Research

Research

The Zigman Lab is composed of Dr. Zigman, our lab manager and senior research scientist, Sherri Osborne-Lawrence, and a core group of talented postdoctoral fellows/students/research associates/technicians. Our work spans the fields of molecular endocrinology, behavioral neuroscience, and neuroanatomy and includes mouse, human, and cell culture experiments.

Our tools include a one-of-a-kind collection of Zigman Lab-generated novel mouse models, novel mouse behavioral models, and novel cell culture models with which to probe ghrelin action, ghrelin secretion, and a coordinated gastric enteroendocrine cellular response to conditions relevant to perturbed metabolic states, stress, and depression.

JCI July 2011 cover
Cover of the July 2011 issue of Journal of Clinical Investigation related to our manuscript, "Ghrelin mediates stress-induced food-reward behavior in mice."

The Zigman Lab investigates the biological basis for complex eating and the neuro-hormonal framework linking eating behavior to affect, with the ultimate goal of designing new methods to prevent and treat extremes of body weight and associated disorders of affect and metabolism.  We mainly have used the ghrelin system as a muse, investigating how this peptide hormone and its receptor influence various eating behaviors (eating when hungry, eating for pleasure, and stress-induced eating), body weight, the body’s responses to gastric bypass surgery and stress, blood glucose, reward behaviors, and mood. We also investigate ghrelin secretion and the relationship of ghrelin cells to other endocrine cells in the gastrointestinal tract.

Ghrelin is secreted primarily by distinct ghrelin cells located in the lining of the stomach and intestine. Its levels rise before set meals, in response to caloric restriction, upon exposure to psychosocial stress, in individuals with certain genetic disorders such as Prader Willi Syndrome, and in the setting of poor sleep. The molecular mechanisms responsible for ghrelin biosynthesis and secretion in those conditions are an active area of investigation in the lab.

Molecular Endocrinology Sept 2011 Cover
Cover of the Sept 2011 issue of Molecular Endocrinology cover art related to our manuscript, "Ghrelin directly stimulates glucagon secretion from pancreatic alpha-cells.”

Ghrelin acts by binding to the growth hormone secretagogue receptor (GHSR; ghrelin receptor), which is a G-protein coupled receptor located in numerous brain sites and peripheral organs. Upon binding to its receptor, ghrelin engages several different physiological processes and behaviors.

Indeed, among ghrelin’s most studied and likely most significant actions are as an orexigenic, glucoregulatory and antidepressant peptide hormone. Its plasma levels rise upon mild caloric restriction to stimulate food intake and fat storage and upon severe caloric restriction to prevent life-threatening falls in blood glucose. Ghrelin levels also rise following psychosocial stress, minimizing stress-induced depression. These key physiologic and behavioral effects of ghrelin action are emphasized by the hypoglycemic and depression phenotypes observed in mouse models of ghrelin, ghrelin receptor, and/or ghrelin O-acyltransferase (GOAT) deficiency upon exposure to prolonged caloric restriction or chronic psychosocial stress.

Milestones

  • Consistent with our mission to understand the biological basis for the strong link between eating behavior and affect, our group was the first to demonstrate a role for the orexigenic hormone ghrelin as a natural antidepressant, preventing exaggerated depressive-like behaviors following chronic stress and inducing an antidepressant-like behavioral response upon caloric restriction. We showed that ghrelin’s antidepressant actions rely on protection of adult hippocampal neurogenesis, leading us in collaborative work with Andrew Pieper to identify antidepressant-like efficacy for the recently-reported P7C3 class of strong, rapid-acting neuroprotective compounds, and paving the way for the development of a potentially superior class of antidepressants.
  • We were first to define essential roles for ghrelin in mediating stress-induced comfort food eating and other complex eating behaviors, including operant responding and conditioned place preference for high fat diet, also confirming a role for the ghrelin system in cue-potentiated feeding.
  • We have identified key central and peripheral sites of ghrelin’s orexigenic, glucoregulatory, and antidepressant actions by comprehensively determining the pattern of ghrelin receptor mRNA expression in the rat and mouse brain and by using cutting-edge mouse genetics to target ghrelin receptor expression to selective cell-types.
  • Using a vast collection of novel models to directly study isolated populations of ghrelin cells and to modify ghrelin cell gene expression, we have led the way in identifying direct modulators of ghrelin release and key elements of the ghrelin cell molecular machinery mediating ghrelin secretion.
  • We have also worked to generate transgenic mouse lines to investigate other gastric endocrine cell types. These findings have immediate relevance to disorders of body weight, which at both ends of the spectrum are frequently accompanied by disorders of affect.

Our studies employ several novel, genetically-engineered mouse models, animal behavioral models, and ghrelin cell line models. In addition, we use several neuroanatomical, surgical, molecular biology and physiological techniques.

Collaborations

 

The Zigman lab has many ongoing collaborations with UTSW researchers and with labs elsewhere in the U.S. and abroad. At UTSW, our collaborations have included those with Drs. Mike Brown and Joe Goldstein in the Department of Molecular Genetics, Drs. Joel Elmquist and Laurent Gautron in Hypothalamic Research, and Drs. Amelia Eisch and Carol Tamminga in the Department of Psychiatry.

We also have ongoing collaborations with Dr. Andrew Pieper at the University of Iowa Carver College of Medicine, Dr. Thue Schwartz at the University of Copenhagen, and Dr. Zane Andrews at Monash University in Melbourne, AU.  The ultimate goal of our studies is to enable the design of therapeutics to treat and/or prevent obesity, depression, diabetes, Prader-Willi Syndrome, cachexia, anorexia nervosa, substance abuse, and other conditions.