Source: UNIVERSITY OF GEORGIA submitted to
ENVIRONMENTAL FACTORS INFLUENCING EFFICIENCY OF ENERGY UTILIZATION
Sponsoring Institution
NIFA
Project Status
TERMINATED
Funding Source
HATCH
Reporting Frequency
Annual
Accession No.
0206037
Grant No.
(N/A)
Project No.
GEO00574
Proposal No.
(N/A)
Multistate No.
(N/A)
Program Code
(N/A)
Project Start Date
Jan 1, 2006
Project End Date
Dec 31, 2011
Grant Year
(N/A)
Project Director
Harris, R. B.
Recipient Organization
UNIVERSITY OF GEORGIA
110 RIVERBEND ROAD
ATHENS,GA 30602
Performing Department
COL OF FAMILY & CONSUMER SCI
Non Technical Summary
The number of people in the United States who are overweight or obese continues to increase. Although a large percentage of the population attempts to lose weight, a majority of those who lose weight are likely to regain it within several years. This project will identify mechanisms that direct how energy is partitioned between heat loss and accumulation as body fat when animal models are exposed to environmental factors that either increase or decrease body weight.
Animal Health Component
(N/A)
Research Effort Categories
Basic
100%
Applied
(N/A)
Developmental
(N/A)
Classification

Knowledge Area (KA)Subject of Investigation (SOI)Field of Science (FOS)Percent
7023840101050%
7033840101050%
Knowledge Area
702 - Requirements and Function of Nutrients and Other Food Components; 703 - Nutrition Education and Behavior;

Subject Of Investigation
3840 - Laboratory animals;

Field Of Science
1010 - Nutrition and metabolism;
Goals / Objectives
This project has three objectives 1. To understand how high-fat diets interfere with the ability of leptin to reduce body fat content. Leptin is a protein that is produced by adipose tissue and secreted into the circulation. It is thought to act in the brain to inhibit food intake and increase energy expenditure when fat stores increase. Although leptin increases with body fat mass, obese individuals are resistant to its activity. We recently showed that low dose infusions of leptin causes a small increase in energy expenditure but large increases in whole body fatty acid oxidation in rats fed a low-fat diet. This suggests that leptin can act in the periphery to promote mobilization of body fat. We propose to measure which aspects of leptin action in the periphery are inhibited in rats fed a high-fat diet in an effort to understand how leptin-resistance develops and whether it can be prevented or reversed. Because all obese people have high circulating concentrations of leptin, restoration of leptin sensitivity could potentially be an effective method of weight control. 2. To identify a circulating factor that is produced in response to significant weight gain and acts directly on adipose tissue to inhibit lipid accumulation. Previous studies have demonstrated that serum from obese rats contains a factor that selectively inhibits lipid accumulation in adipocytes. We will take advantage of the UGA Proteomics Core to determine whether obese rat serum contains novel proteins and, if so, they will be isolated and tested for their ability to inhibit lipogenesis. There are many potential commercial applications for a naturally occurring factor that inhibits accumulation of fat tissue but retains lean body mass. Two such opportunities are in meat production and application to human weight loss programs. 3. To determine the importance of changes in energy expenditure in the down-regulation of weight in response to acute stress and in the weight gain caused by chronically elevated stress hormones. Previously we have shown that acute stress initiates a cascade of events that produces a chronic, or permanent, shift in the metabolic equilibrium of an animal so that a lower body weight is defended. In contrast, continuous low-level activation of central stress pathways results in weight gain. We propose to measure energy expenditure of rats exposed to either acute or chronic stress to determine the pathways involved in mediating stress-induced changes in body weight.
Project Methods
Objective 1: The effects of leptin on peripheral energy utilization Peripheral infusions of leptin have little effect on food intake but reduces body fat. We will measure whole body and adipocyte metabolism of rats that have been fed a high fat diet and treated with leptin. Rats will be fed a 60% kcal fat (HF) or an 11% kcal fat (LF) diet until HF-fed animals do not show a feeding response to a leptin injection. This will be interpreted as leptin resistance. They will be infused with leptin and placed in the calorimeter to measure energy expenditure. Adipocytes will be isolated for measurement of lipogenesis, lipolysis and fat cell number. Liver and muscle glucose and fatty acid oxidation and carcass composition will be measured. If leptin resistance is universal there will not be a leptin effect in HF-fed rats, if it is selective then lipogenesis may be inhibited. Leptin inhibits preadipocyte proliferation by inducing release of another circulating factor. We will test serum from this study for its ability to inhibit preadipocyte proliferation. If serum from HF-fed rats is inhibitory then leptin-resistance induced by a HF diet is selective. Future studies would isolate the factor. Objective 2: Isolation of a blood borne factor that inhibits adipose tissue lipid accumulation Serum from overfed, obese rats contains a factor(s) that inhibits adipocyte lipogenesis. We have a serum fraction that represents a small number of proteins but retains anti-lipogenic activity. Proteomic analysis will be conducted at the UGA Proteomics Resource Facility to identify proteins that are differentially expressed in serum from overfed and control rats as a first step towards identifying the anti-lipogenic factor (ALF). Proteins consistently expressed at least 2.5 fold higher than controls will be excised and processed for identification with MALDI-TOF analysis. The targeted proteins will be identified by mapping against proteins with known sequences. Future studies will investigate the biological activity of these proteins and the conditions that regulate their expression. Objective 3. The role of energy expenditure in mediating changes in body weight of rodents that have been exposed to stress Rats exposed to restraint stress lose weight and do not return to the weight of non-stressed controls. In contrast, chronic infusion of the stress peptide CRF increases body fat, therefore, we will test whether either stressor changes energy expenditure and whether CRF receptors located in the brain stem are responsible for these changes. Future studies will test other receptor antagonists to determine which pathway is activated by CRF to modify thermogenesis. In each study the rats will be housed in the calorimeter during the stress and at the end of each study body composition and circulating concentrations of corticosterone will be measured. We expect an increase in expenditure in restrained rats and a small, but consistent reduction in energy expenditure of the rats that infused with CRF. Future studies would determine whether the effects are mediated by CRF receptors in the brainstem and whether the response is exaggerated by a high-fat diet.

Progress 01/01/06 to 12/31/11

Outputs
OUTPUTS: nothing to report pi has terminated PARTICIPANTS: Not relevant to this project. TARGET AUDIENCES: Not relevant to this project. PROJECT MODIFICATIONS: Not relevant to this project.

Impacts
nothing to report pi has terminated

Publications

  • No publications reported this period


Progress 01/01/08 to 12/31/08

Outputs
OUTPUTS: The goal of this research project is to identify mechanisms that direct how energy is partitioned between heat loss and accumulation in the body, as either fat or lean tissue, when animal models are exposed to environmental factors that either increase or decrease body weight. The calorimetry laboratory, overseen by Dr. William P. Flatt and maintained by Ms Emily Kelso conducted two studies to measure energy expenditure of experimental animals. Dr. Margarethe Hoenig, UGA School of Veterinary Medicine, examined the effects of differences in diet composition on expenditure and nutrient utilization in lean and obese cats. The long-term goals of this project are to identify dietary conditions that prevent the development of obesity in domestic cats. A second study evaluated the importance of forebrain leptin receptors in mediating the increase in energy expenditure caused by leptin. Leptin is a protein released from adipose tissue that is thought to be a signal used by the brain to regulate body weight. High levels of leptin inhibit food intake and cause weight loss. Thus, leptin has potential utility as an opportunity for treating or preventing human obesity, but also for changing efficiency of nutrient utilization and nutrient partitioning in production animals. When animals or people get fat they no longer respond to leptin. We have recently determined that there is a stage in the development of obesity during which leptin accelerates the increase in body fat mass, rather than inhibiting fat accumulation. The calorimetry study was an initial step in determining which areas of the brain are responsible for this weight gain. Other studies in this project examined how leptin signaling in one part of the brain influenced signaling in other areas of the brain known to control food intake and tested a dietary model in which leptin caused an increased rate of weight gain of rats fed a high fat, high sucrose diet. In addition, we recently found that rats fed a high fructose, low fat diet develop leptin resistance, but that when high levels of fructose are combined with high levels of dietary fat, the leptin resistance is reversed. A calorimetry study has been initiated to determine whether there are changes in energy expenditure that correlate with the increases and decreases in leptin responsiveness. In an unrelated project we have previously shown that the stress of repeated restraint in rats causes a chronic down-regulation of weight. If we can identify the mechanistic basis for the long-term down-regulation of body weight in stressed rats, then this will help in the prevention of weight regain in previously overweight individuals. Studies completed this year show an important role for the stress-induced release of the glucocorticoid corticosterone in mediating this weight loss. Studies are in progress to investigate how corticosterone impacts food intake and metabolism in stressed rats. PARTICIPANTS: Participants: Dr Ruth Harris, Dr William Flatt and Ms Emily Kelso in the Department of Foods and Nutrition. Graduate students Isabell Scherer and Samantha Haring, Department of Foods and Nutrition, Paul Cline, Department of Animal and Dairy Science. Undergraduate students Hayden Kramer, Department of Foods and Nutrition, Thomas Sadja, Department of Biology and Rachel Doyle, Department of Psychology. Training Opportunities: The graduate students learn the methodologies associated with measuring energy expenditure and respiratory exchange ratio. In the laboratory they learn assays and techniques that are used as indices of metabolic status. They also learn how to analyze and interpret the results. Several undergraduate and graduate classes from the Department of Foods and Nutrition visit the calorimeter each year to gain a better understanding of the techniques available for measuring energy balance in humans and animals. TARGET AUDIENCES: The scientific, public health and health education community that is responsible for identifying strategies to improve health by reducing risk for obesity and associated diseases. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.

Impacts
Research conducted in this project investigates environmental and endogenous factors that influence energy expenditure and the development of obesity in models of human obesity and in domestic animals. Understanding the basic mechanisms that regulate body weight will help us develop new and effective strategies for preventing and treating obesity. According to a CDC survey 59% of Georgia adults, 26% of Georgia high-school students and 33% of Georgia middle school students are overweight or obese and the state spends 6 percent of its overall health care costs treating obesity. The importance of reducing the incidence of obesity in the state of Georgia has been recognized and is being addressed by Georgia's Nutrition and Physical Activity Plan to Prevent Obesity and Other Chronic Diseases, 2005-2015. The outcome of studies supported by this project will provide new understanding of the systems that normally regulate body weight and body fat mass. This information will provide scientific support for novel strategic approaches to regulating body weight and reducing the incidence of weight gain and obesity.

Publications

  • Wilson, M.E., Fisher, J., Fisher, A., Harris, R.B.S., Bartness, T.J. 2008. Social status differences of consumption of calorically dense diets in rhesus monkeys living in complex social environments. Physiol Behav. 94:586-94.
  • Harris, R.B.S. and R. L. Leibel. 2008. Location, location, location. Preview of paper by Tran et al. Cell Metabolism.7:359-61
  • Nautiyal KM, Dailey M, Brito N, Brito MN, Harris RB, Bartness TJ, Grill HJ. 2008 Energetic responses to cold temperatures in rats lacking forebrain-caudal brain stem connections. Am J Physiol Regul Integr Comp Physiol.295:R789-98.
  • Penn, DM. and Harris, R.B.S. 2009 Changes in glucose and fatty acid metabolism in leptin responsive and leptin resistant rats infused with low doses of leptin. J Physiol Submitted
  • Harris, R.B.S. 2009. Nature or nurture A Focus on Preadipocyte transplantation - an in vivo study of direct leptin signaling on adipocyte morphogenesis and cell size. Am. J. Physiol. Submitted
  • Chotiwat. C., Kelso, E.W., and Harris, R.B.S. 2009. The effects of repeated restraint stress on energy balance and behavior of mice with selective deletion of CRF receptors. Hormones and Behavior. Submitted
  • Ferreira R., Marcondes F.K., Harris, R.B.S. 2009. Effects of chronic mild stress on body weight and food intake. Stress. submitted


Progress 01/01/07 to 12/31/07

Outputs
OUTPUTS: The goal of this research project is to identify mechanisms that direct how energy is partitioned between heat loss and accumulation in the body, as either fat or lean tissue, when animal models are exposed to environmental factors that either increase or decrease body weight. The calorimetry laboratory, overseen by Dr. William P. Flatt and maintained by Ms Emily Kelso conducted four studies to measure energy expenditure of experimental animals. Dr. Margarethe Hoenig, UGA School of Veterinary Medicine, examined the effects of differences in diet composition on expenditure and nutrient utilization in lean and obese cats. The long-term goals of this project are to identify dietary conditions that prevent the development of obesity in domestic cats. A study evaluating the effect of nicotine treatment in rats was conducted in collaboration with Dr Larry Bellinger, Baylor College of Dentistry. People who stop smoking tend to gain weight and Dr Bellinger has developed a model to examine the mechanisms responsible for the down-regulation of body weight by nicotine. The results show that the primary cause of weight loss is due to inhibition of food intake, rather than an increase in expenditure caused by nicotine. Two studies supported the research projects of Dr. Ruth Harris. We have previously shown that the stress of repeated restraint in rats causes a chronic down-regulation of weight following stress. An experiment was conducted to investigate whether inhibiting activation of receptors for stress peptides in the hindbrain of rats would inhibit weight loss in the stressed rats. If we can identify the mechanistic basis for the long-term down-regulation of body weight in stressed rats this will help in the prevention of weight regain in previously overweight individuals. A second project is investigating the metabolic activity of leptin, a hormone that reduces body fat mass when administered to normal animals. Thus, leptin has potential utility both as an opportunity for treating or preventing human obesity but also for changing efficiency of nutrient utilization and nutrient partitioning in production animals. We recently found that rats fed a high fructose diet develop leptin resistance, which may contribute to the correlation between increased consumption of sucrose and corn syrup and increased incidence of obesity in the US. The objective of the calorimetry study was to test whether fructose inhibited the effects of leptin on thermogenesis and nutrient utilization in addition to preventing changes in food intake and loss of body fat. Another aspect of the leptin project focuses on identifying factors that are released into the blood in response to leptin administration. These factors then act in concert with leptin to reduce fat mass. We have two in vitro assays in place to test serum and serum fractions for the presence of factors that inhibit preadipocyte proliferation or lipid synthesis in mature adipocytes. These assays are being used to identify the conditions required for release of the factors and we are in the early stages of fractionating serum to identify the factors. PARTICIPANTS: Participants: Dr Ruth Harris, Dr William Flatt and Ms Emily Kelso in the Department of Foods and Nutrition and graduate students Joanna Miragaya and Aarti Sanglikar, Department of Foods and Nutrition. Training Opportunities: The graduate students learn the methodologies associated with measuring energy expenditure and respiratory equivalency ratio. They also learn how to analyze and interpret the results. Several undergraduate and graduate classes from Department of Foods and Nutrition visit the calorimeter each year to gain a better understanding of the techniques available for measuring energy balance in humans and animals. TARGET AUDIENCES: Target Audience: The scientific community that is responsible for identifying strategies to improve health by reducing risk for obesity and associated diseases. Efforts: Formal education in the classroom for both undergraduate and graduate students resulted from combining a review of the theoretical basis of calorimetry with a visit to the laboratory to see indirect calorimetry in progress. Practical training was received by graduate students who participated in the studies that included calorimetry measures

Impacts
Research conducted in this project investigates environmental and endogenous factors that influence energy expenditure and the development of obesity in models of human obesity and in domestic animals. Understanding the basic mechanisms that regulate body weight will help us develop new and effective strategies for preventing and treating obesity. According to a CDC survey 59% of adults, 26% of Georgia high-school students and 33% of Georgia middle school students are overweight or obese and the state spends 6 percent of its overall health care costs treating obesity. Therefore, a reduction in incidence of obesity is critical from both a health and an economic perspective.

Publications

  • Sharp, C.S., Penn, D.M., Teff, K.L., Harris, R.B.S. 2007 Development of leptin resistance in rats fed a high-fructose diet. Am J. Physiol. Submitted.
  • Miragaya, J.R. and Harris, R.B.S. 2007 Antagonism of Corticotrophin-Releasing Factor Receptors in the Fourth Ventricle Modifies Responses to Mild but not Restraint Stress. Am J. Physiol. Submitted
  • Chotiwat, C and Harris, R.B.S. 2007 Antagonism of Specific Corticotropin Releasing Factor Receptor Subtypes Selectively Modifies Weight Loss in Restrained Rats. Am. J. Physiol. Submitted


Progress 01/01/06 to 12/31/06

Outputs
The goal of this research project is to identify mechanisms that direct how energy is partitioned between heat loss and accumulation in the body, as either fat or lean tissue, when animal models are exposed to environmental factors that either increase or decrease body weight. The Calorimetry laboratory, overseen by Dr. William P. Flatt and maintained by Ms Emily Kelso conducted six experiments to measure energy expenditure of experimental animals. Dr. Margarethe Hoenig (UGA School of Veterinary Medicine) conducted a study examining the effects of differences in diet composition on expenditure and nutrient utilization in lean and obese cats. Other studies supported the research projects of Dr. Ruth Harris. In one project we have previously shown that the stress of repeated restraint in rats causes a transient inhibition of food intake and stimulation of energy expenditure during stress but a chronic down-regulation of weight following stress. An experiment with an antagonist of catecholaminergic receptors was conducted to investigate whether inhibiting the increase in energy expenditure would inhibit weight loss in the stressed rats. If we can identify the mechanistic basis for the long-term down-regulation of body weight in stressed rats this will help in the prevention of weight regain in previously overweight individuals. A second project investigated the effects of physiological doses of leptin on energy expenditure and respiratory exchange ratio (RER) in rats and how these changes correlated with changes in adipocyte metabolism in animals that were either normal weight and responsive to leptin or that had been made obese and resistant to the effects of leptin on food intake. Leptin is a hormone that reduces body fat mass when administered to normal animals; however, it also contributes to the regulation of immune function, reproductive function and heart disease. Thus, leptin has potential utility both as an opportunity for treating or preventing human obesity but also for changing efficiency of nutrient utilization and nutrient partitioning in production animals. Another aspect of this project focuses on identifying factors that are released into the blood in response to leptin administration. These factors then act in concert with leptin to reduce fat mass. We have demonstrated the presence of two factors; one that inhibits proliferation of cells in adipose tissue and the other that inhibits lipid synthesis in mature adipocytes. We have two in vitro assays in place to test serum and serum fractions for the presence of these factors and are in the process of understanding the conditions that promote their release. Future studies will use protein separation procedures to identify the factors.

Impacts
Research conducted in this project investigates environmental and endogenous factors that influence energy expenditure and the development of obesity in models of human obesity and in domestic animals. Understanding the basic mechanisms that regulate body weight will help us develop new and effective strategies for preventing and treating obesity. According to a CDC survey 59% of adults, 26% of Georgia high-school students and 33% of Georgia middle school students are overweight or obese and the state spends $2.1 billion treating obesity, or 6 percent of its overall health care costs. Therefore, a reduction in incidence of obesity is critical from both a health and an economic perspective.

Publications

  • Legendre A., Papakonstantinou E., Roy M-C, Richard D. & Harris R.B.S. (2006) Differences in response to corticotrophin releasing factor following short and long-term consumption of a high fat diet. American Journal of Physiology (submitted)
  • Chotiwat C, Harris RB. 2006 Increased anxiety-like behavior during the post-stress period in mice exposed to repeated restraint stress. Horm Behav. 50: 489-495.
  • Legendre A, Harris RB. Exaggerated response to mild stress in rats fed high-fat diet. Am J Physiol Regul Integr Comp Physiol. 2006 Nov;291:R1288-1294.
  • Penn, DM, C.R. Rooks and R.B.S. Harris. Leptin: A metabolic perspective. Handbook of Contemporary Neuropharmacology John Wiley and Sons (In Press) 2005
  • Harris R.B.S., Mitchell, T.D., Kelso, E.W. & Flatt, W.P. (2006) Changes in environmental temperature influence leptin responsiveness in low- and high-fat fed mice. American Journal of Physiology (submitted)
  • Harris R.B.S., Bartness, T.J. & Grill, H.J. (2006) Leptin responsiveness in chronically decerebrate rats. Endocrinology (submitted)