Leptin: A Key Player In Weight RegulationImportance of Finding TreatmentWhat is Leptin?White Adipose Tissue (WAT)How Does Leptin Interact?Regulating Food Intake and Energy ExpenditureMetabolic Affects of LeptinSlide 8Experimentation on MiceExperimentation on HumansPossible Reasons For Increased Leptin In Obese IndividualsFuture Treatment in Weight RegulationChallenges to FaceRefrencesLeptin: A Key Player In Weight Regulation By Molly LobanImportance 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 processWhat 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 tissueWhite 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 obesityHow Does Leptin Interact?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 tissueMetabolic 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•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 inhibitedExperimentation 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 lostExperimentation 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 levelsPossible 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 starvationFuture 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 groupsChallenges 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