Henry Koopmans, PhD - US grants

The main objective of the proposed research is to determine which internal signals are involved in the control of daily food intake and energy expenditure. The long-term objective is to understand the internal control of energy balance well enough to develop a medical treatment for obesity. Obesity is a risk factor for several debilitating diseases, including diabetes, hypertension, stroke and heart disease. A medical treatment for obesity would greatly reduce human suffering and would decrease the societal cost of health care. The first specific aim is to assess the effect of intravenous infusions of glucose and amino acids and of medical fat emulsions on voluntary food intake and metabolic rate. Pilot studies have shown that the rats respond to these nutrients in very different ways: they reduce their food intake following glucose infusions but not following fat infusions. The second aim is to determine whether the effect of glucose infusions are different during the night when neural and hormonal signals from the digestive tract are present or during the day when these signals are absent. The third specific aim is to determine whether the failure of the rats to respond to intravenous fats was due to the non-physiological form of the infused fats. The fourth aim is to investigate the relative importance of blood metabolites, intestinal hormones and intestinal nerves in the control of energy balance. This will be done by transplanting a supernumerary intestine into the peritoneal cavity of another rat and infusing fat into either the rat's natural intestine, into the denervated transplant or into the bloodstream. The final specific aim is to infuse promising gut peptides directly into the bloodstream in such a way as to mimic the normal blood levels of the hormones after a meal. Analogs of the hormones may provide a medical treatment for obesity.

The crossed intestines surgery in parabiotic rats produces large changes in daily food intake and energy expenditure that appear to be sustained for the rest of the animal's lives. One rat in each pair can eat three to four times as much as its partner. A major objective of this grant proposal is to determine how these large changes in daily food intake will affect gastric distension, gastric emptying and intestinal transit in order to understand the role of the gastrointestinal tract in the control of daily intake. These experiments will determine which sections of the gastrointestinal tract are stimulated by the food eaten by these rats throughout the 17 hour feeding period. Another objective is to extend pilot studies that show that there are also large changes in oxygen consumption and sympathetic nervous system activity in crossed intestines rats. The possible mechanisms for the changes in overall energy expenditure will be assessed by measuring the rate of norepinephrine turnover, the stimulation of hepatic mRNA levels by thyroid hormones and the amount of uncoupling protein in brown adipose tissue. The final objective is to determine how these large changes in food intake and energy expenditure could be caused by changes in the plasma levels of various hormones and metabolites. The major plasma nutrients, glucose, lactate, glycerol, triglycerides and free fatty acids, will be measured in these rats at several times during the 17 hour feeding period and the plasma level of three pancreatic hormones, insulin, glucagon and somatostatin, will be determined. The long-term objective of this research is to find a medical treatment (drug or hormone analog) for obesity. In Western societies, obesity is a major medical problem that causes a great deal of human suffering. It is associated with such chronic and debilitating conditions as diabetes, hypertension, stroke and heart disease. An effective medical treatment for obesity would improve the quality of life for millions of people and would greatly reduce the cost of long-term health care.

Surgery has been the most successful treatment for morbid obesity. The main objective of this grant proposal is to determine why lower gut signals generated in bypass surgery have been so successful in causing reduced food intake and body weight loss. We recently discovered that lower gut signals also cause a 10-25 percent increase in energy expenditure. One objective of this grant proposal is to determine how stimulation of different lengths of the ileum, caecum and colon affect energy balance and the plasma levels of the lower gut hormones: neurotensin; PYY and GLP1. Another objective is to determine the role of the extrinsic nerves to the ileum in altering food intake, energy expenditure and body weight by doing ileal transplantation surgery or denervation of the superior mesenteric nerves. A time course of the changes in energy expenditure, upper gut tissue growth and plasma lower gut hormone levels resulting from ileal transposition will be investigated in preparation for a later peptide infusion study. The role of the various macronutrients in changing energy balance and lowering body weight will be assessed by feeding various diets to rats with a 20 cm segment of ileum moved up to the mid-duodenum. The short-term objective of this research is to understand the internal control of daily intake and energy expenditure. The long-term objective is to find a medical treatment (drug or hormone analog) for obesity. In Western societies, obesity is a major medical problem that causes a great deal of human suffering. Obesity is associated with such chronic and debilitating conditions as diabetes, cancer (breast, endometrial, prostate and colon), hypertension, hyperlipidemia, stroke and heart disease. An effective medical treatment for obesity would improve the quality of life for millions of people and would reduce the cost of long-term health care.