Leptin and Energy Balance Flashcards
what is obesity
BMI greater than or equal to 30
what are the health risks associated with obesity?
diabetes
all cancers
gall stones
hypertension
CV disease
define body weight
function of energy intake balanced with energy expenditure
energy intake
ingestion of protein/fat/carbohydrates
energy expenditure
physical activity
diet-induced thermoregulation
basal metabolic rate
treatment
reduce intake and increase expenditure
what is the fat mass heritability
40-70%
obesity in twins
non-identical twins have variations in body shape
obesity is driven by many genes
obesogenic environment
slow evolutionary adaptation (genes prone to starvation)
rapid environmental change (sedentary lifestyle/motorised transport)
rapid behavioural change
surgical options for treatment
gastric bypass (reduction by ~25%)
gastric sleeve (reduction by ~14%)
pharmacological treatment
orlistat
most drugs removed from market since cause CV/psychiatric side effects
homeostatic integrative centres
hypothalamus
brainstem
ghrelin
meal initiator
increases food uptake TO hypothalamus
grumbling
what is leptin
decreases food intake
secreted from fat stores
PYY3-36
decreases food intake
TO
GLP-1
releases insulin
contacts B cells to release insulin
hypothalamus anatomy and location
located above pituitary gland
leaky BBB
lesions which are an oversimplification
lateral area hypothalamus lesion causes hunger/weight loss
ventromedial area hypothalamus lesion causes satiation/obesity
nuclei in the hypothalamus
obesity:
paraventricular nucleus (PVN)
ventromedial nucleus (VMN)
dorsomedial nucleus (DMN)
anorexia/weight loss:
lateral hypothalamic area (LHA)
arcuate nucleus (ARC)
Ingalls AM et al., 1950 study
normal vs ob/ob mutant
3 weeks WT weighed 12g vs ob/ob 16g 10 weeks WT 29g ob/ob 90g
ob/ob mutant has early onset obesity, hyperphagia, decreased energy expenditure, hyperglycemia, adipocyte hyperplasia
circulating factor mutants
ob/ob - no circulating factor, truncated leptin so cannot bind to receptor
db/db - defective leptin receptor (unresponsive to circulating factor)
parabiosis experiment (fusing circulation of 2 mice)
ob/ob X WT ob/ob mouse loses weight because it receives functional leptin from WT
db/db X WT WT has excessive leptin WT starves to death
ob/ob X db/db ob/ob loses weight
VMH lesion X lean control
control mouse stops eating
leptin R mRNA location
VMN
DMN
ARC
leptin
167 aa of cytokine family
expressed mainly in adipose tissue
levels of leptin = total fat mass
starvation reduces leptin
decreases food intake and adrenal corticosteroids
what is the set point model
maintains constant body weight by controlling eating behaviour and burning excess fuel
adiposity signalling by leptin
1) leptin correlates to body fat levels (circulated)
2) after eating elevated leptin stimulates energy expenditure and inhibits eating
3) fat mass decreases, serum leptin falls. feeding is stimulated and energy expenditure is suppressed
4) fat reserves return to set point
hormonal effects of leptin
more leptin needed in puberty
excessive weight loss causes iregular periods
leptin therapy in humans
blood leptin levels are higher in obese patients
clinical trials are uneffective - no weight loss after injection
only effective in rare humans with severe obesity
leptin receptor
member of the cytokine family
expressed mostly in ARC, liver, muscles, adipose
leptin signalling
leptin-LEPR
phosphorylation of PSTAT3
leptin binds to 2 JAK molecules and phosphorylates PSTAT3 and moves to nucleus
anorexigenic and orexigenic peptides
anorexigenic peptides increases releases POMC CART
orexigenic peptides decreases releases NPY and AGRP
