Circadian Cycle and Metabolic Dysfunction

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Circadian Cycle and Metabolic Dysfunction

Tuesday, February 9, 2010

New York Academy of Sciences Conference Center

Presented By

 

When you haven’t slept, are late for work and skip breakfast: do you know the metabolic havoc you’ve caused? Do you take the incessant daily rising and setting of the sun for granted? If so: IT’S TIME TO WAKE UP! All organic matter, from the simplest plant to the most complex mammal, from chlorophyll in Aradopsis to fibroblasts in people obeys circadian rhythms for health and survival. The 10 leading causes of death in industrialized nations are all linked to disruptions in circadian rhythms. This Tuesday PM symposium brings together 4 leading experts on the metabolic consequences of common phenomena such as shift work, partying and jet lag for glucose control, energy balance, and epidemic obesity. They explain the molecular mechanisms and the practice implications of simple therapeutic interventions for treating and preventing serious disease.

The Diabetes & Obesity Discussion Group brings together experts from widely different disciplines that rarely collaborate, to stimulate new research initiatives and strategies for containing this health crisis. The group places great importance on informal interaction between bench scientists, clinical pharmacologists, representatives of public health organizations, industry leaders, and policy makers, owing to the multifactorial etiology of an epidemic affecting the entire human life-span.

Agenda


Tuesday, February 9

12:30 PM

Registration

1:00 PM

Welcome Remarks

1:15 PM

Nutrient Cycles Coupled to Insulin Signaling and Transcription
Pere Puigserver, Dana-Farber Cancer Institute

2:00 PM

Loss of Nocturnin, A Circadian Deadenylase, confers Resistance to Diet-induced Obesity
Carla B. Green, University of Texas Southwestern Medical Center

2:45 PM

Coffee/Tea Break

3:15 PM

Circadian Clock Gene Disruption in Obesity and Metabolic Disease
Joe Bass, Northwestern University

4:00 PM

Is there a Seasonal Thrifty Phenotype?
Robert Levitan, Centre for Addiction and Mental Health

4:45 PM

Clinical Control of Circadian Phase with Light Therapy
Michael Terman, Columbia University

5:00 PM

Networking Reception

Speakers

Organizers

John G. Kral

SUNY Downstate Medical Center

Dr. Kral studies influences of the intra-uterine environment and early-life stress on the development of chronic overnutrition (“obesity”) and diabetes. His work in monkeys has demonstrated how mild maternal stress in the form of food insecurity may cause infants to develop diabetes, obesity and other risk factors for cardiovascular disease as adults. Furthermore, with surgeons in Quebec he has shown that weight-loss surgery in mothers prior to subsequent pregnancies improves the intrauterine environment such that later offspring are protected from obesity and related metabolic diseases carried into adolescence. In conjunction with surgical treatment of obesity Dr. Kral has studied appetite regulation and adipose tissue function for many years. He initiated and co-organized the NIH Consensus Development Conference: “Gastrointestinal Surgery for Severe Obesity” in 1991, served as President of the NY State Society of Surgeons 1995-7, was co-chairman of the NIH Workshop: “Research Considerations in Obesity Surgery” in 2001 and serves on numerous scientific committees and editorial boards.

Andrew Swick

 

Dr. Andrew G. Swick earned his B.S. in Animal Science from the University of Florida in 1981 followed by an M.S. in Nutrition from the University of Nebraska in 1982. While in Lincoln, he worked on the effects of dietary fiber and fat on serum lipid levels. Andy then moved on to the University of Wisconsin where he conducted research on diet-induced-thermogenesis and brown adipose tissue metabolism and function. After earning his Ph.D. in 1987, Andy moved on to pursue postdoctoral research at the Lineberger Cancer Research Institute at the University of North Carolina where he studied transcriptional regulation of the dihydrofolate reductase gene and the effects of chemotherapeutic agents on transcription and gene amplification. In 1990, Andy joined Dan Lane's lab in the Department of Biological Chemistry at Johns Hopkins University Medical Center where he conducted research on the regulation of adipocyte gene expression and differentiation. In 1992, Dr. Swick joined Pfizer as a Senior Research Scientist in Cardiovascular and Metabolic Diseases working on diabetes and obesity and worked his way up to become Senior Director of Cardiovascular, Metabolic and Endocrine Diseases (CVMED). He was a key member of the CVMED Leadership Team, Obesity Disease Area Working Group and Strategy Team, CVMED Translational Research Team and Obesity Development Team. While at Pfizer Andy was responsible for the delivery >12 compounds to clinical development, including biologicals and small molecules spanning multiple mechanisms across obesity and diabetes, covering Phases 1, 2 and 3. In 2009, Dr. Swick departed from Pfizer and formed Illuminate BioPharma Consulting LLC and provides expert advice to Biotechnology, Pharmaceutical and Venture Capital companies and non-profit organizations on Drug Discovery Research and Development. Andy is an elected member of the following professional organizations: Sigma Xi, the American Society for Biochemistry and Molecular Biology and the American Society for Nutritional Sciences. In addition, he serves on the following committees: New York Academy of Sciences Diabetes and Obesity Steering Committee, American Society of Pharmacology and Experimental Therapeutics Education Working Group, International Union of Basic and Clinical Pharmacology - Integrative and Organ systems Pharmacology committee.

Speakers

Joe Bass

Northwestern University

Joseph Bass is an Associate Professor in the Department of Medicine, DIvision of Molecular Medicine and Endocrinology, at the Northwestern Univeristy Feinberg School of Medicine, and in the Department of Neurobiology and Physiology. The major research focus of his group is on the molecular integration of circuits coordinating feeding, sleep and wakefulness with systems controlling energy balance and nutrient utilization. This work stems from recent discoveries on the role of the circadian clock gene network in the integration of both brain and peripheral tissue energy sensing and metabolism. The Bass lab exploits approaches ranging from cell biology, to whole animal physiology, experimental genetics and behavioral analyses in order to elucidate the pathophysiology of diabetes, obesity and metabolic syndrome in states of circadian and sleep disruption, and the reciprocal interplay between metabolic disease states and circadian disorders.

Carla B. Green

University of Texas Southwestern Medical Center

Carla Green is a Professor of Neuroscience at the University of Texas Southwestern Medical Center. She received her PhD from the Department of Biochemistry and Molecular Biology at the University of Kansas Medical Center where she worked on the structure and function of a human prostate-specific gene with Simon Kwok. Her postdoctoral research with Joseph Besharse in the Department of Anatomy and Cell Biology at the University of Kansas Medical Center marked the beginning of her interest in circadian biology. While in the Besharse lab she identified a number of circadian clock-controlled genes, including a novel rhythmic gene Nocturnin, in the Xenopus retina. After starting her own lab at the University of Virginia in 1997, she continued to use that model system to study molecular mechanisms of retinal clock function, developing tools to perturb clock function molecularly in transgenic Xenopus. She also continued her studies on the Nocturnin gene and demonstrated that this gene encodes a deadenylase – a polyA-specific ribonuclease that removes the polyA tails from mRNAs. More recently, her lab has begun to focus on mammalian model systems and, in addition to a continued focus on Nocturnin and its role in clock control of metabolism, also works on the role of the Cryptochrome proteins in the central circadian mechanism. In September of 2009, she moved to the University of Texas Southwestern Medical Center to join the Department of Neuroscience. Carla Green is a Fellow of the American Association for the Advancement of Science.

Robert Levitan

Centre for Addiction and Mental Health

Dr. Levitan is an expert on atypical subtypes of mood disorders characterized by depressed mood and increased eating behaviour, including atypical depression, seasonal affective disorder, and eating disorders such as binge eating disorder and bulimia nervosa. In many cases, these various disorders co-exist in the same individual, suggesting that one or more vulnerability factors are shared among them. Dr. Levitan integrates clinical research in adults with developmental research focused on the early origins of disease. This includes both genetic association studies and novel methodologies emerging from the rapidly evolving field of socio-biology, which focuses on the interplay of nature and nurture. A better understanding of the complexity inherent in these disorders will lead to new prevention strategies and treatment approaches. Dr. Levitan is a senior clinical investigator in the mood disorders clinic at the Centre for Addiction and Mental Health, Toronto and is a Full Professor in the Department of Psychiatry at the University of Toronto. Dr. Levitan is also the Immediate past-president of the Society for Light Treatment and Biological Rhythms (SLTBR).

Pere Puigserver

Dana-Farber Cancer Institute

Pere Puigserver received his PhD in biochemistry from the University of Illes Balears, Spain, in 1992. He did postdoctoral research with Bruce Spiegelman at DFCI before joining the faculty as an assistant professor of Cell Biology at Johns Hopkins University School of Medicine in 2002. In 2006, Dr. Puigserver rejoined the faculty of Harvard Medical School and DFCI to continue his research on the genetic and biochemical mechanisms underlying the control of intermediary metabolism by nutrients and hormonal signals in mammals. In 2008 Dr. Puigserver was promoted to Associate Professor of Cell Biology at Harvard Medical School and Dana-Farber Cancer Institute.

Michael Terman

Columbia University

Dr. Terman is Professor of Clinical Psychology in Psychiatry at Columbia University, Research Scientist VI at the New York State Psychiatric Institute, Director of the Center for Light Treatment and Biological Rhythms at New York-Presbyterian Hospital / Columbia University Medical Center (www.columbia-chronotherapy.org), and President of the Center for Environmental Therapeutics (www.cet.org) an independent 501(c)(3) nonprofit consortium of mental health clinicians and chronobiologists. His animal research has focused on circadian rhythmicity in visual sensory and retinal function, circadian entrainment by feeding schedules, and the zeitgeber properties of naturalistic dawn-dusk transitions. His clinical research has led to the development of 10,000 lux light therapy, dawn simulation therapy and negative air ionization therapy for depressive disorders. He is a co-author of the first treatment manual in the field, Chronotherapeutics for Affective Disorders (Karger, 2009).

Abstracts

Nutrient Cycles Coupled to Insulin Signaling and Transcription

Pere Puigserver, Dana-Farber Cancer Institute

Changes in expression of genes encoding for proteins that control metabolic pathways is essential to maintain nutrient and energy homeostasis in individual cells as well as in organisms. A hallmark for metabolic diseases is an inability to respond adequately to nutrient levels and fluctuations. In this context, the PGC-1s transcriptional coactivator complexes participate in a large array of glucose and lipid metabolic adaptations in mammals. Using skeletal muscle cells as a metabolic model system we have found two different nutrient sensing pathways that control nutrient utilization. The first pathway involves a response to low nutrients and glucose that in a cell-autonomous manner switches from glucose to fatty acid oxidation via an increase in a specific subset of mitochondrial genes. This coordination switch to fatty acid oxidation and full respiration activities is controlled through PGC-1a and PGC-1b lysine acetylation. This reversible chemical modification is controlled by the deacetylase SIRT1 and the acetyltransferase GCN5. The second pathway involves the nutrient-dependent mTOR kinase that is activated by growth factors and high nutrients such as glucose and amino acids. mTOR positively controls mitochondrial oxidative function through regulation of PGC-1s and other mitochondrial transcriptional regulators. Mechanistically, we found mTOR in transcriptional complexes bound to the chromatin of genes controlling the expression rates. In vivo, mice treated with the mTOR inhibitor rapamycin develop several symptoms of type 2 diabetes including reduction of skeletal muscle mitochondrial oxidation. Gene expression analysis indicates that genes involved in glucose and lipid metabolic pathways are altered in mice treated with rapamycin. Interestingly, the severity of glucose intolerance is dramatically exacerbated in mice fed with high-fat diet. In conclusion, we have identified two nutrient-dependent molecular mechanisms that involve regulation of PGC-1 pathway and mediate control of skeletal muscle mitochondrial nutrient oxidation activities. Our results suggest the possibility to target the enzymes that control this pathway in metabolic diseases.

Loss of Nocturnin, A Circadian Deadenylase, confers Resistance to Diet-induced Obesity

Carla B. Green, University of Texas Southwestern Medical Center

Nocturnin is a deadenylase that controls mRNA expression in a circadian manner by degrading the poly-A tails of target mRNAs, leading to mRNA turnover or translational silencing. Previously we reported that a mouse lacking Nocturnin was resistant to diet-induced obesity and heptatic steatosis. The lean phenotype was not due to increased activity, decreased food intake or a higher metabolic rate. Transcript analysis in liver showed alterations in genes associated with lipid uptake and utilization. Through a subsequent series of in vivo and in vitro studies, we demonstrated that the Nocturnin KO mice are deficient in their ability to take up lipids. These animals have significantly disrupted lipid trafficking in the enterocytes, resulting in decreased absorption via apoB-containing non-HDL lipoproteins. We propose that Nocturnin has a role in the absorption of dietary lipid in bowel, presumably by altering genes necessary for metabolism or digestion through circadian post-transcriptional modifications of targeted transcripts.

Circadian Clock Gene Disruption in Obesity and Metabolic Disease

Joe Bass, Northwestern University

Circadian rhythms of physiology and behavior represent a conserved organizing mechanism to optimize internal systems involved in energy storage and utilization in synchrony with the daily rotation of the Earth. Like the metabolic system, the circadian system involves a complex network of feedback loops involved in both transcriptional and post-transcriptional regulatory pathways in brain and peripheral tissues. In mammals, the core clock in the suprachiasmatic nucleus functions to entrain extra-SCN and peripheral clocks to the light-dark cycle, including regions central to energy homeostasis and sleep, as well as peripheral tissues involved in carbohydrate and lipid turnover. Recent evidence indicates that genetic and environmental disruption of circadian cycles results in impairment of both sleep and metabolism, and may contribute to risk of obesity, diabetes and cardiovascular disease. Our goal is to exploit genetic models of circadian disruption in rodents in order to identify targets and mechanisms coordinating biological timing with feeding, energy expenditure and metabolism.

Is there a Seasonal Thrifty Phenotype?

Robert Levitan, Centre for Addiction and Mental Health

The classic thrifty hypothesis of Barker and Hales is based on the notion that maternal-fetal signaling of an impoverished food environment can trigger a thrifty response in her offspring intended to enhance survival if food supplies remain scarce. In modern developed countries, this otherwise adaptive process becomes a risk factor for obesity and diabetes due to the resulting mis-match between predicted caloric conditions and actual food resources. Over the last 40,000 years of human evolution, which has included several extended periods of glaciation across North America and Europe, it is likely that seasonal changes were a highly predictable signal of low food availability. If so, there ought to be one or more “seasonal thrifty phenotypes” encoded in our genes intended to optimize survival and reproduction in the face of predictable seasonal famines. This talk will provide epidemiological and genetic evidence for at least one putative “seasonal thrifty phenotype”, focusing on a hypo-functional variant of a dopamine receptor gene. This variant, the 7-repeat allele of the dopamine-4 receptor gene, has been shown to influence food intake and has been positively selected over recent human evolution.

Clinical Control of Circadian Phase with Light Therapy

Michael Terman, Columbia University

Disruption, phase shifts and dampening of circadian rhythms, and abnormal internal phase relationships among rhythms are thought to underlie a range of medical and psychiatric disorders. The paradigmatic examples are seasonal affective disorder and delayed sleep phase disorder. Timed light exposure provides the primary corrective measure. The circadian phase-response curve to light is bipolar, with light in the evening and throughout most of the night eliciting phase delays of the internal clock, and light toward the end of the night and the morning eliciting advances. Physiological day and night, however, differs markedly between individuals and is often poorly synchronized with the outdoor day-night cycle. Successful clinical administration of light therapy must therefore be timed individually, in distinction from the dictates of the clock on the wall.

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