Transcript Leptin: A Key Player In Weight Regulation

Leptin: A Key Player In Weight
Regulation
By Molly Loban
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
• Carnitine acyl transferase I, which is normally inhibited by malonylCoA, 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 1520% 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
• 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
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; 12049.
• 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/