Characterization and functional assessment of a novel population of Wnt/beta-catenin driven adopocytes.

Project Summary/Abstract Obesity, caused by the increase in size and the amount of fat cells (adipocytes), is becoming a worldwide pandemic, producing a huge public health problem due to the associated risk with developing other diseases. In mammals, the adipose/fat tissue is composed of classic white adipose tissue (WAT) and brown adipose tissue

(BAT), with WAT serving for energy storage and BAT for energy dissipation to produce heat. A third type of adipocytes exists, known as beige adipocytes that are transiently generated in WA T depots in response to environmental stimulations. BAT/beige fats are the established thermogenic tissues that play an essential role in

human energy homeostasis and therefore in protection of obesity-related metabolic disorders. While white adipocytes and brown adipocytes differentiate from precursors with distinct origins, it is the consensus that Wnt/β- catenin signaling imposes negative effects on adipogenesis by inhibiting adipogenic differentiation. Although

some studies have implicated the requirement of Wnt signaling and its components in adipogenesis and proper functions of adipose tissues, direct evidence is lacking, leaving a critical knowledge gap as if Wnt signaling plays a direct and crucial role in adipogenesis. In our preliminary studies, we have surprisingly discovered the existence

of a population of Wnt/β-catenin signaling driven adipocytes, named as Wnt+ adipocytes, in various fat depots including bone marrow in mice from embryonic stage to adulthood. Using Wnt+ adipocytes induced from SVF cells in vitro, we further showed the requirement of the ligand- and receptor-independent Wnt/β-catenin signaling,

which appeared to depend on active Akt/mTOR signaling, in adipocyte maturation. Our scRNA-seq and scATAC- seq analyses have distinguished this novel population of adipocytes from the classic adipocytes at molecular and genomic levels. We also found that these adipocytes exhibit potentially high metabolic and thermogenic

properties, being able to convert/transdifferentiate into beige adipocytes in response to cold stress, and being implicated in systemic energy homeostasis. Based on these preliminary results, we hypothesize that a novel population of Wnt/β-catenin signaling driven adipocytes is widely present in various fat depots and plays crucial

function in regulating whole body metabolic homeostasis. In this proposal, two specific aims are proposed to test this hypothesis rigorously: 1) to characterize endogenous Wnt+ adipocytes and to investigate the functional mechanism of the intracellular Wnt/β-catenin signaling in adipogenesis; 2) To determine the in vivo function of

Wnt+ adipocytes in regulating whole-body metabolism in fetal/neonatal and adult stage. Overall, we will define the identity at cellular, molecular, and genomic levels of a novel population of Wnt/β-catenin driven adipocytes that exist in various fat depots and exhibit potentially high metabolic and thermogenic properties. We will also

assess overall impacts of this population of adipocytes on adipose tissue function, whole-body metabolic homeostasis, and protection of obesity. The proposal will also address the functional mechanism and identify direct targets of the Akt/mTOR signaling dependent intracellular Wnt/β-catenin signaling during adipogenesis in

this population of adipocytes. Results obtained from proposed studies will reveal the origin, recruitment, activation, molecular regulation, and function of a unique population of thermogenic adipocytes, providing novel knowledge to the biology of adipocytes as well as solid foundation for future application of this population of

adipocytes in the therapy of obesity.