Obesity can lead to lipid accumulation in non-adipose tissues leading to health complications including insulin resistance, T2D and NAFLD. These complications are caused in part by peripheral lipid deposition that occurs in lieu of adipose tissue becoming saturated and unable to store excess lipid. Thus, by redirecting fat from non-adipose tissues back into adipose tissue, complications associated with obesity may be alleviated. Recent studies have shown that activating adipogenesis, or enhancing healthy WAT expansion, can reduce obesity induced complications and results in a metabolically healthy phenotype.
Mitochondria are well known organelles that generate energy in the form of ATP but also play a role in whole body energy homeostasis and cell division. Mitochondrial dynamics is the process of fusion, fission, mitophagy, and biogenesis, which has been shown to be important for maintaining mitochondrial health and recently implicated in healthy WAT expansion. Here, we demonstrate that expression of the E3 ligase March5 is reduced in ob/ob mice, is negatively correlated with fat mass in a panel of genetic diverse mouse strains (HMDP), and reduced with visceral adiposity in men. We also demonstrate in the HMDP, in cells and in ChIP-Seq data, that March5 is a bone fide PPARγ target gene in adipocytes. March5 has been shown to ubiquinate and thus act as an upstream regulator of the mitochondrial dynamics proteins mitofusin2 (Mfn2), and Dynamin-1-like protein. Accordingly, we demonstrate that March5 knockdown using shRNA in 3T3-L1 differentiated cells increases Mfn2 protein levels, suggesting a reduction in fission and an increase in fusion, which leads to increased mitochondrial respiration as measured by the Seahorse flux analyser.
Collectively, these data suggest that altering March5 expression could be a potential mechanism to increase mitochondrial activity in WAT, which might subsequently allow for increased adipogenesis and greater capacity to store lipid in the setting of obesity.