Sebastian Blid Sköldheden – Central neural mechanisms underlying semaglutide effects on energy balance
Dissertation for Medicine Doctoral degree at Sahlgrenska Academy, Institute of Neuroscience and Physiology, Department of Physiology
Opponent and examining committee
Opponent: Professor Tune Pers, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
Examining committee: Professor Elias Eriksson (chair), Associate Professor Ida Nilsson (KI) and Professor Per-Anders Jansson
Good to know
The disputation is held in English
Welcome to attend online via streaming, via Zoom Webinar: link to be announced
Chairperson of the disputation: Associate Professor Line Löken
Neural mechanisms of semaglutide-induced weight loss
Obesity is a pressing global health concern. GLP-1R agonists (GLP-1RAs) represent a fundamental shift in pharmacotherapeutic options, offering novel and efficacious treatments. Semaglutide, one of the most widely used GLP-1R agonists, elicits substantial weight loss. Prior research has established that the brain plays a necessary role in the ability of GLP-1RAs to shift energy balance and induce weight loss. However, the central neural mechanisms governing these effects have remained unresolved.
The overarching purpose of this thesis is to identify and characterize central mechanisms involved in semaglutide-induced weight loss. Using activity-dependent chemogenetics and neuronal tagging, we demonstrate that the dorsal vagal complex (DVC) in the caudal brainstem plays a crucial role in mediating the effects of semaglutide on energy balance. We find that chemogenetic activation of semaglutide-responsive DVC neurons is sufficient to recapitulate semaglutide’s brain-wide activation pattern and reproduce its effects on energy balance. Through molecular profiling and neuronal ablation, we identify AP/NTS Adcyap1+ neurons as crucial for semaglutide-induced suppression of food intake and weight loss, both during acute treatment in lean mice and during subchronic treatment in obese mice. Intriguingly, we find that AP/NTS Adcyap1+ neurons are predominantly involved in semaglutide-induced loss of fat mass, while not driving the aversive response to the drug. Furthermore, we show that they play a key role in semaglutide-mediated activation of downstream structures involved in energy balance. Paper I thus establishes a central role for the DVC and AP/NTS Adcyap1+ neurons in mediating the effects of semaglutide on energy balance. How the effects of semaglutide are mediated downstream of these neurons remains unclear.
In Paper II, we address this knowledge gap by specifically focusing on whether and how semaglutide-responsive DVC neurons affect hypothalamic structures known to be crucial for energy balance. We demonstrate that semaglutide inhibits AgRP neurons and that chemogenetic activation of AgRP neurons during semaglutide treatment abrogates its weight-loss effects in obese mice. Using activity-based chemogenetics and neuronal ablation experiments, we then demonstrate that semaglutide inhibits fasting-induced AgRP neuron activation through the engagement of DVC neurons, including NTS Adcyap1+ neurons.
We then employed optogenetics and found that stimulation of Adcyap1+ NTS projections to the ARC or DMH non-aversively suppresses refeeding after fasting and binge-like chocolate intake, while sparing dark-phase chow intake. In the absence of food, stimulation of the Adcyap1+ NTS-to-ARC pathway elicits increased weight loss and ketogenesis, whereas stimulation of the NTS-to-DMH pathway elicits a reduction in energy expenditure. Importantly, we recapitulated and corroborated key circuit effects using activity-based optogenetics, demonstrating semaglutide’s recruitment of these circuits and implicating their functional contributions to key aspects of the drug’s effects. Lastly, we find that both pathways are capable of suppressing fasting-induced AgRP neuron activation upon stimulation, revealing a novel brainstem-dependent mechanism for AgRP neuron modulation.
Collectively, the work presented in this thesis provides evidence that the brainstem is a central node for the action of semaglutide and that AP/NTS Adcyap1+ neurons are crucial mediators of the drug’s effects. Additionally, brainstem-to-hypothalamus circuits engaged by semaglutide exert context-dependent effects on feeding and metabolism. Ultimately, this work addresses several knowledge gaps regarding GLP-1RA treatment and reveals novel mechanisms implicated in its effects.
