Control of Appetite and Obesity Models

Control of Appetite

  • Classic studies involving lesions and electrical stimulation of specific brain regions identified two hypothalamic areas critical for controlling eating.

    • Satiety Center: Located in the ventromedial nucleus of the hypothalamus.

      • Electrical stimulation induces satiety, even in the presence of food.
      • Lesions cause continuous food intake, regardless of need.

    • Hunger/Feeding Center: Located in the lateral hypothalamic area.

      • Electrical stimulation elicits a voracious appetite, even after adequate food intake.
      • Lesions cause complete and lasting cessation of food intake.

  • Leptin:

    • Informs the brain about the amount of stored fat.

Mouse Obesity Models and Regulatory Mechanisms

  • Study of mouse obesity models has advanced our understanding of regulatory mechanisms that maintain body mass.

  • Monogenic Models:

    • OB/OB Mice:

      • Hyperphagic mice that develop morbid obesity.
      • Typically weigh over a percentage more than unaffected mice of the same strain.
      • Parabiosis experiments:
        • OB/OB mouse surgically connected to a wild-type mouse results in the OB/OB mouse losing weight.
        • This suggests a lack of a blood-borne factor.

    • DB/DB Mice:

      • Develop type 2 diabetes.
      • Hyperphagic with adult body weights over a percentage greater than lean littermates.
      • Parabiosis experiments:
        • DB/DB mouse connected to a wild-type mouse results in the wild-type mouse starving.
        • OB/OB mouse connected to a DB/DB mouse results in the OB/OB mouse losing weight, but the DB/DB mouse remains obese.

  • Interpretation of Parabiosis Experiments:

    1. DB mouse produces an excess of a blood-borne factor that can cure the OB mouse.
    2. DB mouse lacks the receptor for this factor.
    3. Absence of the receptor in the DB mouse removes negative feedback, leading to high levels of the blood-borne factor.

Human Relevance: Neurons in the Arcuate Nucleus

  • Two classes of neurons within the arcuate nucleus contain receptors for leptin and insulin and express neuropeptides.
    • Neurons producing pro-opiomelanocortin (POMC).
    • Neurons producing neuropeptide Y (NPY) and Agouti-related protein (AGRP).

POMC Neurons

  • Insulin and leptin stimulate distinct subgroups of POMC-secreting neurons.

  • At their synapses, POMC neurons release a POMC cleavage product, alpha-melanocyte-stimulating hormone (alpha-MSH).

  • Alpha-MSH binds to MC3R and MC4R melanocortin receptors in second-order neurons.

  • Stimulation of these receptors:

    • Promotes satiety and decreases food intake (anorexigenic effect).
    • Increases energy expenditure via activation of sympathetic pathways.

  • Significance:

    • Approximately 4% of individuals with severe early-onset obesity have mutations in MC3R and MC4R.

  • POMC neurons also synthesize cocaine- and amphetamine-regulated transcript (CART), which is anorexigenic.

NPY and AGRP Neurons

  • Insulin and leptin suppress neurons in the arcuate nucleus that release NPY and AGRP.
  • NPY activates NPY receptors (G protein-coupled receptors, predominantly Y1R and Y5R) on secondary neurons, stimulating eating behavior (orexigenic effect).
  • AGRP binds to and inhibits MC4R melanocortin receptors on secondary neurons in the POMC pathway, inhibiting the anorexigenic effect of alpha-MSH (orexigenic effect).

Summary of Key Molecules and Their Effects

  • Alpha-MSH: Anorexigenic (decreases food intake, increases energy expenditure)
  • CART: Anorexigenic
  • NPY: Orexigenic (stimulates eating behavior)
  • AGRP: Orexigenic (inhibits alpha-MSH's effects)