Immunomodulatory Leptin Receptor+ Sympathetic Perineurial Cells Protect Against Obesity by Facilitating Neuroendocrine-Mediated Brown Adipose Tissue Thermogenesis

Haberman, E. R.; Sarker, G.; Arus, B. A.; Yilmaz-Ozcan, S.; Martinez-Sanchez, N.; Freibergerova, E.; Fernandez-Gonzalez, I.; Zentai, C.; O'Brien, C. J. O.; Grainger, D. E.; Chakarov, S.; Raimondi, A.; Iannacone, M.; Lopez, M.; Ginhoux, F.; Domingos, A. I.

doi:10.1101/2023.05.09.539963

bioRxiv · 10.1101/2023.05.09.539963

Immunomodulatory Leptin Receptor+ Sympathetic Perineurial Cells Protect Against Obesity by Facilitating Neuroendocrine-Mediated Brown Adipose Tissue Thermogenesis

Haberman, E. R.·Sarker, G.·Arus, B. A.·Yilmaz-Ozcan, S.·Martinez-Sanchez, N.·Freibergerova, E.·Fernandez-Gonzalez, I.·Zentai, C.·O'Brien, C. J. O.·Grainger, D. E.·Chakarov, S.·Raimondi, A.·Iannacone, M.·Lopez, M.·Ginhoux, F.·Domingos, A. I.

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Abstract

Adipose tissues (ATs) are innervated by sympathetic nerves, which drive reduction of fat mass via lipolysis and thermogenesis. Here, we report a population of immunomodulatory leptin receptor (LepR)-expressing barrier cells which ensheath sympathetic axon bundles in adipose tissues. These LepR-expressing Sympathetic Perineurial Cells (SPCs) produce IL33, a factor for maintenance and recruitment of regulatory T cell (Treg) and eosinophils in AT. Brown adipose tissues (BAT) of mice lacking IL33 in SPCs (SPCIL33cKO) have fewer Treg and eosinophils, resulting in increased BAT inflammation. SPCIL33cKO mice are more susceptible to diet-induced obesity, independently of food intake. Furthermore, SPCIL33cKO mice have impaired adaptive thermogenesis, and are unresponsive to leptin-induced rescue of metabolic adaptation. We, therefore, identify LepR-expressing SPCs as a source of IL33 which orchestrate an anti-inflammatory environment in BAT, preserving sympathetic-mediated thermogenesis and body weight homeostasis. LepR+ IL33+ SPCs provide a cellular link between leptin and immune regulation of body weight, unifying neuroendocrinology and immunometabolism as previously disconnected fields of obesity research. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=86 SRC="FIGDIR/small/539963v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@195fa69org.highwire.dtl.DTLVardef@16b2e5eorg.highwire.dtl.DTLVardef@1b12b62org.highwire.dtl.DTLVardef@973c1b_HPS_FORMAT_FIGEXP M_FIG C_FIG Highlights- Sympathetic Perineurial Cells (SPCs) co-express LepR+ and IL33 - SPC-derived IL33 prevents BAT inflammation via Treg and eosinophil recruitment - Obesity is worsened in high fat diet-fed SPCIL33cKO mice, despite normal food intake - Adaptive thermogenesis is impaired in SPCIL33cKO mice - Rescue of metabolic adaptation to fasting by leptin is impaired in SPCIL33cKO mice - SPCs link leptin to immunometabolic regulation of body weight homeostasis

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Haberman, E. R., Sarker, G., Arus, B. A., Yilmaz-Ozcan, S., Martinez-Sanchez, N., Freibergerova, E., Fernandez-Gonzalez, I., Zentai, C., O'Brien, C. J. O., Grainger, D. E., Chakarov, S., Raimondi, A., Iannacone, M., Lopez, M., Ginhoux, F., Domingos, A. I.. 2023-05-10. Immunomodulatory Leptin Receptor+ Sympathetic Perineurial Cells Protect Against Obesity by Facilitating Neuroendocrine-Mediated Brown Adipose Tissue Thermogenesis. https://doi.org/10.1101/2023.05.09.539963

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