Hypothalamic Leptin Resistance: Causes and Mechanisms (Prof Ashford) Flashcards
What does CNS disruption of STAT3 induce
Hyperphagia, obesity, diabetes andninfertility (resembles ob/ob and db/db mice)
What tyrosine residue on LEP-Rb undergoes phosphorylation to activate STAT3
Y1138
What happens when Y1138 is changed to S1138
Hyperphagia (reduced energy expenditure-like db/db mice), become less hyperglycaemia (unlike db/db mice) and no increase in NPY mRNA (unlike db/db mice)
What does STAT3 not control in terms of leptins properties
Glucose homeostasis and reproduction control
What is phosphorylated y1077 associated with and what is its action
STAT5 and not much
What does phosphorylated y985 recruit
tyrosine phosphatase (SHP-2)
Look over the y985 pathway
dae it
What do mutant y985 mice show
Reduced feeding, adiposity and ARC orexigenic neuropeptide expression
Increased leptin sensitivity and this site plays a role in the inhibition of leptin receptor signalling
What is the PI3K pathway important for
Glucose homeostasis and NPY mRNA production
Why is Fox01 important in terms of insulin
It mediates many of the metabolic actions of insulin
What does fox01 and STAT3 do in relation to transcription of AgRP and POMC
Fox01 increases AgRP transcription and decreases POMC transcription
STAT3 increases POMC transcription and decreases AgRP transcription
What inhibits the JAK-STAT signalling
Suppressor of the cytokine signalling (SOCS)
How does leptin induced JAK2 phosphorylation introduce a negative feedback loop
Phosphorylation of Y1138 and STAT3 activation results in SOCS3 mRNA induction
What other things inhibit STAT3 (apart from SOCS)
TCPTP
What chromosome is the FTO on and what is it
Fat mass and obesity associated SNP cluster
What does FTO code for
2-oxyglutarate demethylase
What are the importances of gut microbiota
Digestion, metabolism, nutrient extraction and immunomodulation
What are the three types of gut bacteria and its gram stain
Firmacutes (G+ve), bacteroidetes (G-ve) and actinobacteria
What does an increase of fat intake do to gut microbiota
Increase abundance of firmacutes and decreased bacteroidetes
How long does it take to change gut microbiota by diet
24 hours
What medication can change gut microbiota
Antibiotics
What is the connection to obesity and diabetes
Altered LPS (lipopolysaccharides which are endotoxins of gram -ve bacteria) driving inflammation (TLR4 and NFkB)
What is the connection between leptin resistance and obesity
Obesity causes increased leptin resistance. Also reduced leptin in CSF compared to plasma (reduced crossing in the BBB)
What is the relationship between age and leptin resistance
Humans demonstrate a steady increase in body weight and adiposity when ageing and so too does leptin
What can short term fat intake induce in the liver
Steatosis
What negative regulators rise in ageing an obesity
SOCS3 (overexpression of SOCS3 in POMC neurons cause leptin resistance and obesity) PTP1B (overexpression inhibits cells leptin-driven STAT3 phosphorylation) and TCPTP
What does deletion of SOCS3 in the brain do in relation to leptin sensitivity
Causes a high leptin sensitivity
What does leptin administration do to insulin function
Improves insulin function in peripheral tissues
What three tissues are mainly attenuated by leptin resistance
Adipose, liver and skeletal
What are leptin’s impacts on adipose tissues
Has large effect on adipocyte number
Directly inhibits lipid synthesis (suppresses fatty acid synthase)
Inhibits insulin responsiveness
What does leptin resistance do in adipocytes
Leptin resistance leads to proliferation of bigger adipocytes and this leads to excessive fat mass in obese individuals
What two pro inflammatory immune cells cause inflammation in obesity
M1 macrophages and CD8+ T cells
A high fat diet increases what immunoglobulins in the arcuate nucleus
IgG
What is a neuroprotective response to a high fat diet and what can this end up becoming in chronic high fat feeding
Early microglial activation is considered a neuroprotective response to a high fat diet
What receptors do free fatty acids bind to to cause obesity, type 2 diabetes and hypertension
Toll like receptor (4)
What part of the cell is highly responsive to nutrient and energy status
Endoplasmic reticulum
What is switched on in the endoplasmic reticulum under high fat feeding
ER-mediated stress signalling and adaption pathways
Give a brief description of ER stress in high fat diet situations
ER processing
