Our major contributions to the 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 anti-depressant and anxiety-lowering roles for ghrelin – especially following chronic stress, studies confirming roles for ghrelin in food reward behavior and glucagon secretion and studies investigating the molecular mechanisms responsible for ghrelin secretion. We have also worked on examining the role of the ventromedial hypothalamic nucleus (VMH) in body weight homeostasis, profiling of kisspeptin neurons (important in puberty and reproduction), and generating reporter mice with which to study histaminergic neurons, enterochromaffin-like cells and other histamine-containing cells.
Our studies employ several novel, genetically-engineered mouse models, animal behavioral models, and ghrelin cell line models. In addition, we use several state of the art neuroanatomical, surgical, molecular biology and physiological techniques. The Zigman lab has many ongoing collaborations with UTSW researchers and with labs elsewhere in the US and abroad. At UTSW, our collaborations have included those with Drs. Mike Brown and Joe Goldstein in the Department of Molecular Genetics, Dr. Joel Elmquist in the Division of 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, cachexia, anorexia nervosa, depression, diabetes, substance abuse, and other conditions.
Our major research topics include:
Ghrelin's role in food reward
We are interested in further studying behaviors associated with eating for pleasure (why do we choose to eat dessert even after we’re full? Why do we eat “comfort foods” in times of stress?)
For instance, our group and other groups have demonstrated that ghrelin regulates various hedonic aspects of eating behavior, and in particular increases the rewarding value of high-fat diet. Other groups have demonstrated that ghrelin itself has inherent rewarding properties.
We design and use several animal behavioral models (including conditioned place preference, operant conditioning, cue-potentiated feeding and food choice tests) and genetically-engineered mouse models to study food reward. Our current studies are focused on the sites where ghrelin is acting to have its effects on food reward and the downstream pathways and processes that enable this action of ghrelin.
Ghrelin's roles in mood and chronic stress
Ghrelin decreases depression- and anxiety-like behaviors in mice. Its levels rise upon chronic stress and this likely helps minimize stress-induced depression.
However, the chronic stress-induced elevations in ghrelin may serve to predispose individuals with post-traumatic stress disorder towards overweight and obesity. Similarly, calorie restriction methods used by individuals with anorexia nervosa, which increase ghrelin, may help minimize what would otherwise be worsened depression and anxiety in those individuals.
The lab’s mouse models of chronic stress include chronic social defeat stress and chronic unpredictable stress, and we measure depression using the social isolation and forced swim tests and others. Our current studies are focused on the sites where ghrelin is acting to have its effects on mood, the downstream pathways and processes that enable this action of ghrelin, and the mechanisms by which stress induces ghrelin secretion.
Central nervous system and peripheral sites of ghrelin's action
Ghrelin receptors are expressed in several interesting brain sites and neuronal subtypes, including regions/neurons known to be involved in body weight regulation, eating, glucose homeostasis, autonomic nervous system control, addiction, learning/memory, and circadian rhythms. Ghrelin receptors are also expressed on certain peripheral cell types, including pancreatic beta cells and pancreatic alpha cells.
To determine which of those sites are sufficient for ghrelin’s many different actions, we have generated genetically engineered mouse models in which ghrelin receptor can be expressed selectively in a site of interest.
Other transgenic models allow us to use various state-of-the-art neuroanatomical techniques to probe neuroanatomical pathways used by ghrelin to have its effects.
Regulation of ghrelin synthesis and secretion
We have generated several transgenic models to study ghrelin cell physiology. These include reporter mice which express green fluorescent protein and mice in which marked hyperplasia of ghrelin cells is present. We have developed methods to grow and study immortalized ghrelin cell lines in culture and also gastric mucosal primary cultures.
Our current studies include those in which we investigate the molecular pathways present within ghrelin cells that help regulate ghrelin secretion. We also are working to investigate the relationship of ghrelin cells with other enteroendocrine cell types.