In the last decades brown adipose tissue (BAT) rose to attention as therapeutic target to counteract obesity and its related diseases. In both rodents and humans, activated BAT protects from diet-induced obesity and the associated deterioration of glucose metabolism via enhancing energy expenditure. Interestingly, BAT-related features can also be promoted in skeletal muscle (SM) progenitor cells due to the common cell lineage that these tissue share. Differentiation and function of BAT has been shown to be under control of noncoding RNA networks. In particular, various microRNAs (miRNAs) are able to drive both brown fat homeostasis and BAT/SM cell fate regulation.
Here we show a novel miR-328–Bace1 axis involved in metabolic homeostasis through a mechanism that promotes brown adipocyte differentiation and activation. We found miR-328 expression to correlate to BAT activity and to promote brown adipogenesis to the detriment of myogenesis in vitro. This process is dependent on the inhibition by the miRNA of the β-secretase BACE1, a protease known for its detrimental role in Alzheimer’s disease (AD). We could show this protein to act antagonistically to miR-328. Indeed, both knock-down and knock-out of Bace1 resulted in a pro-adipogenic phenotype in both brown adipogenic and even myogenic cell lines. Moreover, conditioned medium from Bace1 knock-out myoblasts revealed paracrine effects by stimulating the adipogenic potential of wild-type myoblasts. Complementary proteomic analyses determined potential substrates of BACE1 involved in this process. In particular, AOC3, a pro-inflammatory, type 2 diabetes-related transmembrane protein, was identified as a putative BACE1 target, with potential paracrine and endocrine functions due to its soluble form sAOC3. This mechanism could be responsible for the beneficial metabolic effects of BACE1 inhibition observed in obese mice. In fact, we showed that diminished BACE1 activity, known to reduce the pathophysiology of AD, enhanced whole-body homeostasis, leading to decreased body weight gain and ameliorated glucose metabolism. BACE1 inhibition was furthermore associated with increased BAT marker expression in the adipose tissue and a global decrease in SM-associated differentiation pathways.
Taken together, BACE1 and its substrates, potentially including AOC3, are promising therapeutic targets against obesity, AD and their sequelae. This warrants the broadening of the scientific scope for BACE1 investigation beyond AD and towards BAT and metabolism regulation
