In-Depth Notes on 5-HT Effects on Appetite and Metabolism

Intended Learning Outcomes

  • Peripheral and Central Synthesis of 5-HT

    • 5-HT (serotonin) is synthesized in both the peripheral and central nervous systems.

  • 5-HT Signalling Pathways

    • Identification of main receptor-mediated 5-HT signalling pathways.

  • 5-HT-Targeted Therapies for Obesity

    • Understanding various treatments targeting 5-HT for obesity.

  • Mechanisms of Centrally-Targeted 5-HT Therapies

    • Mechanistic understanding of how these therapies affect obesity.

  • Potential Role of Peripheral 5-HT in Obesity Treatment

    • Evaluation of 5-HT’s peripheral role in obesity management.

Central Effects of 5-HT

  • Produced by neurons from the raphe nuclei.
  • Contains the largest efferent system in the human brain.
  • Involvement in nearly every function and behavior regulated by 5-HT.

5-HT Therapy History

  • Dexfenfluramine (1996)

    • 5-HT release stimulator/reuptake inhibitor. Approved for obesity.

  • Sibutramine (1997)

    • 5-HT/norepinephrine reuptake inhibitor. Marketed under multiple names.

SSRI and Obesity Treatments

  • SSRIs (Selective Serotonin Reuptake Inhibitors)
    • Associated with weight gain reduction in obesity but not consistently effective.
    • These increase overall 5-HT availability, causing varied interactions across 5-HT receptors, limiting efficacy and causing side effects.

Cardiovascular Side Effects of 5-HT Drugs

  • Side Effects
    • Dexfenfluramine and sibutramine withdrawn due to cardiovascular issues including cardiac valvulopathy and pulmonary hypertension.

5-HT Receptors and Their Locations

  • At least 14 types of receptors identified, primarily G-protein coupled (GPCRs) except 5-HT3 (ion channel).
  • Examples of receptor locations:
    • HTR2A: CNS, liver, skeletal muscle, adipose tissue.
    • HTR1A-1E: CNS.

Appetite Regulation and 5-HT

  • Appetite Regulation: Involves multiple neuron types and hormones including leptin and ghrelin.
  • 5-HT plays a role in food intake signaling and energy expenditure.

5-HT2C Receptor in Obesity Treatment

  • Agonists targeting 5-HT2C have been shown to reduce food intake and body weight.
  • Specific compounds like lorcaserin exhibit this property.

Lorcaserin Clinical Trials

  • Phase III Trials:

    • Patients on lorcaserin lost an average of 3.32 kg compared to placebo.
    • Additional benefits include reduced BMI and improved blood pressure levels.

  • Side Effects: Include headache, nausea, psychoactive experiences, and potential risk of valvulopathy.

Removal of Lorcaserin

  • Cancer Link: FDA requested withdrawal due to a higher cancer diagnosis rate in patients using lorcaserin compared to placebo.

Research and Future Directions

  • 5-HT2C Positive Allosteric Modulators

    • New studies suggest these could enhance the effects of 5-HT while minimizing side effects.

  • TPH1 KO Studies: Highlight the role of peripheral and central 5-HT in body weight regulation, indicating opposite effects on weight.

  • Central 5-HT and Sympathetic Activation: Impacts behaviors related to thermogenesis and metabolism.

  • Liver and Glucose Regulation: 5-HT influences glucose uptake and production in the liver, affecting overall metabolic health.

Summary of Peripheral 5-HT's Metabolic Effects

  • Peripheral Sources: Mostly from enterochromaffin cells in the gut.

  • Effects on Lipogenesis/Lipolysis: Influences energy storage and utilization in adipose tissue and liver.

  • Potential for Treatment: Targeting peripheral serotonin synthesis with TPH inhibitors shows promise for combating obesity and diabetes risks.