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“Because of the increasing rates of obesity, unhealthy eating habits, and physical inactivity, we may see the first generation that will have a shorter life expectancy than their parents.”

U.S. Surgeon General,
Richard Carmona,
March 2004

Presenters


Sarah H. Leibowitz, Ph.D.

Associate Professor at the Laboratory of Behavioral
Neurobiology at Rockefeller University

BIOGRAPHY:
Dr. Leibowitz, using tools of neurobiology, physiology and molecular biology, works to identify the different neurobiological substrates of eating behavior and preferences for dietary macronutrients, fat and sugar. She and her colleagues systematically characterize the essential neurochemicals and neurohormones as they function and interact under normal conditions. At the same time, her laboratory tracks disturbances in these mechanisms, caused by environmental or genetic factors, which may contribute to abnormal behavioral and metabolic responses and ultimately lead to obesity and diabetes. This research includes studies at different stages of development, of gender differences and of dietary effects that occur in utero and have long-term consequences extending into adulthood.

Recent investigations in rats and mice have led to the discovery of two distinct classes of neuropeptides in the hypothalamus that control eating behavior and body weight regulation and are differentially responsive to dietary fat and carbohydrate. They are also remarkably sensitive to changes in circulating nutrients, in particular, triglycerides and glucose, which control their gene expression. These distinct classes of peptides — “fat-responsive” and “glucose-responsive” — function within a positive feedback loop that promotes overeating of fat- and sugar-rich foods.

To allow a more systematic investigation of neurobiological systems involved in eating and body weight regulation, Dr. Leibowitz and her colleagues have also characterized a variety of animal models of complex behavioral and physiological functions that are critical to nutrient homeostasis. These natural models have laid the foundation for their current research programs. These include investigations of the molecular and cellular properties of brain neuronal systems expressing known genes, e.g., neuropeptides, hormone receptors and enzymes, and molecular genetic studies to identify and functionally characterize new transcripts that are overexpressed or underexpressed under particular dietary conditions.

A new series of investigations conducted by Dr. Leibowitz and her colleagues is examining the effects of alcohol on brain systems that, in turn, may contribute to excess consumption of alcohol. Further studies are investigating mechanisms and brain areas that may underlie food cravings and possibly contribute to eating disorders, such as binge eating.

ADDITIONAL INFORMATION:

Address: The Rockefeller University, 1230 York Avenue, New York, New York 10021.

Research areas: Behavioral Neurobiology; Neuroendocrinology; Neuroplasticity; Brain systems controlling eating behavior and body weight regulation; Obesity and eating disorders; Early development.

Education: New York University, B.A. (Psychology), 1964; Ph.D. (Psychobiology), 1968.

Professional Experience: USPHS Postdoctoral Fellow, 1968-1970; Guest Investigator - Assistant Professor, The Rockefeller University, 1970-1971; Associate Professor, Laboratory of Behavioral Neurobiology, The Rockefeller University, 1978-Current.

Research Publications: 200 articles in scientific journals; 58 review articles or book chapters.

Editorial Advisory Boards: Endocrinology, 1998-2001; Physiology and Behavior, 1988-present; Behavioural Brain Research, 1994-2003; Nutrition and Behavior, 1981-1987; Psychosomatic Medicine, 1976-1982.

Current NIH Grants: NIDA (#DA21518); NIAAA (#AA12882, with BG Hoebel)

Honors and Awards: 1) Alfred P. Sloan Foundation Fellowship, 1977-1980; 2) Grass Traveling Scientist Program, Society for Neuroscience, 1986, 1989; 3) Fellow: American Psychological Association, Academy of Behavioral Medicine Research, American Psychological Society, International Behavioral Neuroscience Society; 4) Invited review for special 2004 edition of journal, Peptides, recognizing authorship of three most frequently cited papers over past 25 years; 5) Invited 2005 lecture series in Sweden (Karolinska Institutet, University of Lund, and Uppsala University) recognizing 20 years of work with brain peptides; 6) Board of Directors: Society for the Study of Ingestive Behavior, 1990-1993; International Neuropeptides Society, 1992-present; Eastern Psychological Association, 1988-1992, 2002-present; President’s Council of International Behavioral Neuroscience Society, 1993-1996; Orpheus Chamber Orchestra, 2003-present.

Committee Member: NIMH Psychobiology and Behavior Research Review Committee, 1988-1992; NIMH Psychobiology, Behavior and Neuroscience Review Committee, 1995-1997; Human Rights of Scientists Committee, The New York Academy of Sciences, 1994-present; Program Committee: Society for Study of Ingestive Behavior, 1992, and Eastern Psychological Association, 1984-1987; APA Board of Scientific Affairs, Committee on Animal Research and Experimentation, 1976-1978; Lindsley Prize Selection Committee, Society for Neuroscience, 1979-1982; Elected Member, President’s Council, International Behavioral Neuroscience Society; Member-at-Large, AAAS Neuroscience Section, 1995-present.

Teaching: Courses and seminars for graduate and medical students in Behavioral Neurobiology, The Rockefeller University.

Society Memberships: American Association for the Advancement of Science; American Psychological Association; American Society for Biochemistry and Molecular Biology; Eastern Psychological Association; International Brain Research Organization; New York Academy of Sciences; North American Association for Study of Obesity; Phi Beta Kappa; Sigma Xi; Society for Neuroscience; Society for the Study of Ingestive Behavior; The Endocrine Society.

SUMMARY OF RESEARCH:

Overview
Eating behavior and body weight regulation have evolved in mammals into highly complex processes with multiple feedback loops involving both peripheral and central systems. This complexity helps to explain the notable failure of unidimensional approaches to dieting and treating disturbances in eating and weight control. Over the past 30 years, our laboratory has pursued a multidisciplinary research program to identify and characterize neurobiological substrates in rodents that mediate these complex processes, under both normal and pathological conditions. We have demonstrated that brain mechanisms, diet consumption and circulating nutrients function in a highly interactive and nutrient-specific manner. Imbalanced diets rich in fats or carbohydrates along with their associated changes in circulating lipids and glucose markedly affect neurochemicals in the brain, and these neurochemicals when injected into specific brain sites then alter natural eating patterns and preferences for the macronutrients. Further, studies of these behavioral, physiological and neurochemical processes reveal marked differences between individuals that are prone (or resistant) to overeating and obesity and also dramatic shifts in relation to biological rhythms, developmental stages and gender. Predictive studies demonstrate that individual differences in these parameters expressed before puberty or exposure to sugar- or fat-rich diets early in life are predictive of and possibly causally related to later pathologies. An important concept revealed by these findings is that specific neurobiological systems and diet intake are functionally linked within a positive feedback loop, with a specific diet stimulating particular brain neurochemicals that in turn stimulate further consumption of this same diet. This diet-neurochemical-diet feedback process, while appropriate for producing overeating and gorging under conditions when food is scarce, helps to explain the eating and body weight disorders that develop when sugar- or fat-rich foods are abundant. A surprising recent finding is that similar positive feedback systems exist in the brain for controlling the consumption of alcohol.

Background
Neurochemicals and dietary macronutrients: In our initial pharmacological studies, we first demonstrated that such neurochemicals as norepinephrine and neuropeptide Y, which are known to stimulate food intake, have a close and specific relationship to dietary carbohydrate, specifically sugar, and also to circulating levels of glucose. We then discovered that another set of orexigenic peptides, namely, galanin and the opioids, enkephalin and dynorphin, are closely related, not to carbohydrate but to dietary fat. These investigations provided the first evidence supporting the existence of specific neurochemical systems differentially related to carbohydrate and fat. Further examination of the monoamines, serotonin and dopamine, which are known to reduce feeding and produce satiety, differentiated these neurotransmitters in the hypothalamus in terms of their inhibitory effects on macronutrient intake. These experiments helped to elucidate the actions of such weight-reducing drugs as fenfluramine and amphetamine.

Biological rhythms, development and gender: Subsequent investigations confirmed these associations between the macronutrients and neurochemical systems as they relate specifically to biological rhythms and stages of development. Spontaneous shifts in endogenous gene expression and production of these neurochemicals in the hypothalamus were found to coincide with natural shifts in the animals’ ingestion of carbohydrate or fat. These shifts were detected across the natural feeding cycle, at different stages of development, across the female cycle, and in relation to gender.

Effects of diet and nutrients on the brain: Building on these studies revealing associations between orexigenic peptides and macronutrients, we then investigated whether specific diets and circulating nutrients can have direct impact on these brain neurochemical systems. These investigations provided results supporting an unexpected principle: that the macronutrient to which a specific peptide is closely associated and has a stronger stimulatory effect does, in turn, directly stimulate the expression and production of this same peptide. These results suggest the existence of positive feedback loops that have possible consequences of promoting overeating of a particular macronutrient. The effects of diet on the hypothalamus were found to be amazingly rapid, occurring within the context of a single day – or even a single meal. They were also shown to be anatomically localized, with the “carbohydrateresponsive” peptides expressed in the basal hypothalamus and the “fatresponsive” peptides expressed in nuclei of the dorsal hypothalamus. This evidence provided new information on how peptide systems in the hypothalamus are functionally organized in relation to specific macronutrients.

Physiological mechanisms mediating diet effects: This strong evidence for causal effects of diet on neuropeptide systems encouraged us to explore possible physiological mechanisms mediating these effects. While our work and that of others have suggested that hormones are involved, our recent investigations have provided the first evidence that nutrients circulating in the blood, e.g., glucose or lipids, which shift dramatically in relation to carbohydrate and fat ingestion, have immediate and marked effects on the hypothalamic systems. In fact, the elevated levels of glucose and triglycerides after an imbalanced meal rich in sugar or fat, possibly by over-riding negative feedback signals, are found to promote non-homeostatic overeating that contributes to obesity. These findings relating blood-borne nutrients to neurochemicals provide insight into disturbances within the brain, which may result from the hyperglycemia and hypertriglyceridemia that are commonly seen in obesity and diabetes and serve to further exacerbate the conditions.

Predictive studies and early exposure to diets: Building on these results showing effects of nutrients on the brain, we have explored the possibility that these circulating nutrients may, in turn, provide useful information for identifying subpopulations of outbred animals, early in life and at normal body weight, that have a differential propensity towards overeating and dietary obesity. Evidence to date suggests that, in adult as well as prepubertal animals, circulating triglyceride levels after a fat-rich meal is a strong biomarker for predicting a predisposition (or resistance) to later obesity. We have further discovered that sugar- or fat-rich diets introduced early in life, even during pregnancy, can produce profound and long-lasting changes in circulating nutrients that, in turn, have long-term impact on brain neurochemical systems controlling eating behavior and weight gain.

Alcohol intake: Recent studies (in collaboration with Dr. Bart Hoebel at Princeton University) have revealed that the brain peptides associated with dietary fat and circulating lipids are also closely related to the consumption of alcohol. Voluntary drinking of alcohol increases triglyceride levels and rises with the amount of fat consumed, hypothalamic injection of the fat-related but not carbohydrate-related peptides stimulates alcohol intake, and the intake or injection of alcohol stimulates the expression of these fat-related peptides. Thus, there exists a positive feedback loop between the peptides and alcohol intake, similar to that seen with dietary fat, which may promote the over-consumption of alcohol as well as fat. This and other evidence suggests that alcohol and fat intake during a meal, possibly involving forebrain dopamine that is released by the peptides, may synergize to produce larger meals and greater alcohol consumption.

Current Research Projects
These investigations to date have allowed us, first, to develop a variety of natural animal models with precisely defined behavioral and physiological characteristics and dietary history and, second, to define potential functions for known peptidergic and monoaminergic systems in both normal and pathological states. This work has laid a strong foundation for this laboratory’s current research program. The goal of this research is to apply a variety of molecular biological techniques, including subtractive hybridization, microarrays, real-time quantitative PCR and in situ hybridization, to examine in these different animal models a broader range of neurobiological systems involved in eating behavior and alcohol intake. We are screening and functionally characterizing novel systems in the brain, which respond to dietary manipulations and circulating nutrients and may contribute to states involving excess consummatory behavior and increased weight gain. In these investigations, we are examining small brain areas and distinct cell groups in the hypothalamus as they relate to forebrain and hindbrain systems. Some initial work along these lines, as described in recent publications, demonstrates for the first time that: a) two proteins in the brain, apolipoprotein D and diacylglycerol kinase zeta, are stimulated by consumption of a fat-rich diet and constitute a downstream component of the signal transduction pathway for the adipocyte hormone, leptin, in the brain; and b) a third protein, huntingtin-associated protein 1, is reduced by a high-carbohydrate diet and, through its suppression, mediates the feeding-inhibitory action of insulin in the brain.

This developing body of science holds great promise for a more fundamental understanding of the multiple feedback systems that underlie pathological eating patterns and consequent disturbances in weight gain, in children as well as adults. This research should facilitate the design of more precise approaches for studying and addressing the growing incidence of eating and body weight disorders within modern societies where sugar- and fat-rich foods as well as alcohol are abundantly available.

Recent Publications

1. Leibowitz, S.F., Chang, G-Q., Dourmashkin, J.T., Yun, R., Julien, C. and Pamy, P.P. Leptin secretion after a high-fat meal in normal-weight rats: Strong predictor of long-term body fat accrual on a high-fat diet. Amer J Physiol, 2006, 290, E2 58-E267.

2. Dourmashkin, J.T., Chang, G.-Q., Hill, J.O., Gayles, E.C., Fried, S.K. and Leibowitz, S.F. Model for predicting and phenotyping at normal weight the longer-term propensity for obesity in Sprague-Dawley rats. Physiol Behav, 2006, 87, 666-678.

3. Sheng, G., Chang, G.Q., Lin, J.Y., Yu, Z.X., Fang, Z.H, Rong, J., Lipton, S.A., Li, S.H., Tong, G, Leibowitz, S.F. and Li, X.J. Hypothalamic huntingtin-associated protein 1 as a mediator of feeding behavior. Nature Medicine, 2006, 12, 526-533.

4. Chang, G.-Q., Karatayev, O., Ahsan, R., Gaysinskaya, V. and Leibowitz, S.F. Dietary fat stimulates endogenous enkephalin and dynorphin in the paraventricular nucleus: Role of circulating triglycerides. Amer J Physiol, 2007, 292, E561-E570.

5. Chang, G.-Q., Karatayev, O., Ahsan, R., Avena, N.M., Lee, C., Lewis, M.J., Hoebel, B.G. and Leibowitz, S.F. Effect of ethanol on hypothalamic opioid peptides, enkephalin and dynorphin: Relationship to circulating triglycerides. Alcoholism: Clinical and Experimental Research, 2007, 31, 249-259.

6. Gaysinskaya, V.A., Karatayev, O., Chang, G-Q. and Leibowitz, S.F. Increased caloric intake after a high-fat preload: Relation to circulating triglycerides and orexigenic peptides. Physiol. Behavior, 2007, 91, 142-153.

7. Leibowitz, K.L., Chang, G-Q., Pamy, P.S., Hill, J.O., Gayles, E.C. and Leibowitz, S.F. Weight gain model in prepubertal rats: prediction and phenotyping of obesityprone animals at normal body weight. International J. Obesity, 2007, in press.

8. Leibowitz, S.F., Akabayashi, A., Wang, J., Alexander, J.T., Dourmashkin, J.T. and Chang, G-Q. Increased caloric intake on a fat-rich diet: Role of ovarian steroids and galanin in the medial preoptic and paraventricular nuclei and anterior pituitary of female rats. J. Neuroendocrinology, 2007, in press.