Defining Predictors of Weight Loss Response to Lorcaserin

Area of Science:

• Neuroscience
• Endocrinology
• Pharmacology

Background:

• Individual responses to weight loss medications vary significantly, and predicting efficacy remains a challenge.
• Lorcaserin (LOR) is a 5HT2cR agonist targeting proopiomelanocortin (POMC) neurons involved in energy and glucose homeostasis.

Purpose of the Study:

• To investigate biomarkers associated with lorcaserin use for predicting clinical efficacy in weight loss.
• To identify predictors of weight loss response to lorcaserin.

Main Methods:

• A randomized crossover study involving 30 individuals with obesity, treated with placebo and lorcaserin.
• Cerebrospinal fluid (CSF) POMC peptide measurements, insulin, leptin, and food intake were assessed.
• Nineteen participants continued lorcaserin treatment for 6 months.

Main Results:

• Lorcaserin decreased CSF POMC and increased β-endorphin, with a 30% increase in β-endorphin/POMC ratio.
• Significant decreases in insulin, glucose, and HOMA-IR were observed before weight loss.
• Baseline CSF POMC negatively correlated with weight loss, and a specific cutoff predicted >10% weight loss.

Conclusions:

• Lorcaserin impacts the human brain melanocortin system, with greater efficacy in individuals with lower baseline melanocortin activity.
• Early changes in CSF POMC correlate with weight loss-independent glycemic improvements.
• Assessing melanocortin activity may personalize obesity pharmacotherapy with 5HT2cR agonists.