Weight Regulation and Genetics

Weight Regulation: Long-Term Factors and Genetics

• Today's focus: long-term factors in weight regulation and the role of genetics.
• Yesterday's focus: short-term factors.
• Key topics:
  • Dipostatic body weight regulation: the body's attempt to defend a specific weight.
  • Ideal properties of a dipostatic signal.
  • Leptin: a hormone produced by fat cells with receptors in the brain.
  • Reasons for the continued prevalence of obesity despite knowledge of weight regulation factors.

Genetic Component of Body Weight

• Evidence from adoption studies:
  • Compare body weight and composition of adopted children with both adoptive and biological parents.
  • Weak correlation between adopted children and adoptive parents.
  • Strong correlation between adopted children and biological parents.
• Twin studies:
  • Identical twins raised together are more similar in body weight and composition than fraternal twins raised together.
  • Identical twins raised apart exhibit similar trends.
• Genes vs. environment: a significant question in determining body weight factors.
  • Body mass index (BMI) is highly heritable: 1/2 to 2/3 due to genes.
  • Genetic inheritance plays a substantial role in body weight, comparable to dietary and cultural factors.

Genetic Factors Influencing Body Weight

• Environmental factors previously discussed: metabolic rate, exercise, food intake, and culture.
• Monogenic syndromes: single-gene defects leading to obesity (rare).
• Susceptibility genes: multiple genes predisposing individuals to being overweight depending on environmental conditions.

Case Study: The Pima

• Demonstrates the interaction between environment and genetic susceptibility.
• Seven hundred years ago, the Pima tribe split into two groups:
  • Arizona Pima: adopted a modern lifestyle with access to fast food.
  • Mexico Pima: maintained a traditional lifestyle in a mountainous region, farming and eating traditional foods.
• The Arizona Pima became increasingly obese with access to a Western diet.
• The Mexico Pima did not experience the same obesity issues.
• Arizona Pima are now one of the most obese populations globally.
• Statistics:
  • Average body weight: Arizona (90 kg), Mexico (64 kg).
  • BMI: Arizona (33), Mexico (25).
  • Type 2 diabetes: Arizona (54% males, 37% females), Mexico (6% males, 11% females).
• Distinct differences between the two populations:
  • Arizona: diet high in processed foods, fat, and refined sugar; low physical activity.
  • Mexico: diet high in complex carbohydrates, low in animal fat; high levels of daily physical activity.

Thrifty Phenotype

• Proposed concept: the Pima carry a thrifty phenotype—a genotype that allows them to extract nutrients from foods more efficiently and expend less energy.
• Advantageous in historical times of food shortages.
• Disadvantageous in modern times with easily digested, high-nutrient foods.
• Obesity Development:
  • Obesity arises from the combination of genetic susceptibility and environmental factors rather than genes alone.

Set Point Hypothesis

• The body aims to maintain a stable amount of fat.
• Animal studies: after forced weight gain or loss, animals return to their original starting weight when allowed to choose their own foods.
• Dipostatic body weight regulation: the body defends a usual amount of fat.
• Counter regulations: the body initiates counter regulations to return to expected fat levels after weight gain or loss.
• Requirements: a signal telling the brain and appetite center how much fat the body contains.
• Body fat signal and brain interaction:
  • Signal matches target: intake and expenditure are matched; no weight change.
  • Signal is higher than expected: the brain increases energy expenditure and reduces intake.
  • Signal is lower than expected: the brain increases intake and decreases energy expenditure.
• Weight regain after dieting:
  • Data from 16 studies: almost 100% of people regained initial weight lost after dieting within five years.
  • Even with liposuction, weight tends to be regained, often in different areas.
• Human set point for body weight:
  • Explains yo-yo dieting.
  • The body views weight loss as a problem and attempts to return to its original weight.

Feedback Signals and Ideal Properties

• Long-term regulation of appetite and body weight depends on signals from fat stores to the brain.
• Hypothesized properties for an ideal feedback signal:
  • Hormone secreted from fat cells.
  • Secretion proportional to fat stores.
  • Ability to cross the blood-brain barrier.
  • Receptors located in the brain.
  • The same impact on body weight regulation whether produced naturally or administered externally.

Feedback Loops

• Negative feedback loops: the most common type in regulating physiological systems, where the presence of something inhibits a particular pathway.
  • Example: central heating system: a thermostat set at a temperature switches off the heating system when the set point is reached.
• Brain and hypothalamus in appetite and energy expenditure control:
  • Signal required from adipose tissue through the blood-brain barrier to the hypothalamus, influencing fat in adipose tissue.

Discovery of Leptin

• Mice as models:
  • Specific mutation that led to the discovery of leptin.
  • The "OB" mutation for obese mice.
• Experiment with conjoined circulation:
  • Fat mouse with a lesion in the hypothalamus joined to a normal mouse.
  • The normal mouse became skinny, suggesting the fat mouse produced a circulating factor it couldn't respond to.
• Experiment with DB gene mutation:
  • Similar experiment with a mouse with a DB gene mutation instead of a hypothalamic lesion.
  • The same result, suggesting the mutation leads to an appetite signal production problem or a problem with the receptor.
• Experiment with OB mutation:
  • The obese mouse with the OB mutation lost weight and became a normal-sized mouse when conjoined to a normal mouse.
• Conclusions:
  • Mice lacking the DB gene make plenty of the negative feedback signal but can't respond to it.
  • The OB mouse can't produce the signal but can respond to it.
  • The OB gene encodes a particular negative feedback hormone, and the DB gene encodes a receptor for that hormone.

Ideal Properties of the Feedback Signal

• The OB gene should be expressed in adipocytes.
• It should circulate in the plasma and cross the blood-brain barrier.
• Plasma levels should increase in obese animals and decrease with weight loss.
• If injected, it should cause weight loss in OB mice and normal mice but have no effect on DB mice.

Leptin Discovery

• In 1995, it was discovered that fat cells produce leptin.
  • The OB gene is expressed in adipose tissue.
  • Leptin is secreted into the bloodstream in proportion to body fat.
  • Administering leptin to mice had huge effects on body weight.
  • The effect differed depending on the dose.

Ideal Feedback Signal Properties

• Leptin is a hormone secreted from fat cells.
  • Mutation of the OG gene leads to leptin deficiency and obesity.
• The amount of leptin secreted varies in proportion to fat stores.
  • The brain can understand the amount of fat.
• Leptin can be transported into the brain.
• DB receptors are located in the hypothalamus.
  • The DB mutation in mice stops leptin from binding to the receptors.
• Administering leptin externally causes obese mice to lose weight.

Leptin and Energy Expenditure

• Leptin's effect on energy expenditure:
  • Body temperature in normal mice and mice with the OB gene mutation.
• In normal mice, leptin has little effect on body temperature.
• In OB mice, leptin restores body temperature.
  • The OB gene mutation reduces body temperature.
• Similar effects with oxygen consumption (metabolic rate).
  • Leptin restores oxygen consumption in OB mice.
• Mice lacking leptin overeat and expend less energy.

Leptin and Neuropeptide Y

• Neuropeptide Y (NPY) in long-term regulation:
  • Stimulates food intake and suppresses energy expenditure.
  • Administration to the hypothalamus in rats leads to obesity.
• Leptin decreases the action of NPY:
  • Leptin and NPY interact to influence food intake and energy expenditure.
• Multiple interacting factors in obesity and appetite regulation.
• Impact of NPY gene removal:
  • An OB mouse with the NPY gene removed is thinner.

Leptin Pathway Diagram

• Pathway from adipose tissue to the hypothalamus:
  • Leptin interacts with the leptin receptor in the hypothalamus.
  • Initiates a negative feedback cycle:
    • Reduces food intake.
    • Increases metabolism and energy expenditure.
    • Reduces fat in adipose tissue, reducing leptin circulation.

Leptin Discoveries and Obesity

• Initial excitement: leptin was thought to be a miracle hormone solving obesity.
• Obesity Issues:
  • Most people do not have leptin deficiency.
  • Obese and overweight people have high circulating levels of leptin.

Explanations for Obesity Despite Leptin

• Possible explanations:
  • Leptin resistance: similar to insulin resistance in type 2 diabetes.
  • Problem with leptin's ability to cross the blood-brain barrier and signal the hypothalamus.
  • Defective leptin receptor, like in DB mice.
  • Breakdown in the signaling pathway.
• Ratio of leptin in serum relative to cerebrospinal fluid:
  • Cerebrospinal fluid shows whether leptin interacts with the hypothalamus.
• Leptin and Body Mass Index
  • As body mass index increases, serum leptin concentration increases.
  • Cerebrospinal fluid leptin also increases with body mass index but not as much as the serum.
• Ratio of Serum to Cerebrospinal Fluid Leptin:
  • Cerebrospinal fluid levels do not reflect plasma levels.
  • A lot of leptin is produced but not accessing the hypothalamus.
• Human Obesity:
  • Likely partially linked to insensitivity to leptin.

Leptin Insensitivity and Body Weight

• The main issue: entry of leptin into the cerebrospinal fluid.
• Leptin levels in cerebrospinal fluid plateau in obese humans.
  • A new set point for body weight is reached based on limited access to the hypothalamus.
  • It is unclear what governs this set point.
• Long-term weight changes:
  • Slow changes lead to setting a new set point.
  • Rapid changes result in leptin trying to return to the old set point.

Other Factors in Overweight Issues

• Research focuses on different relationships and leptin resistance.
• Weight Loss:
  • Weight loss results in a drop in plasma leptin, stimulating weight regain.
  • Diets often fail, particularly with quick weight loss.

Genetic Contributions to Obesity

• Human mutations in the OB gene are rare.
  • Other genes predispose people to obesity.
• Disease development:
  • Monogenic obesity: a specific aberrant gene leads to a specific phenotype.
    • Mutation of the OB or DB gene leads to obesity.
    • Rare.
  • Polygenic disease: multiple variant genes lead to different phenotypes and disease levels.
    • Strong genetic component, especially with body mass index (BMI).
    • Each susceptibility gene contributes a tiny proportion, making it difficult to determine all responsible genes and their interactions.

Monogenic vs. Polygenic Obesity

• Monogenic obesity: high contribution from specific genes, low from the environment.
• Polygenic obesity: interaction between genes and environment is crucial.
• Genome-wide association studies (GWAS):
  • Explain less than 5% of heritability in body weight.
  • Models using polygenic scores to predict obesity perform poorly.
• Prediction of Obesity:
  • Children predicted to be in the top 90% likelihood of developing obesity based on gene prevalence.
• Actual Outcomes:
  • Inaccurate Predictions: Many misclassified individuals.
    • Problems:
      • Models use polygenic scores to predict obesity, but perform poorly.
      • Need to improve models using polygenic scores to predict the likelihood of obesity in adulthood.

Future of Genetic Studies

• Ongoing Research and Progress:
  • More information is becoming available on genes contributing to obesity.
  • More computing power allows scanning the whole genome to see which genes are linked.
  • Models are expected to improve significantly in the future.