The Origin, Dynamics, and Function of Postnatal Beige Adipocytes

Obesity is expected to affect nearly 50% of adults in the United States by 2030 and is a major risk factor for type 2 diabetes, cardiovascular disease, and many types of cancer. Obesity is characterized by an accumulation of white adipose tissue, which can become dysfunctional in the setting of chronic overnutrition, contributing to the sequelae of excess adiposity. Mice and humans also possess thermogenic brown and beige adipocytes, which convert chemical energy into heat and have been associated with potent anti-diabetic and cardioprotective benefits. The metabolic effects of thermogenic adipocytes extend beyond energy dissipation, with these cells also serving as a sink for toxic metabolites, suppressing inflammation and fibrosis, and secreting paracrine and endocrine mediators. Murine beige fat shares significant similarities with brown fat described in adult humans, with both displaying highly cold-inducible activity and a common molecular program. Thus, beige adipocytes in mice are an attractive model system for dissecting the mechanisms underlying the broad benefits of thermogenic fat. However, fundamental questions regarding the origin, dynamics, and function of these cells remain unanswered. In studying crosstalk between the sympathetic nervous system and beige fat, we found that beige adipocytes form at postnatal day 10, independent of sympathetic innervation and cold stimulation. Starting at postnatal day 28, these cells suppress their thermogenic properties and become dormant, but can be reactivated upon cold exposure in adults. We also discovered that dormant beige adipocytes possess heretofore undescribed functional properties, protecting against tissue inflammation in obesity. Based on these findings, we propose that postnatal beige adipocytes are developmentally hard-wired cells that become thermogenically dormant in early adulthood and are reactivated to provide the major source of inducible beige adipocytes in adults, while also serving as a central regulator of adipose tissue homeostasis. We will address this hypothesis through two specific aims: (1) We will elucidate the origin and dynamics of beige adipocytes, using lineage tracing models coupled with in vitro characterization and in vivo transplantation experiments to define the committed postnatal beige fat cell progenitor and the tissue niche factors triggering these cells’ development. (2) We will dissect the function of postnatal beige adipocytes in normal physiology and obesity using mouse models with temporally regulated ablation of active or dormant postnatal beige adipocytes, along with single nuclear transcriptomic datasets to define the molecular properties of these cells. We will also employ a new approach to monitor and characterize interactions between active and dormant postnatal beige adipocytes and other adipose tissue cell types. This proposal will provide a new conceptual understanding of beige adipocytes and the first insights into the role of dormant beige adipocytes in adipose tissue and whole-body homeostasis. In addressing key knowledge gaps in the field, findings from these studies could serve as the framework for targeting postnatal beige adipocytes for the treatment of obesity, type 2 diabetes, and associated diseases.