2Obesity - Obesity and Diabetes (continued) Flashcards
How do satiety signals play a role in the control of food intake?
Once eating has begun, food interacts with receptors on the tongue, oropharynx, stomach and duodenum, as well as the liver and other organs.
The detection, processing and absorption of food generate satiety signals that provide negative feedback to the central nervous system.
Vast majority of responses are CNS-mediated (ie non-hormonal); vagal nerve from gut to brain carries satiety signals.
These signals accumulate and interact to bring an end to the meal.
The signals reach the brain through visceral afferent (vagal) nerve fibres and through the blood (cross the blood-brain barrier - ie hormonal).
What is leptin?
Many hormones which regulate energy balance are described as “satiety signals”. This can be misleading - Leptin regulates energy balance but does not cause cessation in feeding due to feeling full - works in a different way.
Leptin - name derived from Leptos = “thin” in Greek
How was leptin discovered?
In 1950, Ob mouse was identified = spontaneous mutation causing affected mice to be grossly obese.
By 1953, the lipostatic theory of body weight control had been proposed = reduction in energy intake in correlation with storage of lipids in adipose tissue.
In 1958, hormonal action on the hypothalamus to regulate body weight was discovered = discovered through ablation of parts of brain.
In 1994, gene defect in Ob mice was discovered and cloned = Leptin discovered.
In 1995, Leptin receptor cloned.
What is the leptin story with regards to its clinical trial efficacy?
Leptin discovered by Friedman in 1994. 2 week trial found that injecting Leptin into normal mice decreased feeding.
Amgen bought the rights to use Leptin as a weight loss product on the back of this trial.
Leptin is part of chronic control of body weight - over an extended period treatment with Leptin has no effect on normal individuals. It will however have an effect on Leptin-deficient individuals.
Leptin does not work as a treatment for weight loss in non-leptin deficient individuals
What evidence is there for leptin deficiency in humans?
A case study of a young girl with a congenital leptin deficiency shows the power of leptin signalling in humans = she was treated with leptin and her weight fell rapidly
How do leptin concentrations change with increasing adipose tissue mass?
Obese people will have higher amounts of leptin in blood
Makes sense with regards to lipostatic theory of body weight control - as body fat mass increases, production of hormone which suppresses feeding increases
Should suppress appetite = doesn’t always work - why not?
Hyperleptinaemia = very high levels of leptin in blood, still obese, still taking in many calories
Not able to prevent obesity but in the absence of leptin, obesity will occur
Describe leptin as a protein.
167 amino acid peptide - found as a 16kDa hormone in the circulation
Synthesised mainly by the adipocytes
Circulating levels correlate with body fat mass, in particular they are elevated in obese humans
Levels fall after weight loss (acutely controlled by energy balance not weight loss) = obese person on low cal diet will feel starving because leptin is controlled by energy balance = as soon as you reach negative energy balance, leading to a drive to eat despite large degree of adiposity
Does NOT cause cessation of a meal - not increased acutely after feeding = not in response to food intake = chronic control of energy balance
Functions in the long term and influences quantity of food consumed relative to the amount of energy expended
How does leptin play a role in the regulation of energy balance?
Negative energy balance leptin levels fall, positive energy balance high levels of leptin
Leptin alone cannot prevent obesity = will not stop person from eating
Absence of leptin alone will cause obesity via extreme hunger
We have not evolved a system to prevent us from eating
Penalty for not feeding during evolution = death, no need to develop system to prevent obesity as hardly ever happened
Evolved to live in a world where food was scarce rather than plentiful
How is leptin sensed in the body?
Deficiency associated with massive obesity in mice and humans
Administration to deficient animals or overexpression in transgenic mice reduces body fat in a dose-related manner
Leptin reduces food intake and increases activity of sympathetic nervous system
Acts via Ob-Rb receptor mainly in the hypothalamus
Absence of receptor also leads to obesity
What is the leptin receptor?
There are 5 leptin receptor isoforms (LRa-e):
LRa = lacks intracellular domain and is highly abundantly expressed in brain capillary endothelium and peripheral organs and proposed to mediate leptin transport (across endothelial barriers) = responsible for transport of leptin across the blood-brain barrier usually in concert with action of insulin - insulin helps leptin to cross the blood-brain barrier
MOST IMPORTANT = LRb = is restricted to the hypothalamus, brainstem and key regions of the brain that control feeding, metabolism and neuroendocrine systems. This receptor signals into the cell.
What is leptin resistance?
Transport of leptin across the blood-brain barrier is saturable = get no more leptin crossing
In the periphery, there may be leptin resistance.
How does leptin signal?
LepRB exists as homodimer or with a co-receptor as a heterodimer
Interacts with JAK2 = JAK/STAT signalling
JAK = Janus Kinase
STAT = Signal transducer and activator of transcription = signalling pathway where signalling molecule binds to a receptor = affects genes being switched on in the nucleus
Leptin binding causes 3 phosphorylation events on the LepRB receptor
Phosphorylation caused by conformational change to LepRB leading to JAK2 phosphorylating 3 tyrosine residues = allows interaction with STAT proteins
How does JAK2 mediated STAT3 phosphorylation and translocation to the nucleus work?
Activation of STAT3 is one of the most important consequences of phosphorylation by JAK2
STAT3 = transcription factor which exists in cytoplasm = leptin receptor phosphorylated, STAT3 recruited = STAT3 phosphorylated - causing it to become a homodimer = this allows it to enter the nucleus where it can switch on gene transcription
STAT3 switches on synthesis of neuropeptides = act in hypothalamus to drive hunger signal in the absence of leptin or in presence of leptin to damp down appetite
SOCS3 (silencing of cytokine signalling 3) = negative feedback loop = goes back and inhibits the leptin signal = switches of leptin receptor
Negative feedback loops exist in nearly all receptor signalling pathways so that signalling only occurs for as long as the signal is there
Also erk signalling = not going to go into this in depth
Leptin signalling also activates IRS/PI3 kinase pathway & neuropeptide synthesis = play majoral role in regulating body weight and energy intake
What is the interplay between leptin and the neuronal circuit regulating weight control?
Enter CNS via receptor-mediated saturable process across brain capillary endothelial cells Acts on hypothalamic nuclei that express neuropeptides and neurotransmitters that regulate food intake/body weight Leptin stimulates proopiomelanocortin (POMC) neurons and inhibits neuropeptide Y (NPY) neurons = dual effect POMC = neuropeptide with anorectic signal = reduction in food intake NPY = neuropeptide with orectic signal = increase in food intake Inhibits anabolic (NPY) pathways and stimulates catabolic (POMC) pathways
How does STAT3 affect POMC and AgRP expression?
Without leptin:
In a POMC neuron = closed chromatin conformation = no transcription
NPY/AgRP/GABA neuron = open chromatin conformation = transcription
Increased feeding
With leptin:
STAT3 signal transduction cascade = STAT3 enters nucleus = binds to POMC neuron in promoter region = opens up chromatin = switches on expression = acts directly as a transcription factor for POMC = elevated levels of POMC = subsequent downstream effects on hypothalamus
(Possibly) STAT3 binding to NPY/AgRP/GABA inhibits transcription
Reduced feeding
