Leptin and Energy Homeostasis

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The risk increases for these diseases with increased body mass
Type 2 diabetes, cholelithiasis (gall stones), hypertension, coronary heart disease
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Describe the balance of body weight
Increases with energy intake, decreases with energy expendature. complex mecanisms ensuring a constant supply of energy for cellular functions.
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What forms of energy expenditure are there
physical activity, diet induced thermogenesis, basal metabolic rate
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What is the thrify gene hypothesis?
genes that predispose obesity would have had an advantage in populations frequently experiencing starvation.
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4 periperal signals regulating appetite
Leptin, ghrelin, PYY3-36, GLP-1.
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Where are they released from/act on?
PYY3-36 and GLP are released from the intestines, PYY acts in the hyp to decrease food intake, GLP-1 acts on the pancrease to release insulin. Ghrelin - from stomach, to hypothalamus, to increase food intake. Leptin - fat cells, hyp, decrease
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Where did the first indication that food intake was related to brain circuts come from
Hypothalamic lesions leading to obesity/starvation, eg the VMH was identified as satiety center (Hetherington 1940) and the LH as the feeding centre (brobeck 1951)
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Hypthalamic centers involved in energy homeostasis x5
PVN, DMN, VMN, ARC, LHA
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Which areas result in obesity when destroyted
PVN, VMN, DMN
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Anorexia results from the destruction of where?
Lateral hypothalamic areas
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What does the mouse ob gene encode?
Leptin - polypeptide hormone, 167 aa protien of the cytokine family
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What is leptin like in the ob/ob mouse and what is the phenotype
truncated inactive protien - so leptin cannot inhibit feeding, so extreme obesity results.
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What happens when the blood from wt is put in ob ob and vice versa
wt becomes fat, ob ob becomes thin
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What determines circulating levels of leptin
proportional to total fat mass.
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How do leptin levels change after eating
levels increase after several days of overfeeding in humans, and decrease rapidly with food restriction.
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What is the effect of leptin treatment in rodents?
decrease food intake, increases energy expendature, reduces weight.
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What is coded for by the db gene in mice? What is the result of db mutant?
the leptin receptor, mutant receptor can't bind leptin so the mice become obese
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Where are leptin receptors found in the hypothalamus?
ARC, VMN, DMN.
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Which mutant mice can be restored with leptin treatment?
ob/ob. hyp lesioned or db are unresponsive to leptin
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Kennedy's lipostatic theory
hypothalamus sense the concentration of a circulating factor which provides information on size of fat stores, to maintain total body fat content
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How does adiposity signalling by leptin work?
in fed state, leptin stimulates hypothalamic neuronal pathways to increase energy expenditure and inhibit eating. Fat mass down, leptin down, feeding stimulated and energy expenditure is suppressed. fat reserves back to normal
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Is leptin anti-obesity or energy sufficency signal?
The biological impact more pronouced when it's decreasing, its role is to protect against starvation rather than obesity.
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Three results of leptin deficiency
drives hunger, supress energy expenditure, inhibition of reproductive competence.
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Can leptin be used to treat human obesity?
clinical trials failed, no weight reducing effects. effective only in rare cases of defective ob genes, generally in obese individuals the ob gene is normal
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Who reported a case study concerning ob mutation
Montague, 1997. 8 year old girl who lost weight following leptin therapy having previously been obese.
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Another study regarding leptin deficiency
Williamson 2005, three cousins from turkish family, considerable weight loss.
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What are leptin levels like in obese humans?
high. they appear to be insensitive to leptin satiety factor.
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Describe the leptin receptor
cytokine receptor family, expressed in ARC, liver, adipose and other tissues
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Signalling cascade resulting from leptin binding
JAK phosphorylates the 2 dimers, recruites STAT. STAT dimers enter the nucleus and promote gene expression.
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What anorexigenic peptides are upregulated by Leptin?
POMC, CART.
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What orexigenic peptides are down regulated?
NPY, AGRP
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Card 2

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Describe the balance of body weight

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Increases with energy intake, decreases with energy expendature. complex mecanisms ensuring a constant supply of energy for cellular functions.

Card 3

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What forms of energy expenditure are there

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Card 4

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What is the thrify gene hypothesis?

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Card 5

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4 periperal signals regulating appetite

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