Molecularly Defined Subpopulations of Leptin Receptor Neurons Dissociate the Control of Food Intake from Blood Pressure
Allison M. Duensing1,2, Dylan Belmont-Rausch3,*, Abigail Tomlinson2, Frederike Sass2, Aiden Crowley2, Elizabeth Heaton2, Bernd Coester3, Jenny M. Brown3, Shad Hassan3, Zhe Wu1, Nathan Qi1, David P. Olson4, Paul V. Sabatini5, Martin G. Myers, Jr.1,2,**, and Tune H. Pers3,**
1 Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI
2 Department of Internal Medicine, University of Michigan, Ann Arbor, MI
3 Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK
4 Department of Pediatrics, University of Michigan, Ann Arbor, MI
5 Department of Medicine, McGill University, Montreal, Quebec
** Co-senior authors
Martin G. Myers, Jr., MD, PhD
Departments of Internal Medicine and Physiology
University of Michigan
2800 Plymouth Rd., NCRC Bldg 20
Ann Arbor, MI 48109
mgmyers@umich.edu
Tune H. Pers, PhD
Novo Nordisk Foundation Center for Basic Metabolic Research
Faculty of Health and Medical Sciences, University of Copenhagen
Maersk Tower, Building: 07-8-78
Blegdamsvej 3B, 2200 Copenhagen, Denmark
tune.pers@sund.ku.dk
While previous studies have suggested that leptin regulates cardiovascular function independently of body weight, the specific leptin receptor (Lepr)-expressing neurons that mediate these distinct effects remain unknown. We found that genes located in blood pressure (BP)-associated genome-wide association study loci were regulated by leptin in Lepr- and glucagon-like peptide-1 receptor (Glp1r)-expressing (LeprGlp1r) neurons. Ablating Lepr from these cells decreased BP despite causing hyperphagic obesity. Single-cell and spatial transcriptomics revealed that LeprGlp1r neurons segregate into two distinct subpopulations of cells located in the arcuate nucleus (ARC) and dorsomedial hypothalamic nucleus (DMH). Activating ARC LeprGlp1r neurons suppressed food intake without impacting energy expenditure or cardiovascular function. Conversely, DMH LeprGlp1r neurons increased energy utilization and BP without altering food intake. Our results identify distinct LeprGlp1r neuron subpopulations that dissociate the control of food intake from outputs related to sympathetic tone, including BP, suggesting the potential therapeutic utility of targeting these subpopulations independently.
Github repository covers the code necessary to reproduce figure 1A-C. MAGMA outputs have been computed and added to the repository. Remaining data files can be found at https://www.ebi.ac.uk/biostudies/ArrayExpress/studies/E-MTAB-17544