2024 Theses Doctoral

Molecularly Distinct Sympathetic Populations Control Brown Adipose Tissue Functions

Neri, Daniele

Brown adipose tissue (BAT) serves as a crucial thermogenic organ, extracting glucose and lipids from circulation to generate heat. Enhancing BAT activity holds potential as a therapy for treating metabolic diseases, such as obesity and diabetes. The sympathetic nervous system (SNS) is the main regulator of BAT activity by increasing extraction and oxidation of substrates. However, the SNS role in metabolic disorders is complex. In obesity, there is increased sympathetic tone, yet reduced BAT responsiveness.

Furthermore, increasing systemic sympathetic tone in individuals already at heightened cardiovascular risk leads to adverse complications, as demonstrated by recent clinical trials. As a result, BAT’s impact on overall health in humans has been challenged in recent years, largely due to the lack of methods to selectively activate BAT without affecting other organs.

Here, I used chemogenetics and retrograde viral injections in the interscapular BAT (iBAT) of mice to selectively activate only the neurons projecting to this tissue. Targeted activation of BAT did increase thermogenesis and improved glucose homeostasis.

Leveraging on the single-cell RNA sequencing from our laboratory, we identified two sympathetic populations innervating iBAT: one primarily targets the small arterioles, while the other innervates the parenchyma. These populations mediate non-overlapping sympathetic-functions in iBAT: activating only the vascular projecting neurons lowers blood glucose without affecting thermogenesis, while activating the other population results in increased energy expenditure, local thermogenesis, and blood flow, with no effect on glycemia.

The findings from this work could pave the way to the development of targeted strategies against metabolic disorders characterized by hyperglycemia, highlighting the potential of selectively activating specific SNS components to normalize blood glucose levels.