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Lutomska, L.M. ; Miok, V. ; Krahmer, N. ; Gonzales García, I. ; Gruber, T. ; Le Thuc, O. ; Murat, C.* ; Legutko, B. ; Sterr, M. ; Saher, G.* ; Lickert, H. ; Müller, T.D. ; Ussar, S. ; Tschöp, M.H. ; Lutter, D. ; García-Cáceres, C.

Diet triggers specific responses of hypothalamic astrocytes in time and region dependent manner.

Glia 70, 2062-2078 (2022)

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Hypothalamic astrocytes are particularly affected by energy-dense food consumption. How the anatomical location of these glial cells and their spatial molecular distribution in the arcuate nucleus of the hypothalamus (ARC) determine the cellular response to a high caloric diet remains unclear. In this study, we investigated their distinctive molecular responses following exposure to a high-fat high-sugar (HFHS) diet, specifically in the ARC. Using RNA sequencing and proteomics, we showed that astrocytes have a distinct transcriptomic and proteomic profile dependent on their anatomical location, with a major proteomic reprogramming in hypothalamic astrocytes. By ARC single-cell sequencing, we observed that a HFHS diet dictates time- and cell- specific transcriptomic responses, revealing that astrocytes have the most distinct regulatory pattern compared to other cell types. Lastly, we topographically and molecularly characterized astrocytes expressing glial fibrillary acidic protein and/or aldehyde dehydrogenase 1 family member L1 in the ARC, of which the abundance was significantly increased, as well as the alteration in their spatial and molecular profiles, with a HFHS diet. Together, our results provide a detailed multi-omics view on the spatial and temporal changes of astrocytes particularly in the ARC during different time points of adaptation to a high calorie diet.

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