Regulation of food intake Flashcards
What is the definition of obesity?
What is BMI?
Obesity is defined as a state of body energy stores (body fat) that exceeds physiologic needs.
The degree of obesity is usually estimated by body mass index (BMI), correlates reasonably well with total body fat
BMI = weight (kg) / [height (m)]^2
25 - 30 = overweight
>=30 = obesity
What is an obesogenic envrionment?
An envrionment that makes us eat more:
- Increased food availability
- Increased portion size
An envrionment that makes us do less:
- Increased sedentary leisure time activities (TV, computers, video games)
- Decreased occupational physical activity
- Increased use of automobiles
What health risks are associated with obesity?
- Type 2 Diabetes (NIDDM)
- Cardiovascular Disease
-
- Hypertension
- Hyperlipidemia (high total cholesterol, low HDL, high LDL, high - Sleep-Breathing Abnormalities a. difficulty breathing b. obstructive apnea
- Gallstones
- Menstrual irregularity, difficulty getting pregnant
- Cancer (colon, endometrial)
What are the 2 complementary systems regulating energy balance/homeostasis?
- Homeostatic system
- When energy stores are depleted, you are hungry, you eat
- Similar as a thermostate, the more you are hungry, the more you eat
- controlled by 2 brain regions → Hypothalamus & Brainstem - Hedonic system
- Controlled by ventral tegmental area in the brain
- Can overwrite the homeostatic system
- Driven by pleasure (eat because you like it, because you are stressed, etc.)
What are the different region of the hypothalamus?
*Multiple nuclei
Dorsomedial Nucleus (DMN)
Ventromedial Nucleus (VMN)
Arcuate Nucleus (ARC)
3rd ventricle in the middle
What experiment 1st associated hypothalamus with obesity?
Brain lesion studies
Destruction of these areas → obesity:
- Paraventricular nucleus (PVN)
- Ventromedial nucleus (VMN)
- Dorsomedial nucleus (DMN)
Destruction/lesion → anorexia/weight loss:
- Lateral hypothalamis area (LHA)
What is a parabiosis experiment? What did it allow to study?
Study genetic causes of obesity → Parabiosis experiments:
- Surgical union of 2 individuals, so that they share a common circulation of the blood
- Connect ob/ob and db/db or with WT
- ob/ob x WT → weight gain of ob/ob mouse suppressed, WT stays normal
- db/db x wt → normal mouse slowly loses weight and dies from stavation, no change in db/db
- ob/ob x db/db → no change in db/db, but ob/ob mouse rapidly loses weight and dies from starvation
*Ob and db are 70-90 grams vs 25-35 grams for WT
Interpretation:
1. Circulating factor involved in energy balance regulation
2. Defects in ob/ob = signal (no leptin)
3. Defect in db/db = receptor for that signal (lack leptin receptor)
*ob/ob mice treated with leptin normalized their body weight
What is a use of leptin in human obesity treatment? What is a problem associated with this?
Leptin restores normal body mass in leptin deficient patients
- If treatment is interrupted, body weight starts going up again
Problem: majority of obese subject, already had high circulating leptin levels and were not responsive to leptin (leptin resistant) so doesn’t work in that case
What pathway does leptin act through?
- Binds to receptor
- Leptin receptor dimerizes → JAK2/STAT signaling pathways
- JAK auto-phosphorylates → STAT3 phosphorylated —> translocation to nucleus and act as TF
*STAT3 phosphorylation is an indicator that this cell is leptin-responsive
What is the arcuate nucleus?
- In bottom of the hypothalamus, under the 3rd ventricle
2 large populations of neurons:
1) NPY/AgRP neurons: - Orexinergic,
- Ghrelin receptor (activated yb ghrelin)
- Neuropeptide Y and AgRP produced by these neurons
- Inhibited by leptin
2) POMC neurons:
- Anorexinergic
- Activation leads to decreased food intake
- Activated by Leptin
Which 2 tools are used in the lab to understand better hypothalamic signaling?
- Neurosurgery (brain lesions)
- Immunohistochemistry → AgRP colocalizes with NPY but not POMC meaning that the same population of neurons express AgRP and NPY, but POMC is expressed by another population of neuron (non-overlapping)
- Genetic manipulation → Tissue/cell-type specific gene disrupting using Cre/loxP technique
- KO LeptinR specifically from neurons
What phenotype was seen in mice lacking the leptin receptor only in either POMC neurons or AgRP neurons (not all neurons?)
They developped mild obesity, but not as severe as when they KO leptinR from all neurons
- Same for KO in VMH neurons
Conclusion:
- Whole body LeprKO → Severe obesity (60-90 g)
- Brain-specific LeprKO → Severe obesity (60-90 g)
- Neuron type/specific-LeprKO → Mild obesity (30-45 g)
*LeptinR is expressed in different hypothalamus nuclei, but specifically in Arcuate nucleus
What type of neurons could they KO LepR from specifically to get the severe obesity phenotype?
KO from GABAergic neurons → severe obesity
The vast majority of leptin’s antiobesity effects are mediated by GABAergic neurons
What experimental method was used to answer the following question, what were the conclusions?
“Activation of AgRP neurons induces feeding?”
Imaging neuronal activity using a genetically encoded calcium indicator (GCaMP6, mutated GFP-Calmodulin peptide) → In the absence of calcium, the mutated cpGFP is poorly fluorescent. Ca2+ binding to the calmodulin moiety results in a structural shift that induces bright fluorescence form GFP
Animals are overnight fasted
When food is presented in the cage, before even eating, AgRP activity decrease
- when false food, activity decreases at 1st and then comes back to previous level
(initial decrease could be simply due to stress from entry of the food into the cage)
Conclusion: Food rapidly reduced activity of AgRP neurons
- Objects of non-nutritive value (false food: red line) failed to sustain decreased AgRP neuronal activity.
