Rasmus Sandsdal, MD

University of Copenhagen, Faculty of Health and Medical Sciences

Title of project

Disrupting the Neuroendocrine Body Weight Defense System of Childhood-onset Obesity

Abstract

Purpose: In this PhD project proposal, I will elucidate the neuroendocrine mechanisms of the brain-coordinated defense system that regulates appetite in childhood-onset obesity.

Background: Most children with obesity will also live with obesity as adults. Attempts to lose weight are most often counteracted by involuntarily increased appetite, diminished cognitive control, and reduced energy expenditure. Magnetic resonance imaging (MRI) indicates that obesity is linked to altered brain activity in the hypothalamus and regions associated with reward and cognitive control. Novel incretin-based pharmacotherapy with glucagon-like peptide 1 receptor agonist (GLP-1 RA) may overrule these central neural processes in childhood-onset obesity.

Hypothesis: Hypothalamic hypoactivity and dysfunction in the brain’s reward and cognitive control regions are associated with treatment resistance in childhood-onset obesity but may be reversed by GLP-1 RA.

Methods: 200 young adults with childhood-onset obesity from the Children’s Obesity Clinic, Holbaek Hospital, will be recruited based on their response to the hospital-based lifestyle intervention as children and BMI at inclusion and allocated to one of three groups:

  • Group A: high degree of treatment resistance (BMI z-score change <0.10) and still have obesity (>30 kg/m2)
  • Group B: lower degree of treatment resistance (BMI z-score change >0.25) but still have obesity (>30 kg/m2)
  • Group C: no treatment resistance (BMI z-score change >0.50) and no obesity (<30 kg/m2)

Groups A and B will be randomized to 68 weeks of treatment with GLP-1 RA, semaglutide 2.4 mg/week, or placebo. Brain MRI, appetite-related outcomes, and continuous physical activity and sleep monitoring will be collected at baseline (all groups) and throughout the study (groups A & B).

State-of-the-art MRI will capture whole-brain and hypothalamic activity to assess neuronal correlates of treatment resistance in childhood-onset obesity and in response to potent GLP-1 RA treatment. Multimodal MRI metrics with structural and functional paradigms will be applied. Additionally, gut hormones, appetite ratings, food preferences, eating behavior, physical activity, and sleep will be assessed.

Perspective: Unraveling the neuroendocrine mechanisms of the brain-coordinated defense against weight loss can increase our understanding of conscious and unconscious homeostatic obstacles of obesity. This can propel a paradigm shift in effective strategies to overcome childhood-onset obesity.

Rasmus Sandsdal, MD
Principal supervisor

Signe Sørensen Torekov, University of Copenhagen, Dept. of Biomedical Sciences

Co-supervisor: Laura Holsen, Harvard Medical School, USA

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