Specific Clinical/Research Interest:
Aging; obesity; diabetes; Alzheimer's disease; life extension; dietary restriction;
Current Students: Cesar Moreno(NEU); Stephanie Lum
Research Personnel: Instructor: Fumiko Isoda
Overview:
Our laboratory studies the molecular basis of aging and age-related diseases, especially metabolic diseases such as obesity and diabetes, and related neurodegenerative diseases. Focusing on the interface between metabolic signals and the neurons that sense those signals and regulate metabolic processes, we have discovered several key molecular pathways that regulate energy balance and glucose homeostasis; impairments in these pathways constitute the main single-gene causes of obesity and diabetes in humans. We have extended discoveries in mammalian systems to the nematode C. elegans, discovering a transcriptional complex that mediates the protective effects of dietary restriction to increase lifespan and protect against age-related diseases, including Alzheimer-type pathology. Pharmacological activation of this pathway increases lifespan and protects against neurodegenerative diseases, and the same complex predicts lifespan and obesity in mice.
Summary of Research Studies:
Our laboratory uses histological, behavioral, electrophysiological, and molecular, methods (including DNA microarrays and RNA interference) to assess the basic mechanisms by which hypothalamic neurons sense and regulate metabolic state (including body weight and food intake), and how these mechanisms are impaired in metabolic diseases and during aging. A driving question of our laboratory is what may be called the metabolic mystery. This refers to the fascinating phenomenon that obesity is a risk factor for most age-related diseases and indeed for mortality, and conversely dietary restriction appears to slow down the aging process and extend maximum lifespan. Considering that almost all major pathologies are influenced by caloric intake, the mechanisms underlying the metabolic mystery may be considered among the most compelling in biomedical science. We really don't understand why caloric intake should lead to diseases, but many lines of evidence suggest neuroendocrine mech! anisms. We have begun to study the nature of the hypothalamic neurons which are sensitive to nutrition and which in turn regulate metabolic state, and we have thus begun to define a "nutritional field" of neurons which contain overlapping domains sensitive to different nutrients and which regulate different aspects of metabolism. Of particular interest is that the maximum overlap of these nutritional stimulation (e.g., glucose and leptin) may occur within the POMC neurons, which we now believe play a critical role in regulating metabolism. This is particularly interesting because the POMC neurons are among the most sensitive to decline during aging. To begin to directly test the role of specific gene products in the developmentof obesity, diabetes, and aging, we have now produced several lines of transgenic mice that overexpress leptin, POMC, insulin, and glucokinase specifically in the brain, and we are now assessing the effects of these transgenes in obesity, diabetes, an! d aging. For example, we have now shown that transgenic enhan! cement of neuronal POMC will completely correct the diabetes and other impairments in genetically obese mice. These studies have led to discovery of a new class of anti-obesity drugs that we are now studying. A new direction in our laboratory involves examining function of metabolic genes we have discovered using microarrays using RNA interference protocols in mice and in C. elegans. Using high-throughput RNAi screening methods we have discovered over 20 novel genes that regulate obesity in C. elegans. Using a similar approach we have also discovered a transcriptional complex that mediates the protective effects of dietary restriction to increase lifespan and protect against age-related diseases, including Alzheimer-type pathology and diabetic complications. Pharmacological activation of this pathway increases lifespan and protects against neurodegenerative diseases, and the same complex predicts lifespan and obesity in mice. We have now also developed novel high-throughput! methods to discover novel anti-obesity and anti-diabetes drugs, and have discovered over 20 drugs in each class so far.
Visit Dr. Charles Mobbs's
Aging and Metabolism Lab for more information.
