Genetic Factors II

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.


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.


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


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.

Regulation of Food Intake

Brain

NPYAGRPgalanin

Orexin-Adynorphin

Stimulateα-MSHCRH/UCNGLP-I

CARTNE5-HT

InibitCentral Signals

GlucoseCCK, GLP-1,Apo-A-IVVagal afferentsInsulinGhrelin

Leptin

Cortisol

Peripheral signals Peripheral organs

+

+

Gastrointestinaltract

Adiposetissue

FoodIntake

Adrenal glands

External factorsEmotionsFood characteristicsLifestyle behaviorsEnvironmental cues

Storage of Macronutrients

Hormonal Control of EatingGhrelin (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

Hormonal Control of EatingIn 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.

Uncoupling Proteins in HumansGumbiner, B. (2001). Obesity. Philadelphia, PA:American College of Physicians

Location Activity

UCP-1 Brown fat Thermogenesis of newborns

UCP-2 Most tissues ATP synthesisEnergy partitioning

UCP-3 Skeletal muscle

ATP synthesisEnergy partitioning

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

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

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

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.

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

Ghrelin Polypeptide produced in the stomach

that increases intake. Levels of Ghrelin are decreased after

gastric by pass surgery

NEJM 346,1423 (02)

Peptide YY Member of the NPY (nueropeptide Y)

family and is secreted in the small and large intestine

Inhibits food intake


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


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


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

insulinNeary NM et al. (2004) Appetite Regulation: From the Gut to the Hypothalamus. Clin

Endocrinology. 60(2):153-160

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


Examples of Genes Involved in and Their Associated Phenotypes

GeneAssociated Phenotype (Characteristic)

Leptin (hormore) Satiation, metabolismMelanocortin (group of hormones) Feeding behavior, binge eatingGhrelin (hormone) Appetite stimulationNeuromedin β (peptide) Feeding behavior, satietyPROP Taste preferencePPAR Fat metabolismMitochondrial uncoupling proteins Energy expenditureMelanocortin 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).

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/

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/

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

Genetic Factors II

Health & Medicine

Transcript of Genetic Factors II