Genetics play a significant role in obesity, accounting for 30-40% of cases. Twin studies show genetics have a strong influence on body mass index (BMI) with monozygotic twins having more similar BMIs than dizygotic twins. While single-gene defects cause rare cases of severe obesity, most common obesity is influenced by dozens to hundreds of genes interacting with environmental and behavioral factors. The roles of these genes are still being uncovered, but genetics are not destiny as lifestyle choices can counteract genetic effects, and not all carriers of obesity genes become overweight.

1. Genetic Factors

2. CAUSES OF OBESITY
 Genetics (30-40%)
 Environment (60-70%)
Pi_Sunyer X.The Obesity Epidemic: Pathophysiology and Consequences of Obesity, Obesity Research,
10:97s-104S (2002)

3. Genetics
 Twin studies: The heritability of human traits such as adiposity is
most robustly assessed by studies of monozygotic versus dizygotic twins.
The strong correlation for BMI between monozygotic twins and its
attenuation with lesser degrees of shared genes suggest a strong genetic
influence on BMI.
 Research:
 Energy Expenditure:
 Uncoupling proteins
 Appetite Regulation:
 Hormones
 Gastrointestinal Peptides
 Orexigenic Hypothalamus Neuropeptides
 Anorectic Hypothalamus Neuropeptides
Gumbiner, B. (2001). Obesity. Philadelphia, PA:American College of Physicians

4. Genetic Influences on Obesity
 Strong genetic influences on body weight
 ~ 40% of variation in BMI is explained by genetic
factors
 BMI is highly correlated among first-degree family
members
 Obese parents produce the highest proportion of
obese children
 Adoption studies suggest a stronger role for genetics
than environment for predicting future weight
 BMI of biologic parents is much more strongly correlated
with the adult weight of the adoptive child than is the BMI of
the adoptive parents

5. Genetics
 The search for human obesity genes began
several decades ago. The success of the Human
Genome Project have intensified the search. This
work has illuminated several genetic factors that
are responsible for very rare, single-gene forms
of obesity.
 Emerging research has also begun to identify
the genetic underpinnings of so-called
“common” obesity, which is influenced by
dozens, if not hundreds, of genes.

6. Genetics
 What’s increasingly clear from these early
findings is that genetic factors identified
so far make only a small contribution to
obesity risk—and that our genes are not
our destiny: Many people who carry these
so-called “obesity genes” do not become
overweight, and healthy lifestyles can
counteract these genetic effects.

7. Single-Gene Defects
 Only a few monogenic causes
of obesity have been described
in humans
 Melanocortin-4 receptor gene
(MC4R) mutations are the
most frequent single-gene
cause of obesity
 MC4 receptors are involved in
suppression of food intake by a-
melanocyte-stimulating hormone
 Deficiency of the MC4 receptor
leads to massive obesity in
humans
 Present in ~5% of persons with
severe obesity
9 y boy homozygous
for mutation in MC4R
16 y brother with
normal genotype
NEJM 2003;348:1085-1095
Mutations in the MC4R gene

8. Polygenic Interactions
 Obesity is a highly polygenic and complex
disorder resulting from the input of multiple
genes and additional interactions between genes
and environment and genes and behavior
 An additional 250 genes, markers and
chromosomal regions have been linked with
obesity
 Clinical importance of each association is not yet
known