Wednesday, January 29, 2012 CC-BY-NC
Hypothalamic control of food intake

Maintainer: admin

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) -

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.


  • 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.