Central Activation of Catecholamine-independent Lipolysis Drives the End-stage Catabolism of All Adipose Tissues

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 . 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 neurosystemic pathway by which the body can rapidly catabolize all adipose tissues.