Leptin: A Key Player In Weight Regulation

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Leptin A Key Player In Weight
Regulation

• By Molly Loban

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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

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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

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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

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How Does Leptin Interact?
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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

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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

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• 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

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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 intracerebroventricul
  ar 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

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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

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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

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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

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Challenges to Face

• Remaining Questions
• Need to determine leptins 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

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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/