Module 2.3

1. Genetic Factors II

2. Regulation of food intake
The regulation of food intake involves a complex interaction of systems that
determine the size, content, and frequency of feedings. Presumably, the brain
is the final processing center that translates central and peripheral signals to
initiate or stop feeding. Neuronal circuits have been identified in the
hypothalamus that affect satiation (level of fullness during a meal which
regulates the amount of food consumed) and satiety (level of hunger after a
meal is consumed which regulates the frequency of eating). Regulatory
mechanisms also must be present that integrate determinants of short-term
energy intake with long-term energy requirements.

3. Regulation of food intake
 The discovery of leptin, the protein product of the ob/ob gene, in 1995 [1]
led to a marked increase in our understanding of the regulation of food
intake. Leptin is produced by fat cells, released into the circulation, and it
crosses the blood-brain barrier to bind to its receptor in the hypothalamus,
which stimulates the expression of neuropeptides and neurotransmitters that
inhibit food intake. Therefore, leptin provides a unique feedback signaling
system that transmits information regarding adipose tissue energy stores to
the central nervous system. Other peripheral organs also communicate with
the brain about energy intake through neural signaling and endocrine
pathways.

4. Regulation of food intake
The gastrointestinal system, which is responsible for digesting and absorbing
ingested nutrients, is particularly involved. The gastrointestinal tract produces
cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), apolipoprotein A-IV
(apo A-IV), ghrelin, insulin, and glucose, which are likely involved in short-
term, and possibly long-term, regulation of food intake. Central neuropeptides
and neurotransmitter signals produced in hypothalamic nuclei stimulate 1)
neuropeptide Y (NPY), 2) agouti-related protein (AGRP), 3) galanin, 4) orexin-
A, and 5) dynorphin, or inhibit 1) a-melanocyte-stimulating hormone (a-MSH),
a peptide derived from proopiomelanocortin (POMC), 2) corticotropin-releasing
hormone/urocortin (CRH/UCN), 3) glucagon-like peptide-1 (GLP-1), 4) cocaine-
and amphetamine-regulated transcript (CART), 5) norepinephrine (NE), and 5)
serotonin (5-HT) [2

5. Regulation of food intake
There is a hierarchy in the relative importance,
magnitude, and duration of each afferent input,
and certain signals can override the effect of
others. The redundancy of these complex signaling
pathways tend to defend food intake and provides
a formidable barrier to treating obesity.
Therefore, a clear understanding of the factors
involved in regulating food intake has important
implications in designing therapeutic agents for
obesity management.

6. Regulation of Food Intake
Brain
NPY
AGRP
galanin
Orexin-A
dynorphin
Stimulate
α-MSH
CRH/UCN
GLP-I
CART
NE
5-HT
Inibit
Central Signals
Glucose
CCK, GLP-1,
Apo-A-IV
Vagal afferents
Insulin
Ghrelin
Leptin
Cortisol
Peripheral signals Peripheral organs
+


+
Gastrointestinal
tract
Adipose
tissue
Food
Intake
Adrenal glands
External factors
Emotions
Food characteristics
Lifestyle behaviors
Environmental cues

7. Storage of Macronutrients

8. Hormonal Control of Eating
Ghrelin (stomach): Made in
response to an empty stomach;
stimulates hunger and feeding.
PYY: Made in response to feeding;
induces satiety.
Leptin (fat cells): made in response
to increasing fat cell size; down
regulates the production of
appetite stimulating neuropeptides
(Neuropeptide Y and agouti related
protein) and upregulates the
anorexigenic factors like a-
melanocyte stimulating hormone
(a-MSH)
Insulin: made in response to
feeding; effects are similar to
Leptin
Genetic defects in these receptors is an
area of intense investigation (Leptin and
Melanocortin Receptors)
↑ appetite
↓ appetite

9. Hormonal Control of Eating
In the arcuate nucleus of the hypothalamus the leptin receptor is
expressed on at least two classes of neurons. One class expresses NPY
and AGRP, two neuropeptides that increase food intake. Another class
expresses POMC, the precursor of alpha-MSH which decreases food
intake.
Leptin suppresses the activity of NPY/AGRP neurons and increases the
activity of the POMC neurons.
In the absence of Leptin, the NPY neurons are stimulated and food
intake is stimulated.
IN the presence of leptin, POMC neurons are maximally active and food
intake is suppressed.

10. Uncoupling Proteins in Humans
Gumbiner, B. (2001). Obesity. Philadelphia, PA:American College of Physicians
 Location Activity
UCP-1 Brown fat Thermogenesis of
newborns
UCP-2 Most tissues ATP synthesis
Energy partitioning
UCP-3 Skeletal
muscle
ATP synthesis
Energy partitioning

11. Uncoupling Proteins: UCP-1
 The brown fat uncoupling protein has a well
established role in temperature regulation and
body weight regulation
 Increased activation of this protein results in the
conversation of energy to heat (thermogenesis)
 Adults were thought to have very low levels of
brown fat, thus UCP -1 did not appear to have a
significant role in obesity
Gumbiner, B. (2001). Obesity. Philadelphia, PA:American College of Physicians

12. New Evidence on Brown Fat
(BAT) Brown Adipose Tissue
 BAT was believed to show rapid involution in early childhood,
leaving only vestigial amounts in adults. However, recent evidence
suggests that its expression in adults is far more common than
previously appreciated, with a higher likelihood of detection in
women and leaner individuals. It is conceivable that BAT activity
might reduce the risk of developing obesity since fat stores are used
for thermogenesis, and a directed enhancement of adipocyte
metabolism might have value in weight reduction.
 However, it is as yet unclear how such manipulation of BAT might
be achieved; even in animal models, the control of thermogenic
activity is incompletely understood.
http://www.medscape.com/viewarticle/743247_1

13. Uncoupling Proteins: UCP-2,
UCP-3
 May be important in ATP synthesis in muscle
 My play a role in fatty acid oxidation
 Pharmacologic manipulation to activate or
increase the expression of UCP-2 and UCP-3
may have important effects on energy
expenditure
Gumbiner, B. (2001). Obesity. Philadelphia, PA:American College of Physicians

14. Hormones Regulating Appetite:
Leptin
 Leptin has many functions in carbohydrate, bone, and
reproductive metabolism that are still being unraveled,
but its role in body weight regulation is the main reason
it became popular.
 A cytokine derived primarily from fat cells
 Acts a signal generated by adipose tissue as part of an
energy feedback loop where it modulates a host of
functions that decreases food intake
 Circulating level of leptin are correlated with the level of
body fat
 A decrease in serum Leptin signals caloric intake
 A study using Leptin injections had a favorable effect on
weight loss with those with a Leptin deficiency
Heymsfield SB et al, Recumbant Leptin for weight loss in obese and lean adults: a randomized,
controlled, dose escallation trial. JAMA. 1999;282:1568-75.

15. Gastrointestinal Peptides
 Ghrelin
 Glucagon
 Peptide YY
 Cholecystokinin
Neary NM et al. (2004) Appetite Regulation: From the Gut to the Hypothalamus. Clin Endocrinology.
60(2):153-160

16. Ghrelin
 Polypeptide produced in the stomach that
increases intake.
 Levels of Ghrelin are decreased after
gastric by pass surgery
NEJM 346,1423 (02)

17. Peptide YY
 Member of the NPY (nueropeptide Y)
family and is secreted in the small and
large intestine
 Inhibits food intake
Neary NM et al. (2004) Appetite Regulation: From the Gut to the Hypothalamus. Clin Endocrinology.
60(2):153-160

18. Glucagon-like-peptide 1
 Co secreted with PYY in response to
nutrients in the the gut
 Plays an additional role in enhancing
insulin secretion and suppressing glucagon
secretion after a meal
 Inhibits food intake
Neary NM et al. (2004) Appetite Regulation: From the Gut to the Hypothalamus. Clin Endocrinology.
60(2):153-160

19. Cholecystokinin
 CCK was the first gut hormone to inhibit
feeding
 Also stimulates pancreatic enzyme
secretion and gallbladder contraction
 The combination of CCK and Leptin results
in greater feeding inhibition and weight
loss
Neary NM et al. (2004) Appetite Regulation: From the Gut to the Hypothalamus. Clin Endocrinology.
60(2):153-160

20. Orexigenic Hypothalamus
Neuropeptides
 NPY and Agouti-related protein (AgRP)
 NPY is a neuropeptide which is the most
potent orexigenic agents known
 Stimulates appetite
 Agouti-related protein (AgRP)
 Central administration leads to an increase in
food intake up to one week
 Both neurons are inhibited by leptin and insulin
Neary NM et al. (2004) Appetite Regulation: From the Gut to the Hypothalamus. Clin Endocrinology.
60(2):153-160

21. Anorectic Hypothalamus
Neuropeptides
 Melanocortins:
 Central administration inhibits feeding
 Thought to be critical in body weight
regulation
 Melanocortin receptor agonists are
currently being developed and potential
obesity treatments
Neary NM et al. (2004) Appetite Regulation: From the Gut to the Hypothalamus. Clin Endocrinology.
60(2):153-160

22. Examples of Genes Involved in
and Their Associated Phenotypes
Gene
Associated Phenotype
(Characteristic)
Leptin (hormore) Satiation, metabolism
Melanocortin (group of hormones) Feeding behavior, binge eating
Ghrelin (hormone) Appetite stimulation
Neuromedin β (peptide) Feeding behavior, satiety
PROP Taste preference
PPAR Fat metabolism
Mitochondrial uncoupling proteins Energy expenditure
Melanocortin and MC4R Energy expenditure
For detailed information about single-gene mutations and their association with obesity, see the Obesity Gene Map Database (9)
and CDC’s Obesity and Genetics: A Public Health Perspective (10).

23. Gene Variants
 A change in just one small section of the
DNA that encodes for a gene can make a
difference in the gene’s action.
 These tiny DNA variations, called "gene
variants" or "single-nucleotide
polymorphisms" (SNPs), are often related
to disease risk.
http://www.hsph.harvard.edu/obesity-prevention-source/obesity-causes/genes-and-obesity/

24. Gene Variants
 In 2007, identified the first obesity-related gene
variants for obesity, (FTO) gene on chromosome
16.
 The second obesity-associated gene variant that
researchers identified lies on chromosome 18,
close to the melanocortin-4 receptor gene.
 These gene variants are fairly common, and
people who carry one have a 20 to 30 percent
higher risk of obesity than people who do not.
http://www.hsph.harvard.edu/obesity-prevention-source/obesity-causes/genes-and-obesity/

25. Proopiomelanocortin (POMC) and alpha-
melanocyte-stimulating hormone (alpha-MSH)
 Both act centrally on the melanocortin receptor
4 (MC 4) to reduce dietary intake.
 Genetic defects in POMC production and
mutations in the MC4 gene are described as
monogenic causes of obesity in humans.
 Data suggest that as many as 5% of children
who are obese have MC4 or POMC mutations.
http://emedicine.medscape.com/article/123702-overview#a0104