Mild mitochondrial uncoupling induces HSL/ATGL‐independent lipolysis relying on a form of autophagy in 3T3‐L1 adipocytes

Abstract

Obesity is characterized by an excessive triacylglycerol accumulation in white adipocytes. Various mechanisms allowing the tight regulation of triacylglycerol storage and mobilization by lipid droplet-associated proteins as well as lipolytic enzymes have been identified. Increasing energy expenditure by inducing a mild uncoupling of mitochondria in adipocytes might represent a putative interesting anti-obesity strategy as it reduces the adipose tissue triacylglycerol content (limiting alterations caused by cell hypertrophy) by stimulating lipolysis through yet unknown mechanisms, limiting the adverse effects of adipocyte hypertrophy. Herein, the molecular mechanisms involved in lipolysis induced by a mild uncoupling of mitochondria in white 3T3-L1 adipocytes were characterized. Mitochondrial uncoupling-induced lipolysis was found to be independent from canonical pathways that involve lipolytic enzymes such as HSL and ATGL. Finally, enhanced lipolysis in response to mitochondrial uncoupling relies on a form of autophagy as lipid droplets are captured by endolysosomal vesicles. This new mechanism of triacylglycerol breakdown in adipocytes exposed to mild uncoupling provides new insights on the biology of adipocytes dealing with mitochondria forced to dissipate energy.

<p>Protein Arginine Methyltransferase 4 Regulates Adipose Tissue Lipolysis in Type 1 Diabetic Mice</p>

“…The previous study had also demonstrated that HSL/ATGL-independent lipolysis relies on the form of autophagy. 44 On the bases of these studies, it is suggested that PRMT4 may promote lipid droplet breakdown and the release of FFAs by activating autophagy. However, these possibilities require further research for their confirmation.…”

FR58P1a; a new uncoupler of OXPHOS that inhibits migration in triple-negative breast cancer cells via Sirt1/AMPK/β1-integrin pathway

“…Although the induction of OXPHOS uncoupling has been recognized as a possible therapeutic strategy for obesity 46,56 , neurodegeneration 57,58 , aging 59 , renal ischemia/reperfusion injury 60 , heart injury 61 and cancer 62,63 , well-known protonophore OXPHOS uncouplers exhibit a narrow therapeutic window 64 and off-target effects at other membranes, producing toxicity 31–33 and limiting their potential clinical uses. In contrast to FCCP, FR58P1a does not depolarize the plasma membrane and induces a mild OXPHOS uncoupling, inducing mitochondrial NADH oxidation with sustained mitochondrial depolarization and a transient ATP decrease that activates AMPK in a Sirt1-dependent fashion.…”

Thyroid hormone (T3) stimulates brown adipose tissue activation via mitochondrial biogenesis and MTOR-mediated mitophagy

“…Although MTOR inhibition may be the main contributor to autophagy in BAT from hyperthyroid mice, it is possible that other upstream signalling pathways also contributed to MTOR inhibition. In particular, it is possible that UCP1-independent mitochondrial uncoupling also could have contributed to MTOR inhibition and/or autophagy, since mild mitochondrial uncoupling by FCCP induced autophagy in adipocytes [48]. In support for adipocytes treated with 10 nM T 3 for 0, 3, 6 and 24 h. Result represents mean ± SD (n = 6) where n represents number of independent experiments.…”