Central activation of catecholamine-independent lipolysis drives the end-stage catabolism of all adipose tissues

Zhang, X.; Majumdar, A.; Kim, C.; Kleiboeker, B.; Magee, K. L.; Learman, B. S.; Thomas, S. A.; Lodhi, I. J.; MacDougald, O. A.; Scheller, E. L.

doi:10.1101/2024.07.30.605812

bioRxiv · 10.1101/2024.07.30.605812

Central activation of catecholamine-independent lipolysis drives the end-stage catabolism of all adipose tissues

Zhang, X.·Majumdar, A.·Kim, C.·Kleiboeker, B.·Magee, K. L.·Learman, B. S.·Thomas, S. A.·Lodhi, I. J.·MacDougald, O. A.·Scheller, E. L.

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Abstract

Several adipose depots, including constitutive bone marrow adipose tissue (cBMAT), resist conventional lipolytic cues, making them metabolically non-responsive. However, under starvation, wasting, or cachexia, the body can eventually catabolize these stable adipocytes through unknown mechanisms. To study this, we developed a mouse model of brain-evoked depletion of all fat, including cBMAT, independent of food intake. Genetic, surgical, and chemical approaches demonstrated that depletion of stable fat required adipose triglyceride lipase-dependent lipolysis but was independent of local nerves, the sympathetic nervous system, and catecholamines. Instead, concurrent hypoglycemia and hypoinsulinemia activated a potent catabolic state by suppressing lipid storage and increasing catecholamine-independent lipolysis via downregulation of cell-autonomous lipolytic inhibitors Acvr1c, G0s2, and Npr3. This was also sufficient to delipidate classical adipose depots. Overall, this work defines unique adaptations of stable adipocytes to resist lipolysis in healthy states while isolating a potent in vivo neurosystemic pathway by which the body can rapidly catabolize all adipose tissues.

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Zhang, X., Majumdar, A., Kim, C., Kleiboeker, B., Magee, K. L., Learman, B. S., Thomas, S. A., Lodhi, I. J., MacDougald, O. A., Scheller, E. L.. 2024-07-31. Central activation of catecholamine-independent lipolysis drives the end-stage catabolism of all adipose tissues. https://doi.org/10.1101/2024.07.30.605812

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