interest is developing into a human trial in which my collaborators and I aim to link surgery-induced changes in hedonic aspects of eating, mood, cognitive function, and body composition to alterations in brain activity and hormonal profiles. As mentioned, many of my team’s studies rely on novel, genetically-engineered mouse models, and I currently have several others under development to further explore the lab’s interests. The ultimate goal of these studies is to enable the design of therapeutics to treat and/or prevent obesity, cachexia, anorexia nervosa, depression, diabetes, and substance abuse.
RESEARCH INTERESTS
Investigation of the ghrelin-responsive neurons required for the development of diet-induced obesity
The role of ghrelin in reward seeking behaviors, such as those responsible for food intake, and in other hedonic (pleasurable) properties of eating
Ghrelin biosynthesis and ghrelin cell physiology
Gastric bypass-associated changes in CNS physiology
Ghrelin's role in mood/depression/anxiety/stress
RECENT PUBLICATIONS
M. Lutter, I. Sakata, S. Osborne-Lawrence, S.A. Rovinsky, J.G. Anderson, S. Jung, S. Birnbaum, M. Yanagisawa, J.K. Elmquist, E.J. Nestler, J.M. Zigman, "The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress" Nature Neuroscience, 11:752-753, June 2008
Dhillon H, Zigman JM, Ye C, Lee CE, McGovern RA, Tang V, Kenny CD, Christiansen LM, White RD, Edelstein EA, Coppari R, Balthasar N, Cowley MA, Chua Jr. S, Elmquist JK, Lowell BB, "Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis" Neuron, 49:191-203, 2006
Zigman JM, Jones JE, Lee CE, Saper CB, Elmquist JK, "Expression of Ghrelin Receptor mRNA in the Rat and the Mouse Brain" J Comp Neurol, 494:528-548, 2006
Zigman JM, Nakano Y, Coppari R, Balthasar N, Marcus JN, Lee CE, Jones JE, Deysher AE, Waxman AR, White RD, Williams TD, Lachey JL, Seeley RJ, Lowell BB, Elmquist JK, "Mice lacking ghrelin receptors resist the development of diet-induced obesity" J Clin Invest, 115:3564-3572, 2005
Zigman JM, Elmquist JK, "Minireview: From anorexia to obesity -- the yin and yang of body weight control" Endocrinology, 144:3749-3756, 2003
SIGNIFICANT PUBLICATIONS
R. Nogueiras, M.H. Tschoep, J.M. Zigman, "Central nervous system regulation of energy metabolism: ghrelin versus leptin" Ann NY Acad Sci, 1126:14-19, 2008
Clegg DJ, Brown LM, Zigman JM, Kemp CJ, Strader AD, Benoit SC, Woods SC, Mangiaracina M, Geary N, "Estradiol-dependent decrease in the orexigenic potency of ghrelin in food intake" Diabetes, 56:1051-1058, 2007
Zigman JM, Elmquist JK, "In search of an effective obesity treatment: A shot in the dark or a shot in the arm?" PNAS, 103:12961-12962, August 2006
Zigman JM, Cohen SE, Garber JR, "Impact of Thyroxine Binding Globulin on Thyroid Hormone Economy During Pregnancy" Thyroid, 13:1169-1175, 2003
Zigman JM, Westermark GT, LaMendola J, Steiner DF, "Expression of cone transducin, Gz-alpha and other G-protein alpha-subunit messenger ribonucleic acids in pancreatic islets" Endocrinology, 135:31-37, 1994
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