32. Appetite Regulation Flashcards
What regulates feeding via a multitude of inputs?
What is the arcuate nucleus?
What are the 2 systems associated with it?
Hypothalamus - integrates peripheral satiety signals. Influences pituitary function, feeding, stress response, water balance, sleep-wake cycle, thermoregulation
Main centre for appetite regulation in the hypothalamus.
1) Based on neuropeptide Y (NPY) and AGRP (agouti-related peptide) neurons
2) Based on POMC (pro-opiomelanocortin) and CART (cocaine-related transcript) neurons
* Balance between these 2 systems: hungry or not*
What does the agouti gene control? Where is it found?
What is the phenotype of a mouse with an agouti mutation?
List the substances that are:
a) orexigenic (appetite stimulating)
b) anorexigenic (appetite inhibiting)
Mice hair colour - but also involved in neurotransmission. AgRP found in hypothalamus co-current with cells producing NPY. Acts as melanocortin receptor antagonist (POMC). High insulin drops AgRP levels (inversely connected).
Fat b/c has unquenchable appetite - never feels full b/c gene is overreacting.
a) NPY, ArGP, MCH
b) POMC, CART
What does POMC do?
What do POMC deficient mice (and humans) develop?
What is alpha-melanocyte-stimulating hormone (alpha-MSH)?
What does deletion of MC4R in mice and humans result in?
(Proopiomelanocortin) undergoes posttranslational modification to generate melanocortins which bind to melanocortin receptors e.g. MCR4 -> supresses appetite. Plays critical role in feeding behviour.
Hyperphagia and obesity (b/c nothing telling them to stop eating)
The predominant POMC-derived product controlling energy balance
Severe hyperphagic obesity. MC4R mutation found in 4-5% severly obese
How is serotonin (5HT) linked to appetite?
List some gut peptides that regulate appetite?
Anorexogenic molecule acting through 2 receptors, HTr1b and Htr2c which interact with ARC. They interact to increase signalling from POMC neurone (HTr2C) and to decrease AgTP neuron signalling (HTr1b)
Cholecystokinin, ghrelin, insulin and glucagon, GLP-1, PYY3-36
How does ghrelin behave over the day?
How does it behave during weight loss?
Where is ghrelin secreted and where are its receptors found? Thus what does ghrelin do?
Have breakfast and goes down, then gradually rises until you eat lunch etc. Linked to hunger.
The more weight lost, the higher the amount of ghrelin they had.
Secreted in stomach, receptors on NPY neurons, stimulates NPY thus increasing food intake both directly and via vagus nerve to arcuate nucleus
What does PYY 3-36 do? Where is it produced?
What does GLP-1 do? Where is it produced?
Inhibits food intake. Produced in intestine, measures whether food in gut, if full = PPY to hypothalamus and inhibits NPY neurons (via Y2 receptor) and stimulates POMC neurons
Glucagon like peptide, released by L cells in gut lining, inhibits NPY and stimulates POMC. Potential T2 diabetes treatment?
What is cholecystokinin? Where is it produced?
What is leptin? What are the 2 genetic defects identified?
What is the phenotype of ob/ob and db/db mice?
Secreted from I-type enteroendocrine cells in duodenum and small intestine, supresses appetite, mutations in CCK receptor in rats = obesity, appetite for fat-based diet.
Hormone secreted mainly by adipose tissue (fat cells). Thus appetite linked to amount of fat we have stored.
1) Defective leptin (ob) -> overweight mouse
2) Defective receptor (db) -> overweight mouse
Obese, increased appetite, diabetes, hyperlipidaemia, hypertension, hypothemia, infertility, overexpression of orexigenics and decresed expression of POMC
Briefly describe parabiosis experiments using leptin.
What is the relationship of serum leptin to body fat?
What is the circadian rhythm of leptin like?
What happens to leptin levels when you fast?
Join two mice, observe results (db = no receptor, ob = no leptin, WT = wild type)(PIC)
Correlation - signals to stop eating as body fat accumulates. Logarithmic relationship
Falls overnight and generally increases throughout day to fall at night again. Varies relating to adipose tissue and how full it is
Drop
There are lots of leptin receptors in the body. Name an important one of apetite regulation in the hypothalamus.
How is leptin linked to insulin? What do they both do?
Rb - often intracellular part that’s missing. Single point mutation can render receptor inactive and unable to respond to leptin.
Downstream responses of leptin receptor feed into downstream responses of insulin receptor via PI3K system. Similar paths activated by both leptin and insulin. Both drop AgRP levels and increase CART paths. (One measures fat and the other sugar). AgRP increased in ob/ob and db/db
N.B: Beneficial effects of daily subcutaneous injections of leptin reducing body weight and fat mass in congenitally leptin deficient children. Major effect = no hyperphagia
Why can’t we use subcutaneous leptin injections as a general treatment for obesity?
Why does the hypothalamus express different enzymes involved in FA metabolism despite the fact that FA are not a major fuel source for this tissue?
Bodies show leptin resistance so despite changing blood levels, levels in brain don’t seem to change much once reach a certain point = ignores leptins singal. (Overweight people already have high leptin levels and the brain is ignoring it). Only treats those with defects in leptin receptor or leptin.
Malonyl CoA (FA metabolism) is potent controller of appetite - imp for controlling switch between fat synthesis and breakdown! Level controlled by AMPK which relates it to AMP/ATP ratio. Can also be Ca2+ regulated (ghrelin). Control via phosphorylation of the synthesis enzyme. In brain receptors similar to carnitinne shuttle which MCoA binds to and supresses appetite.
How does malonyl CoA suppress appetite?
What happens in hunger?
Why are gut microbiomes important in obesity?
Fullness = lots of glucose = lots of ACoA -> citrate. Lots of citrate -> back to cytoplasm, converted to ACoA b/c can’t transport across mit membrane -> converted to malonyl CoA -> high malonyl CoA affects POMC and NPY neurons -> suppresses appetite.
Less fuel from periphery -> ACoA levels fall -> levels in cytoplasm drop -> ACoA carboxylase inactive -> stimulates feeding
Different gut microbiomes between obese and lean. Obese MB can make lean mice obese and change appeite regulation. BUT reverse didn’t work. Antibiotics change MB.
What theraputics increase appetite?
What therapeutics decrease appetite?
Cannabinoids. High expression of CB1 receptors in hypothalamus. CB1 activity in the hunger centres increases food palatability.
Amphetamine and SSRI derivatives (NA and 5-HT), cannabinoid antagonists, GLP-1 agonists (currently most sucessful)
