- Background/objectives: Adipose tissue (AT) autophagy gene expression is elevated in human obesity, correlating with increased metabolic risk, but mechanistic links between the two remain unclear. Thus, the objective of this study was to assess whether elevated autophagy may could cause AT endocrine dysfunction, emphasizing the putative role of adiponectin in fat-liver endocrine communication. Subjects/methods: We utilized a large (N=186) human adipose tissue bio-bank to assess clinical associations between human visceral AT autophagy genes, adiponectin and leptin, by multivariate models. A broader view of adipo-cytokines association with elevated autophagy was assessed using adipo-cytokine array. Finally, to establish causality, ex-vivo studies utilizing a murine adipose tissue-hepatocyte cell line co-culture system was used. Results: Circulating HMw-adiponectin and leptin levels were associated with human omental-AT expression of ATG mRNA, associations that remained significant (beta=-0.197, P=0.011; beta=0.267, P<0.001, respectively) in a multivariate model adjusted for age, sex, BMI, and IL-6. A similar association was observed with omental-AT LC3A mRNA levels. Bafilomycin-A1 pre-treatment of AT explants from high fat fed (HFF) mice had no effect on the secretion of some adipose tissue-derived endocrine factors, but partially or fully reversed obesity-related changes in secretion of a sub-set of adipo-cytokines by >35%, including the obesity-associate up-regulation of IL-6, VEGF, TNFα and certain IGFBP's, and down-regulated secretion of IL-10 and adiponectin. Similarly, decreased adiponectin and increased leptin secretion from cultured adipocytes stimulated with TNFα+IL-1β was partially reversed by siRNA-mediated knockdown of ATG7. AT explants from HFF mice co-cultured with Hepa-1c hepatoma cells impaired insulin-induced Akt and GSK3 phosphorylation. This effect was significantly reversed by pre-treating explants with bafilomycin-A1, but not if adiponectin was immunodepleted from the conditioned media. Conclusions: Reduced secretion of adiponectin may link obesity-associated elevated adipose tissue autophagy/lysosomal activity with adipose endocrine dysfunction.International Journal of Obesity accepted article preview online, 20 January 2016. doi:10.1038/ijo.2016.5.