Leptin: A Key Player In Weight Regulation

1. Leptin: A Key Player In Weight Regulation By Molly Loban

2. Importance of Finding Treatment • Obesity affects one out of three individuals • It is the most frequent and costly metabolic problem in the United States • $70 billion per year of healthcare money is spent directly on obesity • In addition $30 billion per year is spent on special food and weight loss programs • Many people are looking for ways to lose weight • Low long-term success rate of weight reduction progams • 90% of people who diet gain back the weight • Indicates a feed back loop which spontaneously corrects weight to original set point • Leptin has been found to play key role in this regulatory process

3. What is Leptin? • A peptide hormone which is coded for by the obese gene (ob) • Influences the quantity of food consumed relative to the amount of energy expended • When leptin levels are high, appetite is reduced and energy expenditure is increased • Leptin has been found in gastric epithelium, placenta and adipose tissue • Most abundant in white adipose tissue

4. White Adipose Tissue (WAT) • Composed mainly of adipocytes (fat cells) • Store energy in the form of triglycerides in times of nutritional affluence • Release free fatty acids during nutritional deprivation • WAT mass is determined by the balance between energy intake and expenditure • This is influenced by genetic, neuroendocrine, and environmental factors • Under normal conditions this system is carefully regulated so that WAT mass remains constant and close to well defined ‘set point’ • Disruption of the steady state can lead to chronic decreases or increases in the quantity of WAT • Decreaased amounts are associated with weight alterations during peroids of diet, malnutrition, eating disorders, etc • Increased amounts indicate obesity

5. How Does Leptin Interact?

6. Regulating Food Intake and Energy Expenditure • Leptin binds to its receptor which is expressed primarily in the brains hypothalamus region • In turn the hypothalamus modulates food intake and energy expenditure • When low leptin levels are detected, the body is warned of limited energy supplies • If high leptin levels are detected, the hypothalamus senses the body as being overweight • This then trigger the body to eat less and expend more energy • When energy intake and output are equal, leptin reflects the amount of triglyceride stored in the bodies adipose tissue

7. Metabolic Affects of Leptin • Decreases intracellular lipid concentration through reduction of fatty acid and triglyceride synthesis and a concomitant increase in lipid oxidation • It has been postulated that leptin inhibits acetyl-CoA carboxylase • Enzyme involved in the committed step of fatty acid synthesis • This inhibition leads to decrease in malonyl-CoA levels • Together the inhibition of acetyl-CoA to malonyl-CoA encourages the mobilization of fatty acids from storage sites and simultaneously discourages synthesis

8. Carnitine acyl transferase I, which is normally inhibited by malonyl-CoA, is then available to aid in lipid oxidation • This enzyme is required for the transport of Acyl CoA molecules across the inner mitochondrial membrane • Without this step, fatty acid breakdown is inhibited

9. Experimentation on Mice • Mice leptin has an 84% resemblance to human analog • Some obese mice have been found to have mutation in ob gene caused by premature stop codon • Results in absolute lack of leptin which leads to severe obesity • Experimentation done on both obese and normal mice • Intravenous, intraperitoneal, an intracerebroventricular injections were given • Results most significant for intracerebroventricular injections • All mice showed affected • Lower dosages required • Varying degrees of body weight loss related to dosage and time • Decreased food intake and metabolic rate increased • Significant amounts of WAT mass lost

10. Experimentation on Humans • Few experiments done at this point • Leptin is said to circulate freely or attached to a binding protein • It has been found that obese individuals have more circulating bound leptin than lean individuals • The greater the initial level, the more it declines with dieting • Levels tend to vary greatly from person to person • Typically females have more leptin than males • Adipose tissue accounts for 20-25% of weight in females and only 15-20% in males • In general the greater the body mass and percent body fat, the higher the levels • People suffering from obesity have extremely high levels

11. Possible Reasons For Increased Leptin In Obese Individuals • Differences in the fat production rate of leptin • Some obese people may make leptin at greater rate to compensate for faulty signaling process or action • Resistance to leptin at its site of action • If resistance is partial, not complete, more leptin may be required for action • A combination of both could influence eating behaviors and energy use to cause obesity • All these possibilities indicate that obese individuals are in a state of percieved starvation

12. Future Treatment in Weight Regulation • Leptins dual action of reducing appetite while increasing energy expenditure makes it a good candidate for weight regulation • Has applications for both dieters and obese individuals • Dieters: • Prevent reduced energy expenditure normally associated with decreased food intake • Prevent the regaining of weight • The lower leptin levels associated with dieting are said to make the body respond as if in period of starvation • Administering leptin will decrease cravings and speed up metabolism to prevent weight from returning to set point • Obese Individuals: • Prevent health problems associated with obesity • high blood pressure, heart attack, arthritis, stroke, etc • Reduce WAT mass for both groups

13. Challenges to Face • Remaining Questions • Need to determine leptin’s role in other organ systems • More studies on humans • Mode of Administration • Studies show leptin is most affective when injected subcutaneously • Saftey • accessibility • More applicable methods such as inhalation are being looked into • Affect of Increasing Leptin Levels • Increase patients chance of getting Type II Diabetes • Leptin supresses insulins ability to slow down gluconeogenesis • This cause raised blood sugar levels • Potential for Abuse • Society is fixed on “thin is good” • Tendency to forget environmental factors that contribute to weight gain

14. Refrences • Caro, J. Leptin: From 1958 to the Present. Canadian Journal of Diabetes Care 1998; 18-23. • Dallongeville, J., etal. Leptin, a pleiotropic hormone: physiology, pharmacology, and strategies for discovery of leptin modulators. Journal of Medicinal Chemistry 1998; 5337-5352. • Friedman J, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998; 763-769. • Hwa, J., etal. Leptin increases energy expenditure and selectively promotes fat metabolism in ob/ob mice. American Journal of Physiology 1997; 1204-9. • Morton, N. Leptin Action in Intestinal Cells. The Journal of Biological Chemistry 1998; 26194-26201. • Wang, J., etal. A nutrient-sensing pathway regulates leptin gene expression in muscle and fat. Nature 1998; 684-688. • Zhou, YT., etal. Induction by leptin of uncoupling protein-2 and enzymes of fatty acid oxidation. Proceedings of the National Academy of Science of the USA 1997; 6386-90. • http://www.kumc.edu/biochemistry/bioc800/