The role of macrophages in weight loss-induced metabolic health and adipose tissue inflammation resolution

PROJECT SUMMARY Inflammation is at the center of many obesity complications, such as diabetes and heart disease. The most recommended treatment for obesity is weight loss, which results in decrease of the related inflammation and complications, making weight loss a very attractive therapeutic strategy. However, the mechanisms by which weight loss benefits obesity-related inflammation is unknown, representing a major knowledge gap. We recently revealed that in mice, weight loss induced by caloric restriction (CR) promotes resolution of inflammation in atherosclerotic cardiovascular disease. Mechanistically, this is attributed to a new macrophage subtype (termed CR-macrophages) that have increased capability to efferocytose (the phagocytic process by which macrophages clear apoptotic cells) and accumulate mostly in visceral adipose tissue, but also in atherosclerotic plaques. CR-macrophages are distinguishable by their high expression of CD16a, which our data demonstrate is required for their higher efferocytic activity. Therefore, our central hypothesis is that weight loss induces a pro-resolving phenotype in macrophages that subsequently resolves inflammation and improves metabolic health. In the first aim we will determine visceral and subcutaneous adipose tissue macrophage phenotype, function and transcriptome across species (mouse and human) and time of weight loss. Aim 2 will use several strategies, including cell therapy and nanomedicine, to test whether CR-macrophages can be used to treat metabolic dysfunction in obese mice. Our results will unearth novel immunological pathways underlying weight loss-induced inflammation resolution that will suggest new strategies for the treatment of obesity complications, establishing a new paradigm in obesity management.