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Leptin: A Key Player In Weight Regulation

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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 Mode of Administration
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; Dallongeville, J., etal. Leptin, a pleiotropic hormone: physiology, pharmacology, and strategies for discovery of leptin modulators. Journal of Medicinal Chemistry 1998; Friedman J, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998; Hwa, J., etal. Leptin increases energy expenditure and selectively promotes fat metabolism in ob/ob mice. American Journal of Physiology 1997; Morton, N. Leptin Action in Intestinal Cells. The Journal of Biological Chemistry 1998; Wang, J., etal. A nutrient-sensing pathway regulates leptin gene expression in muscle and fat. Nature 1998; 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;

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