Nat8l: a new player in brown adipose tissue development and energy metabolism

Genetic factors, a sedentary lifestyle, and a plethora of food have led to obesity pandemic that is, mainly due to its related disorders, an increasing prevalent health and economic problem. Since weight loss by reducing energy intake is often temporarily and surgical therapy is associated with high costs and undesirable side effects, new therapeutic strategies are required. Mammals possess white adipose tissue (WAT) to store energy and brown adipose tissue (BAT) to maintain body temperature by dissipating energy as heat. Thus, BAT might be a valuable tissue to burn surplus calories and fat depots and recruitment/activation of brown adipocytes could help fighting obesity. Nat8l catalyses the formation of N-acetylaspartate (NAA) from L-aspartate and acetyl-CoA and is involved in lipid formation in brain. However, its function in other tissues remained elusive until we recently showed that Nat8l is highly expressed in ATs and adipogenic cell lines, and localized in mitochondria of brown adipocytes. Overexpression of Nat8l in immortalized brown adipogenic cells increases glucose incorporation into neutral lipids and lipolysis (indicating an accelerated lipid turnover), mitochondrial mass, number, and oxygen consumption rate (OCR). Concordantly, expression levels of brown marker genes, particularly UCP1 are markedly elevated in these cells. The increase in UCP1 protein and OCR are PPARa-dependent. In addition, our preliminary data show that NAA, the product of Nat8ls enzymatic activity, decreases triacylglyceride accumulation when added to differentiating adipocytes and reduces weight gain of mice on high fat diet when provided with the water. The exact mechanism(s) by which Nat8l promotes this increased brown phenotype are matter of further investigation described in this application. To unravel the physiological function of Nat8l, we will perform gain and loss of function studies of Nat8l in primary adipocytes to investigate whether and how Nat8l can influence browning. Further, we will investigate WAT- and BAT-specific Nat8l-tg mice anticipating to provide new insights into the process of adipogenesis and into the development of metabolic disorders which are associated with an imbalance of the amount and the type (white, beige, brown) of AT. Additionally, these mice might also be partly resistant to diet-induced obesity and to obesity-accompanied insulin intolerance. Additionally, we will perform further controlled studies on the impact of NAA supplementation to the diets of mice. As our data indicate that Nat8l overexpression boosts the brown adipogenic program and subsequently, energy expenditure in iBACs, we anticipate that the results of our studies will provide clues for developing novel tools to fight the increasing health and economic burden of obesity and its related metabolic disorders.