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Where do adipocytes differentiate from?
Preadipocytes (immortal, continually dividing cells).
What are the differences between pre-adipocytes and adipocytes? (4)
- (1) Dividing vs. non-dividing
- (2) able to differentiate vs. terminally differentiable
- Adipocytes express different set of genes that :
- (3) facilitate storage of large amounts of TAG - 5% lipid vs. 99% lipid
- (4) Enhance production of adipokines
Can adipocytes be lost?
Yes - we lose a crtain number every year. It IS possible to go back to a baseline number of fat cells.
What enzymes/cytokines are needed to differentiate a preadipocyte to a mature adipocyte? Name a bunch.
- 1. LPL
- 2. GPAT
- 3. ACS
- 4. ACC
- 5. PPARgamma
- 6. Glut4
- 7. Leptin
- 8. Adiponectin
What generally happens to adipocytes in obesity? (2)
What happens to what these adipocytes secrete? (3)
Increased adipocyte differentiation and expansion.
In obesity, adipocytes --> larger and secrete more leptin & TNF-a and less adiponectin.
What is adiponectin?
What happens with less adiponectin? Biochemically - how?
When is adiponectin secretion reduced? (2) Increased?
An adipokine, but really a protein hormone.
Function: Increases liver production of glucose in post-absorptive state --> hyperglycemia.
Biochemically: Decreases hepatic GNG by suppressing gene transcription of G6Pase and PEPCK (by phosphorylating and activating AMPK).
In obese & insulin resistant individuals. Increased in weight-reduced patients (smaller adipocytes).
Where is TNF-a secreted from? What is it?(hormone, cytokine, etc)
How does it affect serum glucose levels? Through what mechanism? (2)
Suppresses insulin signal --> less glucose is removed from circulation by GLUT 4 --> hyperglycemia.
TNF-a activates kinase that p'lates and acivates SH-PTPase, which increases dephosphorylation of IRS tyrosines (blocking insulin signal)
Also, increases p'lation of IRS at serine - interfering with IRS docking and blocks insulin signaling!!
What are the 4 components of satiety signal criteria?
- 1. Must reduce size of meal
- 2. This reduction of size of meal then must be reversed upon application of receptor antagonist or if signal is removed
- 3. Signal must not result from illness/bad tasting food.
- 4. Secretion must be induced by eating & ingesting
Define orexigenic, anorexigenic, short-term, long-term
- Orexigenic: increases appetite and food intake
- Anorexigenic: decreases appetite & food intake
- Short-term: related to a single meal
- Long-term: related to multiple meals
What does the hypothalamus generally control? (2) How?
1. Regulates physiological functions: activity, endocrinological functions, intake of food & water.
2. Maintains homeostasis: receives info from peripheral tissues on external conditions (temp, energy) and institutes changes via hormone secretion to pituitary gland, controlling pituitary gland secretions.
Define lateral hypothalamus, ventro medial hypothalamus, paraventricular nucleus, and arcuate nucleus.
LH - appetite center - responsible for meal initiation. Destruction results in starvation.
VMH - Satiety center. Destruction results in hyperphagia (overeating)
PVN - site of action for neuropeptides important for feeding
AN - site of action for neuropeptides important for feeding
What were characteristics of the ob/ob mouse? 5
- 1. Increased food intake
- 2. Sexual immaturity (infertile)
- 3. Low body temp (low basal metabolic rate)
- 4. Increased adipose stores
- 5. Decreased activity
What happened in the parabiosed experiments? What was the purpose of parabiosing the mice? What were the final interpretations?
- 1. Ob/ob + WT - ob/ob decreased food intake and lost weight
- 2. Db/db + WT - stopped eating and lost weight and died, while db/dbcontinued to eat and gain weight.
- 3. Db/db + ob/ob - Ob/ob ate less and lost weight, but db/db continued to eat and gain weight.
Interpretations: Db/db's hypothalamus receptors could not recognize leptin. When parabiosed with ob/ob mouse (w/ working leptin receptors) leptin could bind & intake was reduced for ob/ob mouse - not db/db.
What type of biological molecule is leptin?
What is its most general role?
What happens to leptin secretion and food intake during lipolysis? TAG synthesis?
- Peptide hormone.
- Long-term regulator of satiety
- Small: less leptin secretion & more food intake.
- Large: more leptin secretion & less food intake.
How does leptin interact with neurons? Are leptin levels in obese people high or low? Why?
Leptin lowers activity of NPY neurons (which activate MCH neurons - increased food intake) and increases activity of POMC neuron (which inhibit MCH neurons - decreased food intake).
High. Because they are eating a lot despite high leptin levels - must be leptin resistant.
Can leptin be given orally? Does administering leptin to obese people help them lose weight? How do NPY and POMC neurons work on MCH neurons? How does leptin affect appetite?
No, bc it's a peptide hormone. Must be given via IV.
No, because they already have levels of leptin - the issue is the problem with the leptin receptor in the hypothalamus.
via G-coupled protein receptor. NPY neurons stimulate appetite, POMC neurons decrease appetite.
Leptin inhibits NPY neurons and activates POMC neurons.
What happens when MCH is injected into brain? Is MCH orexigenic or anorexigenic? What happens to MC4-R knockout mice? What about MCH gene knockout mice?
When MCH is injected into brain, food intake increases.
It is orexigenic
In MC4-R knockout mice, hyperphagia and obesity occur, bc a-MSH secreted from POMC to decrease appetite cannot connect to MCH.
In MCH knockout mice, animals ate less and weighed less than controls.
How does insulin impact food intake?
Also another peripherally produced circulating protein that decreases food intake by decreasing NPY synthesis. Does NOT mediate glucose uptake in brain.
How does ghrelin affect food intake? How does injection of ghrelin into cereobroventricular fluid affect intake and weight?
Ghrelin (orexigen produced by stomach before meals & decreases after).
STIMULATES NPY neurons. Short-term feedback to brain to terminate or initiate food intake. They interact in brain with long-term regulators like leptin.
Injection results in increased food intake and increased weight.
Summarize the roles of MCH, leptin, insulin, and ghrelin on MCH neurons, NPY neurons, and POMC neurons.
- 1. MCH - stimulates food intake
- 2. Leptin & insulin - circulate in proportion to body adiposity: activate POMC neurons, inhibit NPY neurons, and inhibits food intake and promotes weight loss.
- 3. Ghrelin - peptide hormone secreted by stomach endocrine cells that stimulates NPY hormones promoting weight gain.
What happens to insulin, leptin, and ghrelin levels in voluntary weight loss?
During voluntary weight loss, insulin and leptin decrease while ghrelin levels increase, activating NPY neurons and inhibiting POMC neurons to activate MCH neurons.
Why are mice infertile if they can't make leptin? Are most obese people leptin-deficient?
Because leptin helps stimulate release of FSH and LH - integral hormones for fertility.
What signals converge on brain to influence energy homeostasis? 4 types
Satiation signals (CCK, GLP-1, gastric distension)
Adiposity signals - hormones whose secretion is proportional to body fat, stimulating AN (Arcuate nucleus).
External signals (learning, stress, social situations, time of day, hedonics)
What are examples of distal, intermediate and proximal satiation signals?
Rank in terms of degree of reliability with regard to calories?
Rank in terms of occurrence during a meal?
- Distal: sight, smell, taste, mouth feel, viscosity
- Intermediate: Gastric filling, CCK, GLP1, PYY, Amylin, Glucagon
- Proximal: Local levels of nutrients (glucose, lipids, AA or else their acute consequences of metabolism)
Distal < Intermediate < Proximal for all of them.
What happens during a meal? (4)
1. During meals, singals CCK, GLP-1, gastric distension trigger nerve impulses in sensory nerves in hindbrain and influence meal size.
2. Ghrelin from stomach acts on vagus nerve adn stimulates neurons in AN directly.
3. Adiposity signals (leptin & insulin) go to brain and interact with NPY/POMC neurons.
4. ARC neurons affect PVN and LHA - PVN is catabolic and enhances satiation signals while LHA is anabolic suppressing satiation keeping fat constant over long intervals via changes in meal size.
For reference: how signals integrate and affect blood glucose and food intake.
What is CCK? How does it influence uptake? Meals vs. calories
Where is it produced? In response to what? (2)
How does CCK communicate to brain? How does insulin affect CCK? What levels do bulimics have in their brain and how is this restored?
CCK is a short-term satiety factor.
It suppresses intake by reducing the size of a meal, but cannot regulate overall calories eaten.
Produced in duodenum in respones to lipids and proteins.
How do signals from NPY affect food intake? Where is it synthesized (___ of the ___)? Where is it released to interact with receptors (____ of ____)?
What is its role in food intake? How does it affect energy expendituer?
NPY signals incrase food intake. Synthesized in the AN of the VMH and released to interact with receptors in the PVN of the LH.
It is a long-term regulator of food intake. It decreases energy expenditure - an adaptive response to chronic caloric deprivation.
MSH - What neuron is it secreted from? How does it affect appetite and food intake? Who does it bind to and what does it do? Is this found in obese people?
What willhappen if MC4- receptors are defective or absent?
MSH is secreted from POMC neurons. It binds with MC4-R and inhibits appetite and food intake (blocks orexigenic effect).
Hyperphagia and weight gain.
Yes 2-3% of obese people have MC4-R deficiency. And will have red hair.
Which two deficiencies lead to incredibly weight gain?
ACTH and MC4-R deficiencies.
What 3 neurotransmitters control food intake and houw?
Dopamine and NE: tyrosine --> dopamine/NE. Dopamine decreases food intake, while NE stimulates catecholamines and suppresses appetite cravinsg.
Serotonin (tryptophan --> serotonin) --> SSRIs can be used to treat obesity, increasing the amount of serotonin in synaptic space. They exert an anorectic effect by suppressing appetite and stimulating satiety.