Autophagy inhibition blunts PDGFRA adipose progenitors’ cell-autonomous fibrogenic response to high-fat diet

Abstract

Adipose tissue (AT) fibrosis in obesity compromises adipocyte functions and responses to intervention induced-weight loss. It is driven by AT progenitors with dual fibro/adipogenic potential, but pro-fibrogenic pathways activated in obesity remain to be deciphered. To investigate the role of macroautophagy/autophagy in AT fibrogenesis, we used Pdgfra-Cre Ert2 transgenic mice to create conditional deletion of Atg7 alleles in AT progenitor cells (Atg7 cKO) and examined sex-dependent, depotspecific AT remodeling in high-fat diet (HFD)-fed mice. Atg7 cKO mice had markedly decreased extracellular matrix (ECM) gene expression in visceral, subcutaneous and epicardial adipose depots compared to Atg7 lox/lox littermates. ECM gene program regulation by autophagy inhibition occurred independently of changes in the mass of fat tissues or adipocyte numbers of specific depots, and could be mimicked in cultured preadipocytes treated with pharmacological or siRNA-mediated autophagy disruptors. We found that autophagy inhibition promotes global cell-autonomous remodeling of the paracrine TGF-BMP family landscape, whereas ECM gene modulation was independent of the autophagic regulation of GTF2IRD1. The progenitor-specific mouse model of Atg7 inhibition confirms requirement of autophagy for white/beige adipocyte turnover, and combined to in vitro experiments, reveal progenitor autophagy dependence for AT fibrogenic response to HFD, through paracrine remodeling of TGF-BMP factors balance.

Lysosomal Acid Lipase Drives Adipocyte Cholesterol Homeostasis and Modulates Lipid Storage in Obesity, Independent of Autophagy

“…Body composition was analyzed by nuclear magnetic resonance (Bruker Mouse Minispec, LF90). Blood and fat pads (gonadal (OvAT-EpiAT), subcutaneous (ScAT), brown adipose tissue (BAT)) were frozen in liquid nitrogen or fixed with Formalin (Sigma Aldrich, HT501128), or incubated with collagenase as described (11). Oral glucose tolerance test (OGTT) started by gavage with 2.0 g/kg glucose in mice fasted for 6h.…”

New Insights Into the Interplay Among Autophagy, the NLRP3 Inflammasome and Inflammation in Adipose Tissue

“…If adipogenesis was viewed as a mechanism for the healthy expansion of WAT, Atg- knockout mice with favorable metabolic profiles appear contradictory. These findings indicated that Atg5 or Atg7 deletion in mice enhanced oxidation during metabolic activity and reduced browning and fibrosis in WAT ( 65 , 66 , 71 ). The capacity of increased heat production and oxygen consumption may help to explain animals remaining in an insulin-sensitive state, even when WAT adipogenesis is decreased.…”

The multifaceted progenitor fates in healthy or unhealthy adipose tissue during obesity

“…The transcriptional landscape of TGF-β/BMP family can be regulated by the progenitor in a cell autonomous dependent manner [110], as shown in mice harboring autophagy deficient progenitors. In these mice, the emergence of beige adipocyte features in the white fat depot was coincident with lower fibrosis expression (110).…”

“…Most interestingly, adding BMP in a profibrotic environmental promotes the resolution of fibrosis driving myofibroblast dedifferentiation to regenerate the adipocyte pool [109]. The transcriptional landscape of TGF-β/BMP family can be regulated by the progenitor in a cell autonomous dependent manner [110], as shown in mice harboring autophagy deficient progenitors. In these mice, the emergence of beige adipocyte features in the white fat depot was coincident with lower fibrosis expression (110).…”