RESEARCH SUMMARY

Leptin Receptor Signaling and the Control of Mammalian Physiology

Dr. Myers received his undergraduate degree in Molecular Biology (summa cum laude) at Princeton University in 1988 and his M.D. and Ph.D. (Cell Biology) degrees from Harvard Medical School in 1997. He joined the faculty at the Joslin Diabetes Center at Harvard Medical School in 1997, where he began to focus his independent research laboratory on mechanisms of leptin receptor signaling and links to the regulation of mammalian physiology. Dr. Myers joined the faculty of the University of Michigan Medical School, Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes with a secondary appointment in Molecular and Integrative Physiology in the spring of 2004. Dr. Myers received a Michigan Biomedical Sciences Scholar Award in 2004, was elected to the ASCI in 2005, and received the Jerome Conn Award for Excellence in Research in 2006.

Research in the Myers lab focuses on the biology of leptin, a hormone that regulates physiological processes relevant to diabetes and the metabolic syndrome. Circulating leptin enters the central nervous system to inform the brain about nutritional and metabolic status by activating the leptin receptor (LRb) on specific neurons. These neurons regulate metabolism (including glycemic control) and endocrine function. Mutation of leptin or LRb in rodents and humans results in profound diabetes, metabolic syndrome, and endocrine failure. The lab takes a broad-based approach to understanding leptin action by defining the mechanisms of cellular LRb action, studying the neurons that express LRb, and determining the roles of these molecular and neural mediators in leptin action in vivo.

The lab has already learned a great deal about the mechanisms of LRb signaling, as well as the roles of individual LRb signals in the physiologic response to leptin, and continues to explore specific questions about cellular mechanisms of leptin action. Current areas of focus include roles for Jak2, STAT5, and regulators of the proteasome in leptin action. The Myers lab continues to study these mechanisms in cultured cells in addition to examining their physiologic roles in genetically modified mouse models.

While two well studied populations of LRb-expressing neurons in the arcuate nucleus of the hypothalamus mediate important aspects of leptin action, these neurons only account for a fraction of leptin action; indeed they only comprise approximately 20% of all LRb-expressing neurons in the brain. The Myers lab is therefore scrutinizing several other major populations of LRb neurons in the brain; the function of these novel populations of LRb-expressing neurons is likely to be relevant to diabetes and other aspects of the metabolic syndrome and endocrine function.

It is also clear that leptin controls the early development of at least some of the neural populations that are involved in the control of glucose homeostasis and metabolism. This developmental regulation may be involved in the programming of the predisposition to diabetes and the metabolic syndrome. The lab is developing genetic models that will facilitate the interrogation of the mechanisms and consequences of this leptin-mediated neural programming.

Overall, by studying the molecular, cellular, neural and developmental functions of leptin and by understanding the contribution of each of these processes to leptin action, The Myers lab aims to define the mechanisms by which leptin regulates metabolism and how their alteration may contribute to diabetes and other metabolic disorders.

Recent publications: