Leptin: A Key Player In Weight Regulation
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
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
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
How 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 tissue
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
PPT Slide
- 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
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
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
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
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
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
- 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
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/