Ana Domingos - Fundamental biological mechanisms in Sympathetic Neurocircuitry underlying body weight
Effective obesity management medications that elevate energy expenditure, such as brain-acting sympathomimetics, lead to descending widespread sympathetic activity that raises the heart rate1. These adverse cardiovascular side effects have repeatedly resulted in their market withdrawal or rejection by regulatory agencies despite their potency in reducing body weight. Consequently, treatment options have been limited to suppressing appetite, for instance, with Glucagon-like peptide-1 (GLP-1) mimetic drugs, which lead to a compensatory decrease in energy expenditure, increasing the risk of recurrent weight gain2,3. While reducing food intake is crucial for treating obesity, sustaining a higher energy expenditure is necessary for therapies to be durable. This could be achieved by directly manipulating subpopulation of sympathetic neurons as they release factors within metabolic tissues that trigger anti-obesity actions beyond appetite control4–6, and without cardiac side effects1,7.
GLP-1 agonists are clinically used to treat type 2 diabetes and obesity8 . They suppress appetite by activation of the GLP-1 receptors in the central nervous system9. Recent clinical trials have shown that blocking ActRII signalling with the antibody Bimagrumab preserves skeletal mass after dieting, promotes loss of adipose tissues, and improves insulin resistance, while also proving its cardiac safety and efficacy10. In mice, combining Bimagrumab with GLP1R agonist enhances fat reduction11, although the clinical trial is still ongoing (NCT05616013) and the exact biological mechanism is uncertain.
We hypothesise that the synergistic effects of fat reduction with the combination of Bimagrumab and GLP-1 receptor agonists are mediated through specific subsets of abdominal sympathetic neurons. Through single-cell RNA-sequencing of mouse sympathetic ganglia, we discovered that ActRII and GLP1R are co-expressed in the abdominal (celiac) but not in cervical ganglia that innervate the heart. This discovery suggests a new cellular target for burning fat without affecting heart rate. Based on our findings and previous studies, we aim to assess the effect of GLP1 mimetics on abdominal sympathetic neurons and explore whether combining Bimagrumab with GLP1R agonists in these neurons could synergistically stimulate them, ultimately to boost weight loss by burning of visceral fat, while leaving heart function intact. By using postganglionic sympathetic neurons derived from human-induced pluripotent stem cells (hiPSC)12,13, we will assess in vitro the effects of these combined treatments on GLP1R and ActRII co-expressing neurons, which may reveal additional synergistic effects on boosting weight loss without cardiovascular effects.
PhD project : Understanding fundamental molecular mechanisms within sympathetic neural circuitry that sustains energy expenditure without impacting the heart.
Example of a rotation project(in vitro):
Objectives:
- Test for GLP1R and ActRII expression in iPSCs-derived sympathetic neurons
- Evaluate the synergistic effects of Bimagrumab (Eli Lilly) on ActRII on iPSCs-derived sympathetic neurons , using CLARIOstar Plus Ca2+ imaging.
Training: iPSCs cell culture, Ca2+ imaging.
References:
1. Mahú, I. et al. Brain-Sparing Sympathofacilitators Mitigate Obesity without Adverse Cardiovascular Effects. Cell Metab 31, 1120 (2020).
2. van Eyk, H. J. et al. Liraglutide decreases energy expenditure and does not affect the fat fraction of supraclavicular brown adipose tissue in patients with type 2 diabetes. Nutrition, Metabolism and Cardiovascular Diseases 30, 616–624 (2020).
3. Fothergill, E. et al. Persistent metabolic adaptation 6 years after ‘The Biggest Loser’ competition. Obesity (Silver Spring) 24, 1612–1619 (2016).
4. Li, E. et al. Control of lipolysis by a population of oxytocinergic sympathetic neurons. Nature 625, 175–180 (2024).
5. Zeng, W. et al. Sympathetic Neuro-adipose Connections Mediate Leptin-Driven Lipolysis. Cell 163, 84–94 (2015).
6. Zhu, Y. et al. Sympathetic neuron derived NPY protects from obesity by sustaining the mural progenitors of thermogenic adipocytes. bioRxiv 2024.05.18.594804 (2024) doi:10.1101/2024.05.18.594804.
7. Ceddia, R. P. et al. Gβγ-SNAP25 exocytotic brake removal enhances insulin action, promotes adipocyte browning, and protects against diet-induced obesity. J Clin Invest 133, (2023).
8. Wilding, J. P. H. et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. New England Journal of Medicine 384, 989–1002 (2021).
9. Kim, K. S. et al. GLP-1 increases preingestive satiation via hypothalamic circuits in mice and humans. Science385, eadj2537 (2024).
10. Heymsfield, S. B. et al. Effect of Bimagrumab vs Placebo on Body Fat Mass Among Adults With Type 2 Diabetes and Obesity: A Phase 2 Randomized Clinical Trial. JAMA Netw Open 4, (2021).
11. Nunn, E. et al. Antibody blockade of activin type II receptors preserves skeletal muscle mass and enhances fat loss during GLP-1 receptor agonism. Mol Metab 80, (2024).
12. Winbo, A. et al. Functional coculture of sympathetic neurons and cardiomyocytes derived from human-induced pluripotent stem cells. Am J Physiol Heart Circ Physiol 319, H927–H937 (2020).
13. Wu, H. F., Art, J., Saini, T. & Zeltner, N. Protocol for generating postganglionic sympathetic neurons using human pluripotent stem cells for electrophysiological and functional assessments. STAR Protoc 5, (2024).