Wednesday, January 29, 2012

Hypothalamic control of food intake

1Main idea¶

This lecture talks about why people are fat.

2global control regions in the brain¶

• Homeostatic system :
  • stimulate food intake when energy is low.
  • areas of the brain:
    • hypothalamus: dorsomedial nucleus(DMN), ventromedial nucleus(VMN), arcuate nucleus (ARC)
    • brainstem
• hedonic system : stimulate food intake base on pleasure of eating.
  • ventral tegmental are (VTA)
  • can overwrite homeostatic system and lead to obesity.
• brain lesioning studies
  • sites of lesions that lead to obesity: paraventricular nucleus (PVN), VMN, DMN
  • sites of lesions that lead to weight loss : lateral hypothalamic area (LHA) - http://1loseweightfast.com/

3Parabiosis experiment¶

• there are two types of obese mice: ob/ob and db/db
• experiments were done to see what would happen if circulation of those mice are connected.
• Parabiosis (surgial union of blood circulation) experiments:
  • between wild type and ob/ob mice: ob/ob mice weight returns to normal
  • between wild type and db/db mice: wild type mice loss weight and dies of starvation
  • between ob/ob and db/db mice: ob/ob mice also dies of starvation.
• explainations : something in the circulation. both mutants have defect in that factor in circulation or defects in receptor for that factors
• discovery:
  • ob/ob mice lack leptin, which is suppose to suppress appetite. union of wild type introduces leptin into the ob/ob mice so its weight returns to normal
  • db/db mice lack leptin receptor, thus have high circulating leptin.
    • union of db/db with ob/ob or wild type introduce this high circulating leptin into those two types of mice. their appetite is thereby suppressed and they die of starvation.

4leptin and body weight¶

• leptin restores normal body mass in leptin deficient patients.
• however, cannot be used for anti-obesity drug because obese people actually have high circulating leptin
  • during starvation, leptin levels fall and that induce appetite
  • during fed state, leptin acts to reduce appetite and increase thermogenesis, preventing against obesity.
  • however, as leptin rises with increased feeding and fat stores, leptin action fails to rise futher : leptin resistance.
    • basically, leptin signals energy sufficiency rather than excess (when you over eat, it doesn't play a role any more)
• leptin receptor is type 1 cytokine receptor family
  • associated with JAK kinase
  • dimerized when activated
  • downstream effects are carried out by STAT (dimerized) as transcription factors

5leptin in arcuate nucleus¶

• two populations of nuclei in ARC express leptin receptor:
  • NPY/AgRP nucleus (cuz staining of NPY and AgRP show overlapping, suggest that they are express in the same population of cells)
    • orexigenic: increase food intake
    • inhibited by leptin
    • also have ghrelin receptor (ghrelin is released from gastrointestinal tract)
    • GABAnergic
  • POMC nucleus
    • anorexigenic: decrease food intake
    • stimulated by leptin
• both group of nuclei project to Mc3/4R nucleus
  • depending on orexigenic or anorexigenic signal is stronger, food intake or energy expenditure is illicted.
• brain specific knockout (using Cre and loxP mode) of leptin receptor shows obese phenotype

5.1blackboxes in leptin study¶

• knockout of NPY or AgRP or both have no effect on weight. However, when NPY/AgRP nucleus is removed, weight loss.

  • a more precise experiment: mice with diphtheria toxin receptor gene hooked on AgRP promoter, when treated with diphteria toxin, AgRP neurons are killed --> weight loss , mice die of hunger.
    • However, this only happen in adult mice. These neurons are essential for adults to survive.
    • when experiment is repeated in newly born mice, no effects on weight.
      • younger mice might have a compensatory mechanism for loss of AgRP neurons.
  • Therefore, there must be some other player in the NPY/AgRP neurons (other than NPY and AgRP).
    • it was found that those neurons are also GABAnergic (release GABA, inhibitory)
  • experiment is done to see if GABA released by NPY/AgRP neurons have to do with lack of effect of NPY/AgRP knockout
    • yes, chronic administration of GABA receptor agonist elicits recovering from weight loss in AgRP/NPY neurons-ablated mice.

• specific knockout of leptin receptor (in nuclei that are identified as a player in energy balance) in mice show mild obesity relative to whole body leptin receptor knockout.

• so we look at if it has to do with GABAnergic or glutamatergic neurons, since it was previously shown that GABA agonist can rescue starvation in adult mice with ablated agRP nuclei.
  • leptinR knockout in GABAnergic neurons in mice show more dramatic increase in body weight than leptinR knockout in glutamatergic neurons.
  • so GABAnergic neurons are probably main site of action
• However, out of all the nuclei we know that play a role in energy balance and are first-order neurons that contribute directly to obesity, AgRP neurons are the only ones that are GABAnergic and express leptin receptors
  • however, experiment already showed that that neuron-specific leptin receptor knockout induces only mild obesity.
  • conclusion: there are other nuclei GABAnergic nuclei with leptin receptor that we don't know about yet.
    • in other words, the majority of leptin's antiobesity must be mediated by previously uncharacterized first-order (directly being acted on) leptin-responsive GABAergic neurons.

6Leptin and reproduction¶

• starvation is characterized by decrased gonadal hormone, delayed ovulation in female
• leptin administration to fasted mice recover fall in hormone level
• both excessivly skinny and fat women are infertile
  • skinny women: low leptin level, low lepin signaling, fall in hormone level.
  • fat women: too much circulating leptin, leptin resistance, low leptin signaling, fall in hormone level.
• speicifc impariment of leptin signaling causes fertility dysregulation
  • has nothing to do with body-weight change.
• leptin regulates reproductive axis by activating gnRH neurons
  • but GnRH neurons don't express leptin receptors
  • so leptin probably act somewhere upstream. other neurons express leptin receptor and project to GnRh neurons.

7Other peptides¶

• produced in GI tract
• remember, ghrelin is the only one in this list that promotes food intake.

7.1Grehlin¶

• peaks up just before food intake
• the only hormone produced in gut that is orexigenic
• anti-ghrelin IgG suppresses feeding
• ghrelin stimulates adiposity build up in mice.
• responsible for rebound weight gain
  • people who fast incrase their plasma ghrelin level, which stimulate appetite.
  • surgerically remove part of GIT would help curbing ghrelin
• ghreiln increases energy intake in cancer patients with ipaired appetite

7.2CCK (cholecystokinin)¶

• short half-life
• secreted within the duodenal and jejunal mucosa
• CCK is also synthesized within the CNS
• two receptors: CCK1 and CCK2
  • CCK1: localized in the gastrointestinal system
  • CCK2: found in CNS
• inhibits food intake via CCK1 receptor
• CCK release from the intestine occurs in response to nutrient stimulaion, stimulated by fat and protein in the chyme.
• elicits effects on gastrointestinal system (digestion action)
• however, CCK must be administered within 15 minutes before the start of meal.
• even though meal size is decreased by CCK, animals compensate by increasing meal frequency
  • no effect on weight loss

7.3GLP (glucagon-like peptide)¶

• a incretin, molecule that incrase insulin secretion without increasing blood glucose levels.
• receptor GLP-1r found in periphery(gut and endocrine pancrea) and CNS
• very short half-life. (~2 min)
• get degraded by DDP-IV (dipeptidyl peptidase IV)
  • drug target to develop analog taht doesn't get degraded as fast.
  • can be used to treat diabete

7.4PPY (Peptide YY)¶

• produced by enteroendocrine cell in the ileum and colon.
• secreted after a meal.
• delay gastric emptying.
• inhibit food intake by binding to Y2 receptor to inhibit NPY neuron
  • depress food intake
  • however, this was pretty controversial. People debated over PPYY's anorexigenic effect.
  • recent findings in primates suggest it does modestly reduce food intake.