Flashcards
Leptin
Cards in this deck (29)
- 1Describe leptinmember of the cytokine family, 146 aa long, made & secreted
from adipocytes
circulates in proportion to body adiposity
specific transport system for leptin to enter brain
high levels of leptin receptors (Ob-Rb) expressed on arcuate
nucleus (ARC) hypothalamic neurons
icv leptin inhibits food intake and decreases body weight of
rodents
neuron specific deletion of the leptin receptor (Ob-Rb) results
in obesity - 2What are the biological roles of leptin?A PLEIOTROPIC HORMONE
Food intake/energy expenditure/fat deposition
Peripheral glucose homeostasis/insulin sensitivity
Maintenance of immune system
Maintenance of reproductive system
Angiogenesis
Tumourigenesis
Bone formation - 3Describe insulincirculates in proportion to body adiposity
transport system for insulin to enter brain
high levels of insulin receptors expressed in hypothalamus
most notably in the arcuate nucleus (ARC)
intracerebroventricular (icv) insulin inhibits food intake and
decreases body weight of rodents
neuron specific deletion of the insulin receptor results
in obesity
NB. Peripheral actions of insulin are opposite - anabolic - 4Describe neuropeptide Y (NPY)NPY - a 36 aa peptide; one of the most abundant in the human brain.
Significant number of NPY-containing neurons in the ARC
Injection of NPY into hypothalamus potently stimulates food
intake and reduces energy expenditure
Repeated administration of NPY leads to obesity.
NPY receptor antagonists attenuate feeding, reduce obesity
Mice lacking NPY receptor subtypes, Y1 or Y5 pre-disposed
to obesity. - 5Describe Melanocortins - a-MSHaMSH - alpha melanocyte-stimulating hormone a non-opioid
peptide encoded by the proopiomelanocortin (POMC) gene
POMC gene expression is reduced on fasting and increased
following attainment of a positive energy balance
aMSH levels are high in the hypothalamus and this peptide
inhibits food intake.
Melanocortin receptor subtypes - MC-3 & MC-4 are mainly
expressed in brain. Synthetic agonists and antagonists to
these suppress and enhance food intake respectively.
Deletion of MC-4 or MC-3 receptor produces obesity in mice. - 6Describe the Ay mouse featuresAy - yellow mouse mutant (lethal in homozygotes)
Heterozygotes - yellow coat colour
increased growth
and obese
hyperglycaemic
insulin resistant
leptin resistant - 7Describe AgoutiAy gene encodes a small protein - AGOUTI - natural
antagonist of the melanocortin 1 (MC-1) receptor in
melanocytes - responsible for hair colour
Mutation results in gene rearrangement causing
ubiquitous ectopic expression
Agouti also an antagonist at hypothalamic MC-4 receptors
Aberrant hypothalamic MC-4 antagonism the cause of Ay
obesity - 8Describe Agouti-related protein (AgRP)Agouti - abnormally expressed in brain mimics the
homolog neuropeptide - agouti-related protein
AgRP - is co-expressed with NPY in ARC neurones.
Agouti and AgRP are antagonists to MC-3 & MC-4
receptors.
icv AgRP causes long-lasting increased food intake. - 9Describe the fa/fa mousefa gene - Zucker (fa/fa) strain of rats has point mutation at
position 269 (Q269P) of Ob-R - results on obesity.
fa mutation (all forms of Ob-R) results in leptin insensitivity - 10Describe the fat mutation mousefat mutation - point mutation in carboxypeptidase E (CPE),
enzyme partly responsible for cleavage of POMC, generating aMSH
fat mice develop massive obesity
mutation causes CPE inactivation, with resultant missorting and unregulated secretion of POMC - 11Describe the tubby mutation mousetubby - obese mouse- produces a truncated protein – good
model for adult onset obesity (expressed in hypothalamic areas
associated with control of energy homeostasis) - alters lifespan
CHO metabolism and fat storage – a transcription factor. - 12Describe human obesity genesMonogenic causes for human obesity are generally rare.
Ob mutations extremely rare - humans without detectable leptin
identified - massively obese - recombinant leptin effective treatment
Leptin receptor (db) mutation (truncated receptor) reported
Loss of function POMC mutations (absence of aMSH and ACTH)
No CPE mutations, but deficiency in prohormone convertase 1
(PC1) another POMC processing enzyme linked to obesity
A much more common cause of human obesity (up to 4%) due to
mutations in MC4-R - most affected humans have a single mutant
allele resulting in reduced signalling.
However the vast majority of human obesity is presently of unknown
origin (recent studies indicate multiple genes may contribute) - 13Describe leptin therapyRecombinant leptin works in ‘ob’ humans
Daily sc injections of leptin @ 10% of predicted serum concentration
Vast majority of human obesity characterized by high leptin levels (correlates with high fat level)
Use of leptin therapeutically is limited by severe leptin resistance present in most obese individuals - 14How does diet-induced obesity result in leptin resistance?Defective leptin transport into brain
Altered signal transduction following leptin
binding to its receptor - 15What signalling pathways does the leptin receptor utilise and how do they contributes to leptin's actions?Leptin receptor utilises multiple signalling pathways for outputs
JAK2-STAT3 – alters transcription – e.g. POMC and SOCS3
IRS-PI3K – alters transcription and electrical activity of neurons
ERK and AMPK – also contribute to leptin signals
These pathways contribute to leptin’s actions and modulate:
Food intake and energy expenditure
Peripheral glucose homeostasis (and insulin sensitivity)
Immune and reproductive function - 16How do leptin and insulin relate to PI3-kinase?Both hormones activate PI3-kinase in hypothalamic
neurons
Inhibitors of PI3-kinase prevent leptin and insulin actions in ARC - reduction in food intake ablated
IRS-2 knockout mouse displays neuronal resistance to leptin
and insulin (PI3-kinase activity)
PTP-1B knock-out mouse - resistant to diet induced obesity
and diabetes
PTP-1B - an enzyme that curtails leptin and insulin signalling
in the hypothalamus. PTP-1B levels are raised in obesity - 17Describe SOCS3Suppressor of cytokine signalling (SOCS) family of intra-
cellular proteins -inhibit JAK-STAT signalling
SOCS3 - a STAT3-regulated gene - binds to Ob-Rb and
prevents leptin-mediated signalling
Resistance to leptin associated with induction of SOCS3
in hypothalamus
SOCS3 levels elevated in rodent models of obesity -
suggested to be mediator of leptin resistance
SOCS3 also negatively regulates insulin signalling through
reduced IRS-mediated signalling - 18What factors contribute to hypothalamic resistance?SHP2 – protein phosphatase and adapter protein for
leptin and insulin receptor signalling (no SHP-2 –
obesity and leptin resistance)
Hyperleptinemia – driven by HFD – if decrease [leptin]
in circulation restore hypothalamic leptin sensitivity
ER Stress – hypothalamus – associated with loss of
leptin sensitivity
Inflammation – HFD promotes chronic low grade
inflammation of tissues, including hypothalamus - 19Describe noradrenergics as a treatment for obesityDiethylpropion* (Tenuate)
Mazindol*
Phentermine (USA not UK)
Appetite suppressants acting to inhibit noradrenaline uptake. Reports of cardiovascular side-effects. Phentermine approved for short-term use in USA - 20Describe serotonergics as a treatment for obesityFenfluramine*
Dexfenfluramine*
Fluoxetine*
Appetite suppressants acting on 5-HT system (uptake,release). Fenfluramine and Dexfenfluramine no longer used - induced heart disease. Fluoxetine effects on weight modest and weight returned.
* No longer prescribed in USA/UK - 21Describe Fen-Phen as a treatment for obesityFen-Phen: combination of fenfluramine and phentermine – very effective
BUT caused potentially fatal pulmonary hypertension and heart valve problems
FDA withdrew it in 1997; cost Wyeth over $13b in legal damages so far - 22Describe Sibutramine as a treatment for obesitySelectively inhibits re-uptake of noradrenaline,
5-HT and dopamine.
Decreases food intake and may also increase
thermogenesis.
Effective - though limited (10lbs lost in 1 year)
Major concerns over side-effects (cardiovascular
events and strokes)
Withdrawn (2010), but can be purchased on-line
in weight-loss products - 23Describe Orlistat as a treatment for obesityInhibits pancreatic lipase decreasing triglyceride absorption
Reduces efficiency of fat absorption (~30%) in small intestine
Side-effects include cramping and severe diarrhoea
Need to take vitamin supplements (fat soluble vitamins)
May not be particularly effective over long-term
(weight loss small (3 kg in 12 months,get ‘rebound’ in weight) - 24Describe Rimonabant as a treatment for obesityAntagonist of cannabinoid (CB1) receptors – high levels in hypothalamus
Counteracts obesity, argued to assist smokers to quit smoking, reduce addiction
to ethanol, cocaine and opiates and to improve short-term memory
Approved for use in EU in 2006 for obesity (FDA did not approve in 2007)
Reports of severe depression and anxiety in some patients (suicide risk)
As endocannabinoids neuroprotective – worries about neurodegeneration
2008/9: Rimonabant sales suspended/drug withdrawn - 25Describe Lorcaserin (Belviq – Lorqess (UK)) as a treatment for obesityAgonist at 5-HT2c receptors –
designed to target a different site to fenfluramine (5-HT2b). Inferior to
rimonabant or sibutramine in efficacy (3%). Safety issues raised in
2010 and 2012. FDA approved in June 2012; EMA rejected (2013) - 26Describe Qsymia as a treatment for obesityCombination therapy – phentermine + topiramate (an
anticonvulsant). Weight loss in DIO rats better than sibutramine
or rimonabant (5-10%). FDA rejected. But dosage of each drug in
Qsymia reduced – Approved in July 2012; EMA rejected (2013) - 27Describe Contrave as a treatment for obesityCombination of bupropion (dopamine re-uptake
inhibitor) + naltrexone (opioid antagonist). Effective in obese
subjects (~5%). FDA declined in 2011. Cardiovascular safety issues.
Further studies and FDA recommended approval in 2014
EMA approved 2015 – to be marketed in UK as Mysimba - 28Describe Liraglutide (Saxenda) as a treatment for obesityLicensed for treatment of type 2 diabetes (Victoza), causes weight loss
Glucagon-like peptide 1 receptor agonist (GLP-1 - a satiety peptide)
Higher doses than used for diabetes produce significant weight loss
FDA approved for obesity treatment, December 2014
EMA recommended for approval January 2015
Mechanism for anti-obesity action unclear – has to be injected
Some concerns remain regarding thyroid and pancreatic cancer - 29Describe gastric bypass as a treatment for obesityGastric by-pass surgery – produces substantial weight loss (50-60%)
in one year that is sustainable (also significantly reduces mortality)
Surgery induces high level of complete resolution of Type 2 Diabetes
(reverses insulin resistance in most cases)
By-pass restricts calorie intake and induces malabsorption of nutrients
BUT resolution of T2D is not simply due to decreased energy intake
Exact mechanisms unclear at present – but involve altered
secretion of peptides from stomach and gut that affect beta cells
and hypothalamus: e.g. GLP-1, PYY3-36, ghrelin, oxyntomodulin
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- Regulatory physiology and pharmacology Flashcards on Leptin, created by Megan MacLeod on 16/06/2019.
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- Megan MacLeod
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