LAM dynamics during weight cycling

Obesity, the excess of adipose tissue (AT), is a global health problem with, as it is strongly associated with many co-morbidities such as diabetes, cardiovascular disease as well as systemic and tissue inflammation. Although weight loss interventions have been markedly improved over the past years, substantial weight re-gain after cessation of life-style changes or pharmacotherapy, and even in some bariatric surgery patients, currently poses a big clinical challenge. Understanding the mechanisms of weight re-gain after weight loss is therefore crucial to develop long-term weight management strategies. While weight loss reverses many metabolic derangements of obesity, inflammation of AT persists long into weight loss periods and might be a contributor to rapid weight regain (the yo-yo effect). The major fraction of immune cells within AT are macrophages and we recently showed that a specific subset called lipid-associated macrophages (LAMs) increase in number upon weight loss through intermittent fasting in an obese mouse model. Interestingly, these LAMs have been shown to be prevalent in many metabolic diseased tissues such as in liver and atherosclerotic plaques. On the molecular level, we could show that the increase in AT LAMs is dependent on the activity of the transcription factor p53 in adipocytes. In a cohort of diabetic patients, we could further show that a metabolically relevant p53 polymorphism correlates with the long-term efficacy of a fasting-mimicking diet. In this project, we investigate the dynamic changes of LAM recruitment and development in AT during weight cycling and which p53-regulated molecules mediated these processes. For this we employ state-of-the-art sequencing-based methods that can delineate the cellular composition of AT and investigate mouse models and obese patients during weight loss and weight regain. In mice (using an inducible, adipocyte-specific p53 knockout model) and in cell co-culture experiments we will define the gene/protein profile regulated by p53 in adipocytes and determine the key players of LAM recruitment and development. Through collaboration with the Leipzig Obesity BioBank (LOBB) we, will receive AT samples from obese patients undergoing bariatric surgery and will correlate LAM abundance with potential for weight regain and p53 mutations. Furthermore, with an antibody-based single cell method we currently develop for AT (Zman-seq), we will unravel dynamic changes of LAM abundance during fasting and re-feeding cycles. In sum, this work will uncover mechanisms and dynamics of LAM recruitment to AT in weight cycling and how LAM abundance impacts weight loss efficiency and retention. Thus, this project is designed pave the way for novel therapies modulating LAM abundance to achieve long-term weight management and for changing the trajectory of the global epidemic of obesity.