Leptin stimulates autophagy/lysosome-related degradation of long-lived proteins in adipocytes

Abstract

Obesity, a condition most commonly associated with hyper-leptinemia, is also characterized by increased expression of autophagy genes and likely autophagic activity in human adipose tissue (AT). Indeed, circulating leptin levels were previously shown to positively associate with the expression levels of autophagy genes such as Autophagy related gene-5 (ATG5). Here we hypothesized that leptin acts in an autocrine-paracrine manner to increase autophagy in two major AT cell populations, adipocytes and macrophages. We followed the dynamics of autophagosomes following acute leptin administration with or without a leptin receptor antagonist (SMLA) using high-throughput live-cell imaging in murine epididymal adipocyte and macrophage (RAW264.7) cell-lines. In macrophages leptin exerted only a mild effect on autophagy dynamics, tending to attenuate autophagosomes growth rate. In contrast, leptin-treated adipocytes exhibited a moderate, ~20% increase in the rate of autophagosome growth, an effect that was blocked by SMLA. This finding corresponded to mild increases in mRNA and protein expression of key autophagy genes. Interestingly, a long-lived proteins degradation assay uncovered a robust, >2-fold leptin-mediated stimulation of the autophagy/lysosome-related (bafilomycin-inhibited) activity, which was entirely blocked by SMLA. Collectively, leptin regulates autophagy in a cell-type specific manner. In adipocytes, autophagosome dynamics is moderately enhanced, but even more pronounced stimulation is seen in autophagy-related long-lived protein degradation. These findings suggest a causal link between obesity-associated hyperleptinemia and elevated adipocyte and AT autophagy-related processes.

Primary cilia mediate early life programming of adiposity through lysosomal regulation in the developing mouse hypothalamus

“…As for the mechanism behind this phenomenon, our study shows that leptin lowers the lysosomal pH by increasing the proton-pump v-ATPase activity and promotes lysosomal degradation of autophagolysosome in a primary cilia-dependent manner. In line with our findings, leptin activates autophagy in non-neuronal cells and cancer cells 50 , 51 and stimulates the autophagy/lysosome-mediated degradation of long-lived proteins in adipocytes 50 . Early postnatal leptin replacement completely reversed the short cilia phenotype, lysosomal dysfunction, and disruption of POMC neural circuits in the hypothalamus of ob/ob mice.…”

STAT3 phosphorylation in central leptin resistance

“…In contrast, mice with specific deletion of Atg7 in AgRP neurons showed reduced food intake and body fat, as well as a long term effect on energy homeostasis, suggesting improvement in leptin sensitivity [ 117 ]. Notably, a recent study indicated that leptin may contribute to the dysregulated/activated adipocyte autophagy and to its dysfunction in obesity [ 118 ].…”

Communication Between Autophagy and Insulin Action: At the Crux of Insulin Action-Insulin Resistance?

“…This would suggest that there is a reduction in adipocyte-mediated macrophage recruitment in conditions of deficient autophagy. Illustrating a reciprocal cellular crosstalk between cytokines and autophagy, the adipokine leptin moderately enhanced autophagosome dynamics in cultured adipocytes (Goldstein et al, 2019). This finding is of particular interest, as leptin is considered and insulin sensitizing adipokine (Amitani et al, 2013) and therefore future work should examine whether leptin mediated changes in autophagy contribute to its whole-body insulin sensitizing actions.…”