A catecholamine-independent pathway controlling adaptive adipocyte lipolysis

Several adipose depots, including constitutive bone marrow adipose tissue, resist conventional lipolytic cues. However, under starvation, wasting or cachexia, the body eventually catabolizes stable adipocytes through unknown mechanisms. Here we developed a mouse model of brain-evoked depletion of all fat, including stable constitutive bone marrow adipose tissue, independent of food intake, to study this phenomenon. Genetic, surgical and chemical approaches demonstrated that catabolism of stable adipocytes required adipose triglyceride lipase-dependent lipolysis but was independent of local nerves, the sympathetic nervous system and catecholamines. Instead, concurrent hypoglycaemia and hypoinsulinaemia activated a potent catabolic state by suppressing lipid storage and increasing catecholamine-independent lipolysis via downregulation of cell-autonomous lipolytic inhibitors including G0s2. This was also sufficient to delipidate classical adipose depots and was recapitulated in tumour-associated cachexic mice. Overall, this defines unique adaptations of stable adipocytes to resist lipolysis in healthy states while isolating a potent catecholamine-independent neurosystemic pathway by which the body can rapidly catabolize all adipose tissues. Overall design: To identify candidate mechanisms of stable fat lipolysis, we performed RNAseq on caudal vertebrae (CV, stable cBMAT-enriched) from 4- to 5-month-old male and female BMAd-Pnpla2+/+ (WT) mice treated for 9-days with either ICV PBS or 100 ng/hr ICV leptin. Inguinal white adipose tissue (iWAT, responsive fat control) and lumbar vertebrae (LV, no fat control) from the same WT females were included to identify cBMAT-enriched genes. CV samples from age- and sex-matched BMAd-Pnpla2-/- (cKO) mice were also included to isolate the effect of ATGL-mediated fat depletion. To determine which of the differentially expressed lipolysis genes by ICV leptin treatment were reversed with insulin supplementation in vivo, we also included CV samples from age-matched WT males treated with either ICV PBS or 100 ng/hr leptin along with subcutaneous insulin for 9-days.