Our Research Interests

One of the major overlying research interests of the Zigman lab is to gain a better understanding of the controls of eating behavior, food intake and body weight.  To that end, we have developed several models to study the peptide hormone GHRELIN.  Ghrelin levels in the blood stream are influenced mainly by the release of ghrelin from specific endocrine cells (ghrelin cells) lining the stomach and intestine.  Ghrelin is of particular interest to both obesity and cachexia researchers because it stimulates food intake and its levels are raised in association with hunger, diet-induced weight loss, and certain forms of obesity in humans.  In addition, our group has shown that ghrelin levels rise in the setting of chronic stress, and that this mechanism may influence eating behaviors as well as alterations in mood associated with stress.  Our group has also shown that ghrelin motivates animals to work hard to obtain and eat fatty foods, and thus enhances the pleasurable aspects of fatty foods.  Ghrelin also has several other functions, including modulation of insulin release and roles in gastrointestinal motility, gastric acid secretion, and growth hormone release, among others.  The exact mechanisms by which ghrelin influences these behaviors, body weight, mood and pancreatic islet function or how ghrelin biosynthesis and release are controlled remain to be determined.

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, a study describing new antidepressant and anxiety-lowering roles for ghrelin – especially following chronic stress, and a study confirming a role for ghrelin in food reward behavior.  I have also worked on examining the role of the ventromedial hypothalamic nucleus (VMH) in body weight homeostasis, further characterization of ghrelin cells in the stomach and profiling of kisspeptin neurons (important in puberty and reproduction).    

My current research focuses on gaining a better understanding of ghrelin’s roles in the regulation of body weight, the regulation of hedonic/pleasurable aspects of eating (food 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 to/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 several novel transgenic mouse models, including one in which green fluorescent protein is expressed under the control of the ghrelin promoter.  

I am also interested in further elucidating the changes in various aspects of physiology induced by different types of bariatric (weight loss) surgery.  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.  We also are participating in a human trial.  The Zigman lab has many ongoing collaborations with both UTSW researchers and labs elsewhere in the US and abroad.  At UTSW, we work or have worked closely with Drs. Joel Elmquist and Carol Elias in the Division of Hypothalamic Research, Drs. Lutter,Tamminga and McClung in the Deparatment of Psychiatry, Dr. Clegg in the Touchstone Diabetes Center and Drs. Brown, Goldstein and Liang in the Department of Molecular Genetics.  The ultimate goal of our studies is to enable the design of therapeutics to treat and/or prevent obesity, cachexia, anorexia nervosa, depression, diabetes, substance abuse, and other conditions.