Preoptic PNOC neurons-originated sympathetic circuits modulating adipose tissue functions

• Applicant: Alexander Jais, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 537071551

The increasing prevalence of obesity and its associated metabolic diseases poses substantial challenges in healthcare, society, and the economy. Genetic studies have highlighted the central nervous system as significant contributors to obesity development. Among the hypothalamic regions involved in energy balance regulation, the preoptic area (POA) has emerged as a crucial player in energy balance control and thermoregulation. Our previous work focused on a specific cluster of neurons within the POA that express the neuropeptide prepronociceptin (PNOC). Using chemogenetic techniques, we selectively activated PNOC-expressing neurons in mice and observed a significant reduction in brown adipose tissue (BAT) temperature and energy expenditure. Interestingly, the activation of PNOC(POA) neurons initiated an acute inflammatory response in BAT, characterized by the upregulation of immediate early genes associated with inflammation and chemotaxis. Further examination of PNOC(POA) neuronal projections unveiled robust connectivity to various brain regions involved in autonomic control, including the dorsomedial hypothalamus (DMH), a key relay in BAT thermogenesis regulation. Therefore, based on our preliminary findings in BAT, we hypothesize that the activation of PNOC(POA) neurons results in a decrease in sympathetic tone, which subsequently initiates acute inflammatory signaling within white adipose tissue (WAT) depots. Given that obesity is associated with chronic, low-grade inflammation and this metabolic inflammation plays a crucial role in driving insulin resistance, our research project aims to understand the impact of PNOC(POA) activation on inflammation and metabolic regulation in WAT. We will investigate acute changes in inflammatory markers in WAT upon PNOC(POA) activation, utilizing bulk and single-nucleus RNA sequencing. We will examine the long-term effects of PNOC(POA) ablation on adipose tissue inflammation and metabolic responses in mice subjected to a high-fat diet. Finally, we will bridge the gap between mouse models and human physiology by validating the relevance of early inflammatory markers identified in previous experiments using human serum samples from lean and obese study participants from the Leipzig Obesity BioBank. By unraveling these intricate regulatory mechanisms, we can significantly advance our understanding of the underlying processes governing neuronal control of metabolic inflammation and pave the way for novel therapeutic interventions.

• DFG Programme: Research Grants